The relationship of negative schizophrenia to parkinsonism.

0 1990 Gordon and Breach Science Publishers S.A.

Intern. J . Neuroscience, 1990, Vol. 55, pp. 1-59 Reprints available directly from the publisher Photocopying permitted by license only

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THE RELATIONSHIP OF NEGATIVE SCHIZOPHRENIA TO PARKINSONISM REUVEN SANDYK and STANLEY R. KAY*

Int J Neurosci Downloaded from informahealthcare.com by University of British Columbia on 10/29/14 For personal use only.

Department of Psychiatry, Albert Einstein College of MedicinelMonte$ore Medical Center, Bronx, NY, 10461, U.S.A. (Received July 16, 1990)

The positive-negative distinction of schizophrenia has emerged as a valid means of clarifying its heterogeneity. Despite evidence that the two symptom classes may reflect different dimensions of the disease, there is presently no integrated model for understanding of the pathophysiology of these symptoms and their co-occurrence in schizophrenia. We propose that negative phenomena of schizophrenia may be a variant of Parkinsonism. This view is supported by the overlap with Parkinsonism in terms of clinical features, neurochemistry, pharmacology, as well as neuroradiological and neuropathological aspects. As such, negative symptoms may be a manifestation of disease of the basal ganglia and constitute the core pathology in schizophrenia. Positive symptoms, conversely, may reflect an “accessory” process related to a compensatory increase in striatal and limbic dopamine activity following an injury to the dopaminergic system. In the present communication we present a series of studies that support the association of negative schizophrenia and Parkinsonism. Based on this evidence, we suggest that schizophrenic patients with prominent negative symptoms might be managed like patients with Parkinson’s disease, namely, with dopaminergic drugs and MAO-B inhibitors. Finally, the association of negative schizophrenia with Parkinsonism raises the possibility that adrenal medullary tissue transplantation, which may benefit a selected group of Parkinsonian patients, may be a future promising therapy for refractory negative schizophrenia. Keywords: Negative Schizophrenia, Parkinsonism, Basal Ganglia, Dopamine

The Positive-Negative Model of Schizophrenia

Since Bleuler’s (1 91 111950) description of the “schizophrenias” early in the century, this disorder has been recognized to be heterogenous in terms of symptoms, prognosis, and probably also etiology. With the advent of neuroleptics three decades ago, the diversity in drug response also has become plainly evident. Clearly, not all schizophrenic patients and not all facets of psychopathology are effectively treated by neuroleptics. But this very diversity that confounds treatment and research may, once clarified, provide answers to the nature of this complex disorder. In this pursuit, Strauss et al. (1974) first presented, on the basis of factor analytic study, the division of schizophrenic symptoms into positive type (abnormal production) and negative type (deficit or loss of function). Much earlier, Hughlings Jackson (1 887), in describing neurological conditions, had proposed that negative symptoms result directly from damage to brain areas that are responsible for production of human behavior. He regarded positive symptoms as a release phenomenon exercised by the damaged, brain. Although B’’ ler (191 111950) never used the term “negative symptoms,” he perCorrespondeno Psychiatric Cente *Deceased This study was Institute, NY. T b Movement Disorc

Reuven Sandyk, M. D., MSc. at the Schizophrenia Research Program, Bronx 500 Waters Place, Bronx, NY 10461, U.S.A.

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lertaken in part in the Department of Neuropsychiatry, New York State Psychiatric ithors gratefully acknowledge Dr. S . Mukherjee for providing part of the CT Data, Ratings and Clinical Data. 1


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R. SANDYK AND S.R. KAY

ceived them as the fundamental deficiency of schizophrenia, while positive symptoms such as delusions and hallucinations played a variable, “accessor” role in the illness. Crow (1980) presented the hypothesis that these symptom classes reflect two etiologically and prognostically distinct schizophrenic subtypes, in which negative symptoms are associated with gross structural abnormality (i.e., cerebral atrophy) and positive symptoms with biochemical dysregulation involving dopaminergic overactivity. In this much-cited model, the two syndromes are independent and may occur separately or simultaneously. Andreasen ( 1 985) has since popularized Crow’s model as a typological one, referring to positive and negative “subtypes,” but her own data indicated that a majority of schizophrenic patients have mixed syndromes. Subsequent research by our group has found that these phenomena represent orthogonal components (Kay & Sevy, in press), coexist in the majority of patients (Kay et al., 1987), and are uncorrelated in the drug-free state (Kay & Singh, 1989). For the purposes of the present discussion, therefore, the term “negative schizophrenia” is applied as a dimensional rather than typological construct, i.e., as a condition characterized by a preponderance of negative symptoms. In a direct exchange with Crow (1980), Mackay (1980) presented a divergent hypothesis that has never attained comparable recognition. He proposed that negative symptoms may reflect chronic dopaminergic underactivity, while positive symptoms emerge when there is a burst of dopaminergic overactivity. According to MacKay (1 980), the negative symptoms in schizophrenia are chronically present and form the background on which positive symptoms are periodically acutely superimposed. Neither Crow nor MacKay, however, could explain why these two types of symptoms occur together in schizophrenia. In terms of symptom presentation, flat affect, reduced quantity of speech, emotional withdrawal, motor reduction, and cognitive deficit have been considered the key elements of the negative syndrome by most investigators. Patients with this clinical profile are more likely to have been born in winter (Opler et al., 1984), to have had poor premorbid cognitive and social adjustment (Opler et al., 1984; Pogue-Geile & Harrow, 1984; 1985), to respond inadequately to neuroleptics (Breier et al., 1987; Meltzer et a]., 1986; Johnstone et al., 1987), to have family members with history of schizophrenia (Kay et al., 1986), and to show morphological brain abnormalities (Andreasen et al., 1982; Weinberger et al., 1980). In contrast, positive symptoms are characterized phenomenologically by delusions and hallucinations and also by a more favorable response to neuroleptics and absence of gross structural brain abnormalities on CT scan (Andreasen et al., 1982).

Similarity of Negutive Syndrome and Parkinsonism The characteristic symptoms of negative schizophrenia, such as blunted affect, poverty of speech, emotional withdrawal, motor retardation, and cognitive deficits (Crow, 1980; Crow, 1980a; Andreasen, 1985), are also hallmarks of Parkinson’s disease (Lidsky et al., 1979; Pirozzolo et al., 1982; Alpert & Rush, 1983; Rogers et al., 1986; Growdon & Corkin, 1986). In particular, akinesia is one of the features of Parkinsonism most likely to be confounded with negative schizophrenia (Hoehn et al., 1976; Sommers, 1985; Sandyk & Kay, see below). Hoehn et al. (1976) found in 37 untreated Parkinsonian patients a high correlation between MMPI-8 scores (which are indicative of schizophrenic-like looseness of thinking) and akinesia. This correlation was the highest between any psychological and any neurological or biochemical variables in these patients. In addition, we found a significant association between features of negative syndrome in schizophrenia and positive glabellar tap reflex, which reflects decreased striatal dopaminergic activity (see below).


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Narrowly defined, akinesia represents a motor anomaly characterized by slowness of movement, poor arm swing, and rigid posture (Chien et al., 1974). More broadly viewed, akinesia overlaps with negative symptoms along dimensions other than pure motor behavior (Rifkin, 1981; Rifkin et al., 1975; Van Putten & May, 1978; Van Putten et al., 1980); it includes lack of emotional reactivity, lack of goal-directedness, retarded spontaneous speech, sluggishness, decreased sociability, and decreased physical movements. In addition, the classic “mask-like facies” of Parkinsonism cannot be distinguished from the absence of facial expression in blunted affect that is attributed to the negative syndrome (cf. Sommers, 1985). Thus, negative schizophrenia and Parkinsonism apparently share common clinical features that cannot be easily distinguished from each other. Carpenter et al. (1985) cautioned that, in assessing negative phenomena, one must be careful to avoid confound from Parkinsonian symptoms. Indeed, studies by our group (Kay et al., 1986) have indicated a significant direct correlation between negative syndrome on the Positive and Negative Syndrome Scale (PANSS) and scores on the Extrapyramidal Symptoms Scale, even though the PANSS negative scale excludes motor items (Kay et al., 1987). We propose that this overlap between symptoms of negative schizophrenia and Parkinsonism is not merely coincidence, confound, or rather misjudgment. We suggest the possibility that negative schizophrenia may, in fact, constitute a variant form of Parkinsonism and, therefore, may reflect a primary disorder of the basal ganglia. As we shall discuss, this hypothesis is supported by a network of neurochemical, pharmacological, neuroradiological, and neuropathological data. We, furthermore, contend that positive symptoms, which are generally believed to issue from increased dopaminergic functions, are the result of compensatory mechanisms to overcome the primary dopaminergic deficiency. In addition, we postulate that positive symptoms may reflect compensatory mechanisms of brainstem noradrenergic mechanisms. Our hypothesis suggests that the two prominent symptom clusters in schizophrenia are interrelated and attributable to a single neurostructural impairment, which is also responsible for the Parkinsonian symptoms that frequently emerge with neuroleptic treatment. Table 1 summarizes the range of similarities between negative schizophrenia and Parkinsonism. In the following sections we review the evidence that they constitute a single pathophysiological entitity. We will attempt to show that this hypothesis provides novel implications toward future research and treatment strategies for negative schizophrenia.

The Co-occurrence of Schizophrenia and Parkinsonism The presence of psychotic features in conjunction with Parkinsonism has been cited extensively in the past (Jackson et al., 1923; Jellife, 1927; Fairweather, 1947; Hollister & Glazener, 1961). More than 60 years ago McCowan and Cook (1928) described the mental status in some cases of Parkinsonism as “extremely difficult to distinguish from ordinary cases of paraphrenia.” Psychotic symptoms are particularly notable in postencephalitic Parkinsonism; during the acute illness, some of these patients develop catatonic psychotic states, hallucinations, akinetic rnutism, obsessional behavior, and Korsakoffs-like psychosis (Benedek, 1925). In 1971, Misra and Hay published the case reports of three patients who developed symptoms of acute schizophrenia in the context of an encephalitic process. One patient developed post encephalitic Parkinsonism and a second remained in a chronic schizophrenic state. Crow et al. (1976) observed four cases in which an illness with schizophrenic features developed in conjunction with longstanding Parkinsonism. Based on these observations, they concluded that the “dopaminergic overactivity hypothesis of


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TABLE 1 Comparison of negative schizophrenia and Parkinsonism


Areas of study

Features in common

SYMPTOMS

Decreased motor activity Blunted affect Impoverished speech Social withdrawal Anhedonia Emotional withdrawal Cognitive dysfunction Extrapyramidal symptoms Frontal lobe symptoms

EPIDEMIOLOGY

Male gender

NEUROCHEMISTRY (1) Neurotransmitters

Decreased dopamine functions Increased cholinergic functions Decreased serotonergic functions Decreased norepinephrine functions

(2) Neuroendocrinology

Glucose intolerance Decreased melatonin secretion DST-nonsuppression

(3) Neuropeptides

Decreased CCK Abnormal POMC processing

PHARMACOLOGY

NEURORADIOLOGY CT scan PATHOLOGY

DIFFERENCES

Response to L-dopa Response to amphetamines Response to anticholinergics Response to atypical neuroleptics Lesser response to neuroleptics Cortical atrophy Enlarged lateral ventricles Pineal gland calcification Periventricular. diencephalic gliosis Basal ganglia degeneration Lew body formation Neurobrilldry tangles Distinguishing Features of Parkinsonism Later age of onset Predominance of motor symptoms Relative lack of positive symptoms Premorbid differences Course of illness Relatively intact prernorbid-adjustment (?)

schizophrenia faces the difficulty that Parkinsonism and schizophrenia-like illness can coexist as post-encephalitic sequelae” (p. 232). Friedman et al. (1987) reported a patient with schizophrenia who later, during the course of the illness, developed what appeared to be a form of idiopathic Parkinson-



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ism. More recently, Friedman and Lannon (1989) described five patients with Parkinsonism who, during the course of the disease, suffered a severe psychotic illness that responded to clozapine. Attenuation of psychotic symptoms with clozapine is, in fact, associated with improvement in Parkinsonism (Friedman & Lannon, 1989), underscoring the possibility that both conditions are interrelated. Indeed, Mettler (1955) suggested a basal ganglionic dysfunction in schizophrenia on grounds o f : (a) a high incidence of Parkinsonian symptoms among schizophrenic patients (Mettler, 1955), and (b) a high incidence of “schizoid states” in Parkinson’s disease patients (Mettler & Crandell, 1959). Bowman and Lewis (1980), furthermore, observed a high prevalence of schizophrenic features in diseases of the basal ganglia. Several studies have suggested more specifically that the negative syndrome of schizophrenia is associated with an increased risk of Parkinsonism. Epidemiologically, both negative schizophrenia (Kay et al., 1986; Todd, 1989) and Parkinson’s disease (De Jong, 1966) are preponderantly associated with male sex, which may represent a genetic or constitutional marker of vulnerability. Neuroradiologically, schizophrenic patients with increased lateral ventricular size, which Andreasen et al. (1982) described as a marker of the negative syndrome, have been reported to be at high risk for developing neuroleptic-induced Parkinsonism (Luchins et al., 1983). More recently, Hoffman et al. (1987) found that the severity of drug-induced Parkinsonism covaries significantly with a larger ventricular brain ratio (VBR). In addition, negative symptoms of schizophrenia and a pattern of cognitive dysfunction common in idiopathic Parkinsonism were also significantly associated with drug-induced Parkinsonism (Hoffman et al., 1987). These findings suggest that cerebral atrophy and abnormalities in dopaminergic functions may underlie the increased risk for druginduced Parkinsonism as well as the behavioral and cognitive abnormalities of negative schizophrenia.

Frontal Lobe Deficits There is considerable evidence that negative schizophrenia is associated with frontal lobe dysfunction (Seidman, 1983; Goldberg, 1985; Goldberg et al., 1987; Merriam et al., in press). Personality alterations similar to negative schizophrenia frequently accompany frontal lobe disease (Teuber, 1964; Luria, 1966; Blumer & Benson, 1975). Among these are blunted affect, apathy, impaired social judgment, and psychomotor abnormalities (Blumer & Benson, 1975; Flint & Eastwood, 1988). In Schizophrenia, blunted affect has been shown to correlate with impairment on motor tasks that depend on frontal lobe integrity (Cox & Ludwig, 1979). Neuropsychological studies have revealed pronounced cognitive deficits in negative schizophrenia which are consistent with frontal lobe damage (Kolb & Whishaw, 1983; Goldberg et al., 1987). Specifically, the patients score poorly on the Wisconsin Card Sorting Test, which suggests a prefrontal cognitive deficit (Goldberg et al., 1987), and they show neurological soft signs associated specifically with the frontal region (Merriam et al., in press). Parkinson’s disease also is associated with various personality changes and cognitive deficits that are observed after frontal lobe lesions (Javoy-Agid & Agid, 1980; Agid et al., 1986). These abnormalities may be related in part to lesions in the basal ganglia (Rafal et al., 1984) and the mesocortical dopaminergic system (Javoy-Agid & Agid, 1980), or to damage of diencephalic neurons which project to the prefrontal cortex (Agid et al., 1986). Similarly to negative schizophrenia, metabolic studies have indicated hypofrontality in patients with Parkinson syndromes (Bes et al., 1983; D’Antona et al., 1985). In addition, Parkinsonian patients showed also deficits on the

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Wisconsin Card Sorting Test (Taylor et al., 1986) which is characteristic for prefrontal cortical damage.


Neurochemical Studies (1) The dopaminergic system and negative schizophrenia There is substantial evidence that negative schizophrenia, like Parkinsonism, is related to decreased dopaminergic functions and, thus, is responsive to dopamine agonists. (a) Prolonged administration of alpha-methyl-p-tyrosine in primates, a drug that inhibits tyrosine hydroxylase and thus limits catecholamine synthesis, has been shown to produce a syndrome characterized by decreased social interactions and initiative, reduced social expression, and retarded motor activity. Some of these symptoms appeared to be partially reversed with L-dopa treatment (Redmond et al., 1971). (b) Administration of L-dopa (Gerlach & Luhdorf, 1975; Alpert & Rush, 1983; Friedhoff, 1983) and amphetamines (Angrist et al., 1980) have been reported to improve blunted affect, emotional withdrawal, and apathy in patients with prominent negative symptoms. (c) Encephalitis lethargica, a presumed viral illness with a propensity to affect the dopaminergic neurons, is associated with emotional deterioration and “psychic torpor” similar to that identified with negative symptoms (Economo, 1931). (d) Neuroleptic drugs, which block dopaminergic receptors, frequently produce affective flattening, anhedonia, loss of initiative, and apathy (Andreasen, 1985). These effects are attributed to the specific properties of neuroleptic drugs and not to their nonspecific sedative effects (Wise, 1982). (e) Homovanillic acid (HVA) accumulation in the cerebrospinal fluid (CSF), serving as an indicator of dopamine turnover, has been reported to be decreased particularly in schizophrenics characterized by retarded depression, emotional blunting and poor premorbid social adjustment (van Praag & Korf, 1971; Bowers, 1974). Van Praag and Korf (1971) reported that patients with low CSF HVA accumulation following administration of probenecid were more likely to develop extrapyramidal side effects regardless of the dose of neuroleptic used. More recently, van Kammen et al. (1986) found that schizophrenic patients with CSF dopamine utilization below the mean had more severe negative symptoms. ( f ) Apomorphine-induced growth hormone response in schizophrenic patients significantly correlates with negative symptom scores on the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-C), suggesting that these patients may have decreased dopaminergic activity (Carpenter et al., 1985). (g) Facial seborrhea, which is associated with decreased hypothalamic dopaminergic activity, has been found to covary significantly with Parkinsonian motor disability and the two major features of negative schizophrenia described by Crow (1980), namely blunted affect and poverty of speech (Sandyk & Kay, see below). (h) Patients with enlarged lateral ventricles on CT scan have decreased CSF HVA levels (van Kammen et al., 1986; Lindstrom, 1985) and are more likely to develop Parkinsonism (van Praag & Korf, 1971; Chase, 1974).

( 2 ) The cholinergic system and negative schizophrenia Several lines of evidence suggest that negative schizophrenia, like Parkinsonism, is associated with cholinergic hyperactivity (see for review, Tandon & Greden, 1989). Pharmacological evidence includes:



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(a) Administration of cholinomimetics to normal controls produces a syndrome characterized by psychomotor retardation, anergy, malaise, lethargy, and slowed thoughts (Bowers et al., 1964; Davis et al., 1976), a behavioral profile resembling that of negative schizophrenia. (b) Anticholinergics have been reported to produce substantial improvement in negative symptoms, particularly in the areas of affective blunting, anhedonia-asociality, and avolition-apathy (Tandon et al., 1988; Tandon & Greden, 1987; Fayen et al., 1988). Comparable improvements are not found for the positive symptoms of schizophrenia, which instead are exacerbated by anticholinergic drugs (Johnstone et al., 1983; Singh et al., 1987). (c) Atypical neuroleptics such as clozapine (Honigfeld et al., 1984) and zotepine (Fleischhacker et al., 1987), which are reported to be more effective in negative schizophrenia, possess high anticholinergic activity, which might account for their efficacy in negative schizophrenia (Tandon & Greden, 1989). (d) Cholinergic drugs have consistently been found to decrease drive-reduction behavior (Domino & Olds, 1968), which may be related to the prominent negative symptoms of anergy, apathy, and avolition. (3) The noradrenergic system and negative schizophrenia Deficit symptoms such as those observed in negative schizophrenia may be produced by reduction in the noradrenergic reward system (Carpenter et al., 1985). In rats, 6-hydroxydopamine lesions of the noradrenergic reward system result in symptoms reminiscent of the negative phenomena of schizophrenia (Stein & Wise, 1971). It has been suggested (Carpenter et al., 1985), therefore, that loss of the structural integrity of the noradrenergic reward system may be causally related to symptoms of negative schizophrenia. Van Kammen et al. (1983) found low CSF dopamine-beta hydroxylase (DBH) activity in a subgroup of schizophrenic patients with cerebral atrophy. Wise and Stein (1973) found a decrease in central DBH activity in whole brainstem of schizophrenics who had presented predominant deficit symptoms. Markianos and Tripodianakis (1985) reported low plasma DBH in demented schizophrenics. Rosen et al. (1985) found that lower levels of platelet 'H-clonidine binding sites were associated with more negative symptoms and lesser response to neuroleptics in drug-free schizophrenics. Decreased cerebral noradrenergic function has also been demonstrated in patients with Parkinsonism (van Dongen, 1981; Hurst et al., 1985; Jellinger, 1986; Cash et al., 1987; Sandyk & Iacono, in press). Specifically, degeneration of noradrenergic neurons in the locus coeruleus (LC) has been associated with the akinesia and decreased cognitive functions in these patients (Narabayashi et al., 1984; Cash et al., 1987). (4) The serotonergic system and negative schizophrenia Several investigators found decreased CSF serotonin (5-HT) metabolites in schizophrenic patients (Ashcroft et al., 1966; Potkin et al., 1983). The latter group noted that the decrease in CSF 5-hydroxyindoleacetic-acid (5-HIAA) was present only in patients with enlarged cerebral ventricles. These findings suggest that decreased 5-HT metabolism may be more closely related to negative schizophrenia. It is noteworthy that both clozapine and risperidone, which have 5-HT antagonistic properties, significantly reduce negative symptoms without worsening Parkinsonism (Kane et al., 1988; Peuskins et al., 1989). Decreased brain and CSF 5-HT levels have been found also in patients with Parkinson's disease, specifically in depressed Parkinsonian patients (Jellinger, 1986; Sandyk & Fisher, 1988).

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Neuropep tides


Several peptidergic abnormalities have been found in schizophrenia (Meltzer, 1987). Decreased brain cholecystokinin (CCK) levels have been found both in patients with negative schizophrenia (Ferrier et al., 1983) and in those with Parkinson’s disease (Studler et al., 1982). Impaired processing of pro-opiomelanocortin (POMC) peptides in the hypothalamus has been found in schizophrenic patients (Wiegant et al., 1988). These abnormalities were unrelated to the subtype of schizophrenia. Similarly, there is evidence that abnormal POMC processing may be associated with the pathophysiology of Parkinson’s disease (Sandyk, 1989). Neuroendocrine Studies Glucose metabolism In 1899 Sir Henry Maudsley In the Pathology of the Mind (p. 113) wrote “Diabetes is a disease which often shows itself in families in which insanity prevails.” High prevalence of impaired glucose tolerance has been reported in patients with a variety of neuropsychiatric disorders, as well as schizophrenia (Bramabilla et al., 1976; Wilkinson, 198 1). Thonnard-Neuman (1968) found that 25% of his group of several hundred female schizophrenic patients developed hyperglycemia when treated with neuroleptics. In a quarter of the affected patients, hyperglycemia remitted following dose reduction or discontinuation of therapy. Other studies (Schwartz & Munoz, 1968) found that phenothiazines had little effect on patients’ diabetic state. A high prevalence of abnormal glucose tolerance has also been observed in patients with Parkinson’s disease. Elner and Kandel (1965) reported an 83% incidence of abnormal glucose metabolism in 80 patients with Parkinson’s disease and Boyd et al. (1971) found 50% of Parkinsonian patients to have abnormal intravenous glucose tolerance tests. Lipman et al. (1974) found a 52.4% incidence of abnormal glucose tolerance in Parkinsonian patients and speculated that “hypothalamic involvement might be logically suspected as explaining the abnormal glucose metabolism in these cases” (p. 577). Indeed, a number of investigators have noted changes in the hypothalamus in Parkinson’s disease (Lewy, 1923; den Hartog & Bethlem, 1960; Langston & Forno, 1978). Similarly, degenerative changes in the hypothalamus have also been noted in schizophrenic patients (Morgan & Gregory, 1935; Stevens, 1982; Nieto & Escobar, 1972), an observation which may account for the high incidence of diabetes mellitus in these patients. A particularly high prevalence of diabetes mellitus has been reported recently in schizophrenic patients with drug-induced Parkinsonism (Sandyk & Kay, in press h; Sandyk et al., in press). In a group of 44 consecutive patients with abnormal involuntary movements who were referred to a movement disorders clinic, we identified 16 (36.4%) who had drug-induced Parkinsonism together with diabetes mellitus. These patients were distinguished as having an almost pure Parkinsonian syndrome, lower ratings of tardive dyskinesia (TD), and a far higher rate of dementia. They had also significantly more severe global Parkinsonism as compared to nondiabetic patients. Since Parkinsonism is a covariate of negative schizophrenia (Luchins et al., 1983; Hoffman et al., 1987; Kay & Sandyk, 1990; Sandyk & Kay, see below), the risk of diabetes mellitus may be a facet of an underlying Parkinson’s disease. (1)

(2) Pineal melatonin functions Pathological changes in the form of gliosis have been detected in the pineal gland of schizophrenic patients (Nieto & Nieto, 1988). In


NEGATIVE SCHIZOPHRENIA A N D PARKINSONISM

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addition, several studies have found decreased melatonin secretion in schizophrenic patients (Ferrier et al., 1982; Fanget et al., 1989). We have elsewhere suggested that diminished melatonin secretion may be associated with the pathophysiology of a subgroup of schizophrenic patients characterized by cerebral atrophy and ventricular enlargement, negative symptoms, impaired cognitive and psychosexual development, onset at pubescence, poor response to neuroleptic medication, and an increased risk of extrapyramidal symptoms (Sandyk & Kay, in press i ) . We found also a high prevalence of pineal gland calcification among schizophrenic patients with druginduced Parkinsonism (Sandyk & Kay, in pressj). The role of the pineal gland in Parkinsonism is poorly understood, but there is indirect evidence that decreased melatonin secretion may be associated also with the pathophysiology of Parkinson’s disease (Sandyk, 1990). Indeed, we found that pineal gland calcification was associated with drug-induced Parkinsonism in neuroleptictreated schizophrenic patients (Sandyk & Kay, in press j ) , an observation which underscores the association of abnormal pineal functions in both negative schizophrenia and Parkinsonism. (3) Dexamethasone suppression Numerous studies reported that a high proportion of schizophrenic patients are dexamethasone nonsuppressors (Saffer et al., 1985; Tandon et al., 1989). Dexamethasone nonsuppression is generally attributed to hypothalamic-pituitary adrenal (HPA) axis hyperactivity (Rose & Sachar, 1981) and is reportedly associated with negative schizophrenia (Saffer et al., 1985; Tandon et al., 1989). Dexamethasone nonsuppression has been observed also in patients with Parkinson’s disease (Pfeiffer et al., 1986; Kawamura et al., 1987); one study found nonsuppression related to Parkinsonian akinesia and freezing (Kawamura et al., 1987), thus underscoring the similarity of Parkinsonism with negative schizophrenia. Pharmacological Studies Based on evidence that negative schizophrenia is associated with reduced dopaminergic and increased cholinergic activity, several investigators have initiated therapeutic trials with dopaminergic and anticholinergic drugs in negative schizophrenia. Dopaminergic agonists such as amphetamine and L-dopa, which alleviate symptoms of Parkinsonism, have been reported to improve some negative features of schizophrenia (Angrist et al., 1980; Alpert & Rush, 1983; Friedhoff, 1983; Desai et al., 1984; Kay & Olper, 1985). Angrist et al. (1980) observed that neuroleptic-free patients with predominant negative symptomatology who were treated with a single dose of damphetamine (0.5 mg/Kg) showed significant reduction of negative symptoms three hours after its administration. This effect was not obtained in schizophrenic patients with predominant positive symptoms. Similarly, prolonged treatment with L-dopa has been reported to be effective in improving blunted affect, emotional withdrawal, and apathy in patients with prominent negative symptoms (Alpert & Rush, 1983; Friedhoff, 1983) and in ameliorating the negative but not the positive syndrome scale of the PANSS (Kay & Opler, 1985). Desai et al. (1984) reported two patients in whom oral d-amphetamine produced long-term improvement of negative symptoms (alogia, affective flattening, anhedonia). An open pilot study on the effects of the anticholinergic antiparkinsonian drug, trihexyphenidyl, on negative symptons demonstrated substantial improvement in the area of affective flattening, anhedonia-asociality, and avolition-apathy in four out of five patients (Tandon et al., 1988; Tandon & Greden, 1987). Another study reported a similar improvement of negative symptoms with trihexyphenidyl in comparison


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with amantadine when these agents were employed to treat neuroleptic-induced extrapyramidal side-effects (Fayen et al., 1988). Conversely, independent studies by Johnstone et al. (1983) and Singh et al. (1987) found that anticholinergic compounds significantly exacerbate the positive spectrum of psychopathology in schizophrenia. This may be related in part to the anticholinergic effects of neuroleptics, as cholinergic underactivity has been hypothesized to be associated with positive symptoms (Tandon & Greden, 1989). Recently, the antihistamine agent famotidine has been reported to improve symptoms of negative schizophrenia (Kaminsky et al., 1990). It is noteworthy that antihistamines such as diphenylhydramine are also efficacious in the management of Parkinson’s disease. These preliminary observations support the dopaminergic deficiency-cholinergic excess model of negative schizophrenia (Tandon & Greden, 1989). A similar model has been suggested for Parkinsonism, for which both dopaminergic and anticholinergic agents are presently the most efficacious drugs in its management. Recently, Friedman et al. (1987) and Friedman and Lannon (1989) described six patients with coexisting schizophrenia and Parkinson’s disease for whom Parkinsonism was successfully treated with levodopa and the schizophrenic disorder with clozapine. It is noteworthy that clozapine, which unlike most classical neuroleptics does not promote the emergence of Parkinsonism, has been shown to be an efficacious antipsychotic drug for negative schizophrenia (Hongifeld et al., 1984). Likewise, risperidone, which similarly does not induce such effects, significantly diminishes the negative syndrome (Peuskins et al., 1989). These psychopharmacological findings underscore the parallel between negative schizophrenia and Parkinsonism. Radiological Studies Computed tomographic (CT) scan studies of the brains of schizophrenic patients with negative schizophrenia have demonstrated ventricular enlargement, third ventricular dilatation, cortical and cerebellar atrophy, and atypical asymmetry between the cerebral hemispheres (Weinberger & Wyatt, 1980; Andreasen et al., 1982; Maser & Keith, 1983; Nasrallah et al., 1983; Dewan et al., 1983; Houston et al., 1986). The most consistent abnormality included enlargement of the lateral ventricles associated with an increased ventricular brain ratio (VBR)(Andreasen et al., 1982; Weinberger et al., 1979, 1980; Weinberger & Wyatt, 1980). These abnormalities are in accord with the concept that negative schizophrenia is associated with organic brain damage (Crow, 1980) and with the neuropathological findings reported by Stevens (1982), which demonstrated neuronal damage in diencephalic, periventricular, and mesencephalic periaqueductal regions. Enlarged lateral ventricles have been reported also in patients with drug-induced Parkinsonism (Luchins et al., 1983; Hoffman et al., 1987; Sandyk & Kay, see below), and it has been suggested that ventricular dilatation may be a risk factor associated with increased susceptibility for the development of drug-induced Parkinsonism. Hoffman et al. (1987) found a significant association between increased VBR, Parkinsonism, and negative schizophrenia. Our own analysis (Sandyk & Kay, see below) revealed a significant association between VBR and the severity of bradykinesia in patients with drug-induced Parkinsonism. Neuroradiological changes similar to those observed in negative schizophrenia, have been found also in patients with Parkinson’s disease (Selby, 1968; Steiner et al., 1985; Sroka et al., 1981; Gath et al., 1975). Indeed, it has been considered that cerebral atrophy is an essential feature of Parkinson’s disease (Selby, 1968). Selby (1968) found a 57% incidence of cortical (sulcal) atrophy and 30% ventricular enlargement in 250 Parkinsonian patients, and he noted a “greater incidence of ventricular dilatation in



I1

the Parkinsonian patients with an impaired mental state.” Gath et al. (1975) found cortical atrophy in 47% and ventricular dilatation in 78% of their Parkinsonian patients, the latter feature being the dominant abnormality in their series, in contrast to that of Selby. Neither study showed any significant correlation between duration of the Parkinson’s disease and either cortical and ventricular dilatation. Becker et al. (1976) found that 53.4% of 172 Parkinsonian patients had ventricular dilatation, which was observed to occur earlier than cortical atrophy. Sroka et al. (1981) found abnormal CT scan in 65% of 93 Parkinsonian patients. These included: 40% generalized atrophy (ventricular and sulcal enlargement); 40% primary cortical atrophy; and 12% primary ventricular enlargement. Ventricular enlargement was more strongly correlated with organic mental disorder than cortical atrophy. Portin et al. ( 1 984) found a significant correlation between Parkinsonian mental disturbances and cerebral atrophy in 28 patients. Correlations between motor symptoms and cerebral atrophy were less pronounced. Since Parkinson’s disease is associated also with pathological changes in extrastriatal structures (Greenfield & Bosanquet, 1953; Jellinger, 1968; 1968), these alterations probably lead to structural changes in the brain, as mediated in part through the various connections of the nigrostriatal system. Pathological Studies (1) Diencephalic pathology Since the turn of the century, there have been many attempts to find structural abnormalities in the brain of schizophrenic patients. In a landmark neuropathological study on 25 schizophrenic patients, Stevens (1 982) reported a patchy, fibrillary gliosis that, in various degrees and distributions, affected principally the periventricular regions of the diencephalon and substantia innominata. There was neuronal loss or infarction in the globus pallidus in five patients. Nieto and Escobar (1972) also noted a widespread gliosis with a predilection for the periventricular and perivascular regions in the diencephalon and midbrain of schizophrenic patients studied at postmortem examination. These findings were confirmed by Fisman (1979, who similarly observed gliosis, especially in the midpons and medial reticular nuclei. Lesch and Bogerts (1984) found reduced thickness of the periventricular grey matter of 15 schizophrenic patients, 4 of whom had predominant negative symptoms. The finding of subependymal gliosis in the diencephalon and hypothalamus or of pallidal neurons dropout in these brains from schizophrenic patients is consistent with the evidence of moderate enlargement of the third and lateral ventricles, which may be characteristic of negative schizophrenia (Weinberger et al., 1979; Dewan et al., 1983; Houston et al., 1986).

(2) Basal ganglia pathology in schizophrenia Buscaino (1 920) was the first to point out possible involvement of the basal ganglia in the genesis of schizophrenic symptoms; he stated that, particularly in typical catatonic patients, serious alterations, especially of the globus pallidus, could be found. Similar observations were reported in an extensive study by Hopf (1925). Recently, Stevens (1982) described neuronal loss within the pallida in four cases, and pallidal gliosis in six of 28 qualitatively investigated schizophrenics. Bogerts et al. (1985) performed a morphometric study of the basal ganglia in 13 schizophrenic patients and found decreased volume of the internal pallidum. The latter was interpreted as degenerative shrinkage of unknown etiology. The pathological lesions in chronic schizophrenia overlap with those found in postencephalitic Parkinsonism, with the exception that Lewy bodies are usually absent in patients with post-encephalitic Parkinsonism (van Dongen, 1981; Howard & Lees, 1987). Lewy bodies are the hallmark of Parkinson’s disease (Forno, 1986).


12


The frequency and occurrence of Lewy bodies in the brain of “patients with psychosis or mental deficiency” is similar to that in a large sample of individuals “without predominance of psychiatric symptoms” (Woodard, 1962). Lewy bodies were found, however, to be much more frequent (28%) in cases of “mental disturbance without established morphological basis”; the clinical features found in these patients with Lewy bodies are paranoia, violence, confusion, affective disorder, and intellectual deterioration (Woodard, 1962). In the same study, interestingly, Woodard (1962) found a relatively high prevalence of Alzheimer’s pathology, suggesting an interrelationship between schizophrenia and Alzheimer’s disease. Coexisting Parkinson’s and Alzheimer’s pathology has been also observed in patients with idiopathic Parkinson’s disease (Growdon & Corkin, 1986; Gibb & Lees, 1989) and those with post encephalitic Parkinsonism (van Dongen, 198 1). Gliosis, the most ubiquitous abiiormality found in the brains of schizophrenic patients (Nieto & Escobar, 1972; Stevens, 1982), reflects a response to brain injury. The location of gliosis in these patients indicates injury in proximity to or involving principally the subependymal and subpial regions of the midbrain, diencephalon, and basal forebrain (Stevens, 1982). Although cerebral gliosis is merely indicative of past injury, several reports have suggested that the observed gliosis in schizophrenia may be secondary to infectious or immunologic disorder (Albrecht et al., 1980; Tyrrel et al., 1979). Fisman’s (1975) findings of glial knots and perivascular infiltration in the brainstem of schizophrenic patients is consistent with past or present encephalitis. It is noteworthy that the pathological lesions of post-encephalitic Parkinsonism are most severe in the brainstem and basal ganglia (Howard & Lees, 1987). These lesions include nonpurulent, nonhaemorrhagic perivascular infiltration and nerve cell necrosis limited to the gray matter, with preferential localization to the midbrain. Although the changes are most severe in the brainstem and basal ganglia, there is also involvement of the cerebral cortex and spinal cord. The neurofibrillary tangle in the substantia nigra is regarded as the hallmark of post-encephalitic Parkinsonism (Forno, 1986). Typically, the tangles are found in connection with severe diffuse nerve cell loss. Since post-encephalitic Parkinsonism may be associated with schizophrenic symptoms (Howard & Lees, 1987), Crow (1 983) cited the presence of such symptoms in these patients as supportive evidence for the theory that schizophrenia could be due to a virus which is transmitted preponderantly from schizophrenic patients to genetically predisposed individuals. Indeed, Alizan et al. (1980) found an increased frequency of HLA B14 (44%) in postencephalitic Parkinsonism as compared with matched controls, which suggested to him a genetic susceptibility for this disorder. In addition, increased levels of serum antibodies against herpes simplex virus (HSV) have been found in patients with Parkinson’s disease, but their relationship to the pathogenesis of the disease remains unknown (Marttila et al., 1984). Furthermore, Pouplard and Emile (1984) demonstrated in the sera of 62.7% of Parkinsonian patients circulating antibodies reacting against sympathetic ganglion neurons, which suggest that autoimmune mechanisms may be involved in the pathogenesis of Parkinson’s disease (Abramsky & Livin, 1978). Thus, it is possible the delayed appearance of Parkinsonism following a seemingly full recovery from acute encephalitic illness may be due to a continuing virally-mediated striatonigral damage. A similar mechanism may conceivably operate in the pathogenesis of schizophrenia. Compensatory Mechanisms and Positive Schizophrenia

(1) Doparninergic mechanisms While negative schizophrenia may thus relate to decreased dopaminergic functions, as per MacKay (1980), positive schizophrenia has



13

alternatively been thought to reflect a neurochemical abnormality associated with increased dopaminergic functions (Crow, 1980a; MacKay, 1980; Andreasen, 1985). Yet it remains unclear how increased dopaminergic functions are linked to the positive symptoms and why these paradoxically occur together in patients with negative symptoms. Studies derived from Parkinsonian patients have suggested that the clinical symptoms of Parkinsonism emerge following 80% loss of striatal dopamine neurons (Hornykiewicz & Kish, 1986). A phase of subclinical Parkinsonism usually precedes the onset of the motor symptoms (Hornykiewicz & Kish, 1986). It has been shown that the preclinical phase of Parkinsonism is associated with compensatory mechanisms of striatal dopamine neurons aimed at overcoming the progressive dopaminergic deficiency (Zigmond et al., 1984; Agid et al., 1986). Similarly, the increased dopaminergic activity which is associated with the positive symptoms of schizophrenia may reflect a compensatory increase in dopamine turnover in the mesolimbic pathways as a result of damage to dopaminergic neurons. The favorable response of positive symptoms to neuroleptics is consistent with this position. As such, this hypothesis may offer an integrated model of schizophrenia that explains, with a single underlying pathophysiological mechanism, the emergence of both positive and negative symptoms as well as their coexistence in the same patient. (2) Norepinephrine mechanisms Positive symptoms may also be associated with compensatory mechanisms at the level of the noradrenergic locus coeruleus (LC). There is evidence that productive psychotic behavior is related to increased brain norepinephrine (NE), turnover. Amphetamine-induced psychosis (Mason, 1979) and L-dopa-induced psychosis in Parkinsonian patients (Birkmayer et al., 1974) are associated with increased NE levels in several brain regions, and it has been suggested that the antipsychotic effects of neuroleptics may be related in part to their blockade of beta and alpha,-adrenoreceptors (van Dongen, 1981). Elevated NE levels in the LC terminals have also been found in patients with paranoid schizophrenia (see van Dongen, 198 1). Increased NE turnover in schizophrenia may reflect a compensatory increase in LC activity subsequent to damage of the LC or its projections to other regions of the CNS. LC fibers regenerate after damage, in contrast to most other CNS regions. After damage, the intact part of the fiber shows sprouting and regrowth, and the regrown LC fibers contain and accumulate NE (see van Dongen, 1981). The regrowth of LC fibers is age- and region-dependent. The various LC terminal regions have different critical periods of regrowth, with aging being a limiting factor. It has been shown that the original connections are often accurately restored, but occasionally hyperinnervation is found (Bjorklund & Lindvall, 1979). Similar compensatory mechanisms have been shown for the alpha,-adrenoreceptors (U’Prichard et al., 1971). Since the activity of NE LC neurons is linked to cognitive functions and level of arousal (see van Dongen, 1981), reinnervation and hyperinnervation of the NE LC neurons may account also for the alterations in the level of arousal, attention, and information processing capacity observed in schizophrenic patients (Cornblatt et al., 1985; George & Neufeld, 1985). It is the hyperarousal in schizophrenia that is believed to underlie the florid symptoms such as hallucinations, delusions, and disorganized thinking (Kay, 1981; Kay & Singh, 1979), and its regulation may explain the therapeutic action of neuroleptics (Venables, 1966; Gruzelier & Hammond, 1978). Integrated Model of Schizophrenia

It appears, based on the above discussion, that negative schizophrenia is associated

R. SANDYK A N D S.R. KAY


14

with decreased dopaminergic activity (MacKay, 1980) and increased cholinergic activity (Tandon & Greden, 1989). This neurochemical profile is also characteristic of the Parkinsonian state, suggesting that we may be dealing with the same fundamental disease process. Indeed, we have seen that the clinical features of negative schizophrenia are found as well in Parkinsonism. Also, the favorable response of negative symptoms to dopaminergic drugs and anticholinergic agents supports the hypothesis that negative schizophrenia may be a variant of Parkinsonism. Positive schizophrenia, on the other hand, may reflect a compensatory increase in dopaminergic and noradrenergic activity as a result of damage to dopaminergic and noradrenergic pathways, respectively. This view is consistent with the seminal model of Bleuler, who regarded negative features as cardinal in schizophrenia and positive features as accessory symptoms. Similarly, the emergence of spontaneous or levodopa-induced psychotic symptoms in patients with Parkinsonism may reflect increased dopaminergic activity either as a compensatory mechanism or drug-induced. Thus, the coexistence of negative and positive symptoms in the same patient may reflect different processes in the dopaminergic and noradrenergic systems. Table 2 summarizes the key elements hypothesized in the pathophysiology of schizophrenia versus Parkinsonism. Our model postulates similarities in the origins, anatomical regions affected, and neurochemical disturbances. It is, of course, important to recognize that there are a few differentiating features which are salient enough to mask the fundamental similarities outlined herein. It will be recalled from Table 1 that a crucial difference between schizophrenia and Parkinson's disease is the timing of the onset. Schizophrenia tends to be manifested symptomatically in mid- to late adolescence or early adulthood, whereas Parkinson's disease usually affects individuals in late adulthood. This very difference in age of onset could explain the differences in the clinical presentation, namely the predominance of motor deficits and the relative lack of positive symptoms in patients with Parkinson's disease. In cases of late onset of illness, we would expect lesser pathological impact on cognitive and social functions, which by now have been fully developed in the TABLE 2 Pathophysiological model of schizophrenia and Parkinsonism Origins

Genetic and/or constitutional vulnerability to viral infectious disease or environmental toxins

Anatomical regions affected

Basal ganglia, periventricular, and limbic systems

Neurochemical disturbances

Low dopamine, low serotonin, low norepinephrine increased dopaminergic and noradrenergic activity

Onset in adolescence (schizophrenia)

(1) Core negative symptoms (affective, social, cognitive. and motor deficits) (2) Compensatory mechanisms (increased dopdmine functions and brain norepinephrine turnover) (3) Associated positive symptoms (hyperarousal, hallucinations, delusions, etc.)

Onset in late adulthood (Parkinson's disease)

( 1 ) Core negative symptoms (with particular prominence of motor deficits) (2) Diminished capacity for compensatory adaptation (3) Paucity of associated positive symptoms



15

individual and are well established. In schizophrenia, by contrast, the maturational course is itself interfered with by the disease process, leading to premorbid social and cognitive dysfunctions that seem to antedate the negative schizophrenic syndrome (Pogue-Geile & Harrow, 1984; 1985; Kay et al., 1986) and, subsequently, to resist neuroleptic intervention (Kay & Singh, 1979). Secondly, we may expect diminished capacity for compensatory adaptation in the aged organism. Accordingly, one would predict a comparatively less increase in dopaminergic functions and norepinephrine turnover in Parkinson’s disease, and hence a paucity of associated positive symptoms that emerge. Finally, in understanding the distinction between negative schizophrenia and Parkinson’s disease, we stress that our proposal is not that they are the same condition, but rather that they are variants of the same disorder, sharing a common pathophysiological mechanism. Further studies on the comparison of the two illnesses in terms of genetic liability, premorbid history, and catamnestic course are clearly required. The hypothesis that negative schizophrenia is a variant of Parkinsonism carries several implications; (a) Pharmacologically, negative schizophrenia might be managed like Parkinsonism, i.e., with dopaminergic and anticholinergic drugs rather than neuroleptics, which in fact may facilitate the progression of the disease. (b) Ldeprenyl, an MAO-B inhibitor which has been shown to halt the progression of Parkinson’s disease (Birkmayer et al., 1985; Tetrud & Langston, 1989), may be useful in negative schizophrenia. (c) Patients with both negative and positive features might be managed like psychotic Parkinsonian patients, namely with levodopa combined with clozapine (Friedman & Lannon, 1989).(d) Adrenal medullary tissue transplantation, which has shown some promising results in Parkinsonism, may be a future promising therapy for drug-resistant negative schizophrenia.

EXPERIMENTAL STUDIES Negative Schizophrenia as a Variant of Parkinsonism

Since Bleuler’s (1950) description of the “schizophrenias” early in the century, this disorder has been recognized to be heterogenous in terms of symptoms, prognosis, and probably also etiology. Strauss et al. (1974), on the basis of factor analytic study, first proposed the division of schizophrenic symptoms into a positive type (abnormal production) and a negative type (deficit or loss of function). Much earlier Hughlings Jackson (1 887), in describing neurological conditions, had suggested that negative symptoms result directly from damage to brain areas that are responsible for production of human behavior. He regarded positive symptoms as a “release” phenomenon exercised by the damaged brain. Although Bleuler (1950) never used the term “negative symptoms,” he perceived them as the fundamental deficiency in schizophrenia, while positive symptoms such as delusions and hallucinations played a variable, “accessory” role in the illness. Crow (1980; 1980a) and later Andreasen (1985) hypothesized that these symptom classes reflect two etiologically and prognostically distinct schizophrenic subtypes, in which negative symptoms are associated with gross structural abnormality and positive symptoms with biochemical dysregulation involving dopaminergic overactivity and hence a more favorable response to neuroleptics. In a direct exchange with Crow (1980; 1980a), MacKay (1980) presented a divergent hypothesis that has never attained comparable recognitions. He proposed that negative symptoms may reflect chronic dopaminergic underactivity, while positive symptoms emerge when there is a


16


burst of dopaminergic overactivity. According to MacKay (1 980), the negative symptoms in schizophrenia are chronically present and form the background on which positive symptoms are periodically acutely superimposed. Neither Crow nor MacKay, however, could explain why these two types of symptoms occur together in schizophrenia. The characteristic symptoms of negative schizophrenia, such as blunted affect, poverty of speech, emotional withdrawal, motor retardation, and cognitive deficits (Crow, 1980; 1980~;Andreasen, 1985), are also hallmarks of Parkinson’s disease (Alpert & Rush, 1983; Lidsky et al., 1979; Rogers et al., 1985; Taylor et al., 1986). In particular, akinesia is one of the features of Parkinsonism most likely to be confounded with negative schizophrenia (Sandyk & Kay, see above; Hoehn et al., 1976; Rifkin et al., 1975; Carpenter, 1985). Hollister and Glazener (1961) studied the association of Parkinsonism and schizophrenia and concluded that: “a mental syndrome indistinguishable from schizophrenia may precede paralysis agitans” (p. 189). Hoehn et al. (1976) found in 37 untreated patients a high correlation between MMPI-8 scores, which are indicative of schizophrenic-like looseness of thinking, and akinesia. Bowman and Lewis (1 980) found an unusual high degree of basal ganglia involvement in diseases which have symptoms in common with schizophrenia. We found recently a significant association between features of negative schizophrenia and Parkinsonian bradykinesia (see below) and positive glabellar tap response, which reflects decreased striatal dopaminergic activity (see below). Narrowly defined, akinesia represents a motor anomaly characterized by slowness of movement, poor arm swing, and rigid posture (Chien et al., 1974). More broadly viewed, akinesia overlaps with negative symptoms along dimensions other than pure motor behavior (Rifkin et al., 1975; Van Putten & May, 1978; Van Putten et al., 1980); it includes lack of emotional reactivity, lack of goal-directedness, retarded spontaneous speech, sluggishness, decreased sociability, and decreased physical movements. In addition, the classic “mask-like’’ facies of Parkinsonism cannot be distinguished from the absence of facial expression in blunted affect that is attributed to the negative syndrome (Sommers, 1985). Thus, negative schizophrenia and Parkinsonism apparently share common clinical features that cannot be easily distinguished from each other. Carpenter et al. (1985) cautioned that, in assessing negative phenomena, one must be careful to avoid “confound” from Parkinsonian symptoms. Studies by our group (Kay et al., 1986) have indicated a significant direct correlation between negative syndrome on the Positive and Negative Syndrome Scale (PANSS) and scores on the Extrapyramidal Symptoms Scale, even though the PANSS negative scale excluded motor items (Kay et al., 1987). TABLE 3 Sample characteristics ( N = 46)

Age Years of schooling Age at onset of illness Years of illness Days of institution (past 18 months) Full Scale IQ (WAIS-R) Verbal IQ (Quick Test) Chlorpromazine stabilization dose (mg) Positive Syndrome (SAPS) Negative Syndrome (SANS)

33.1 10.4 21.3 11.7 410.0 17.2 81.6 1065.8 9.13 11.23

8.3 2.4 6.0 6.9 249.3 10.0 11.1 1001.9 4.54 4.84


17

We, therefore, have proposed that the overlap between symptoms of negative schizophrenia and Parkinsonism is not merely coincidence, confound, or rather misjudgment. We suggested the possibility that negative schizophrenia may in fact constitute a variant form of Parkinsonism and, therefore, may reflect a primary disorder of the basal ganglia (see above). To investigate this hypothesis further, we examined the association between negative symptoms and Parkinsonism in chronic schizophrenic patients. For comparison, we also studied the association of Parkinsonism with positive symptoms.


METHOD Subjects and Design

A sample of 46 patients (42 men, 4 women) was recruited on a consecutive basis from predominantly male wards of an urban psychiatric hospital. They were selected on the basis of a diagnosis of schizophrenia according to both Research Diagnostic Criteria (RDC)(Spitzer et al., 1978) and DSM-I11 criteria (American Psychiatric Association, 1980), an extensive history of psychiatric illness, signing of informed consent for research participation, and cooperation in taking all measures. The sample characteristics are summarized in Table 3. As conditions of entry into the study, all patients were found free of focal abnormalities on a screening neurological examination, and none were diagnosed with organic brain syndrome, substance abuse disorder, or mental retardation. The average Full Scale and Verbal IQs (Table 3) were in the normative range for a long-term schizophrenic population (Payne, 1973). To standardize the psychotropic regimen, patients were switched from their existing drug regimen to chlorpromazine (CPZ) upon entering the protocol. They were stabilized on this medication within a period of 4-5 weeks at a dose that was titrated to achieve optimal therapeutic benefit (group mean = 1065.8mg/d). At the end of this stabilization phase, the patients underwent assessment on the batteries described below. The clinical and extrapyramidal measures were administered within a week’s time by research psychiatrists who were kept blind to the objectives of the study. Clinical Evaluation

The symptom assessment was undertaken by a psychiatrist who, after standard patient interview, performed ratings on the Andreasen’s scale for Positive and Negative Syndromes (Andreasen, 1982). The four items that comprise the positive evaluation (hallucinations, delusions, thought disorder, and bizzare disorganized behavior) derive from the Scale for Assessment of Thought, Language, and Communication (Andreasen, 1979) and the SADS (Edicott & Spitzer, 1978); the five items that constitute the negative evaluation (affective flattening, alogia, avolition-apathy, anhedonia-asociality, and attentional impairment) derive from the Scale for the Assessment of Negative Symptoms (Andreasen, 198 1). The authors reported interrater reliabilities between .58 and .88 for the negative items (Andreasen, 1982) and have described clinical validation study of the scale as a whole (Andreasen et al., 1982). Extrapyramidal Symptom Assessment

Parkinsonism was assessed on the Extrapyramidal Rating Scale (ERS) of Alpert et al.

18


(1978). This 5-point severity rating scale, which is similar to Borison’s (1984) Scale for Recognizing Acute EPS, evaluates Parkinsonian symptoms along seven dimensions: abnormal gait, rigidity, tremor of extremities, bizzare movements, expression, restlessness, and reduced motor activity.


RESULTS The mean ERS score for the sample as a whole was 11.5, which indicates mild to moderate Parkinsonism. Pearson product-moment correlations revealed that the ERS ratings were unrelated to demographic, historical, and cognitive variables such as age, years of illness, IQ, as well as CPZ stabilization dose. However, it was significantly associated with the number of days institutionalized during the past 18 months ( p < .OOl). The mean negative symptom score on the SANS was 1 1.2 (SD = 4.8) and the mean positive symptoms score on the SAPS was 9.1 (SD = 4.5). Pearson product-moment correlations of the ERS revealed that it was significantly associated with global negative symptoms ( r = 27,p < .05, one-tailed), and, among individual items of the SANS, with alogia (Y = .31, p < .05) and avolition-apathy (Y = .29, p < .05). By contrast, the ERS was unrelated to the global positive symptom rating. Accordingly, these findings reveal an association between ERS and negative symptoms, confirming the prediction of a relationship between negative schizophrenia and Parkinsonism. DISCUSSION

As predicted, we found a significant association between negative symptoms of schizophrenia and Parkinsonian symptoms. By contrast, ERS was unrelated to the positive syndrome, confirming our prediction of a specific association between negative schizophrenia and Parkinsonism. The view that negative schizophrenia is a variant of Parkinsonism is further underscored by the following findings: (a) Pharmacologically, both negative schizophrenia and Parkinsonism are associated with decreased dopaminergic and increased cholinergic functions (MacKay, 1980; Bowers, 1974; Tandon & Greden, 1989; van Kammen et al., 1986); (b) Dopamine agonists such as L-dopa and amphetamines and anticholinergics improve negative symptoms of schizphrenia (Angrist et al., 1982; Kay et al., 1985; Desai et al., 1984; Friedhoff, 1983) and Parkinsonism; (c) Encephalitis lethargica, a presumed viral illness with a propensity to affect the dopaminergic neurons, is associated with emotional deterioration and “psychic turpor” similar to that identified with negative symptoms (Economo, 1931); (d) Neuroleptics are reported frequently to produce both Parkinsonism (Ayd, 1961) and negative symptoms such as affective flattening, anhedonia, loss of initiative, apathy (Andreasen, 1985); (e) There is an unusual degree of pathological involvement of the basal ganglia in schizophrenia (Buscaino, 1920; Hopf, 1925; Bogerts et al., 1985) and in diseases which resemble schizophrenia (Bowman & Lewis, 1980); (f) Psychotic symptoms are commonly associated with Parkinsonism (Hollister & Glazener, 1961; Fairweather, 1947; Jelliffe, 1927; Klawans, 1988) and specifically with the postencephalitic type (Crow, 1983; Howard & Lees, 1987); e.g., McCowan and Cook (1928) described the mental status in some cases of Parkinsonism as “extremely difficult to distinguish from ordinary cases of paraphrenia,” and Hollister and Glazener (196 1) concluded that ‘‘a mental syndrome indistinguishable from schizoph-



19

renia may precede paralysis agitans by many years” (p. 189); (g) Clozapine, an atypical antipsychotic which has been shown efficacious in negative schizophrenia, diminishes psychotic symptoms in patients with Parkinson’s disease (Friedman & Lannon, 1989); (h) Both negative symptoms of schizophrenia and Parkinsonism predict poor performance on visual-spatial tests (Boller et al., 1984; Hoffman et al., 1987; Green & Walker, 1985); (i) Lewy bodies identical to that seen in Parkinson’s disease have been reported to be more frequent (28%) in cases of “mental disturbance without established morphological basis” (Woodard, 1962); indeed, Woodard (1962) observed Lewy bodies in the brainstem nuclei of 25 of 224 (10.3%) institutionalized psychiatric patients over age 50, 26% of whom had “clinical Parkinsonism” that either preceded the mental disturbances or occurred at any time during its course; and Q) Schizophrenic patients with enlarged lateral ventricles on CT scan have decreased CSF dopamine metabolites (Bowers, 1974; van Kammen et al., 1986) and are at increased risk for drug-induced Parkinsonism (Luchins et al., 1983; Hoffman et al., 1987). In summary, our findings and the evidence discussed above provide a consistent basis for postulating negative schizophrenia to be a variant of Parkinsonism (cf. Sandyk & Kay, see above), both sharing common pathophysiological mechanisms. From a pragmatic standpoint, our hypothesis suggests that patients with negative schizophrenia might be managed like those with Parkinson’s disease, namely with dopaminergic drugs. Further, since L-deprenyl (an MAO-B inhibitor) has been shown to halt the progression (Tetrud & Langston, 1989) and increase life expectancy of patients with Parkinson’s disease (Birkmayer et al., 1985), it might be of benefit for the negative features of schizophrenia. Finally, the association of negative schizophrenia with Parkinsonism raises the possibility that adrenal medullary tissue transplantation, which may benefit a selected group of Parkinsonian patients, may be a future promising therapy for refractory negative schizophrenia. BRADYKINESIA IS ASSOCIATED WITH VENTRICULAR ENLARGEMENT IN CHRONIC SCHIZOPHRENIA Several computed tomographic (CT) brain studies have shown enlargement of the cerebral ventricles in a subgroup chronic schizophrenic patients (Nasrallah et al., 1982; Andreasen et al., 1982; Weinberger & Wyatt, 1983). These findings, however, have varied considerably, perhaps reflecting the diversity in samples. The proportion of schizophrenic patients with ventricular size greater than 2 SDs above the mean of normal controls have ranged from 3% to 35% (Jernigan, 1986). In terms of psychopathology, patients with enlarged cerebral ventricles have been reported to have preponderant negative symptoms including poorer premorbid adjustment, greater neuropsychological deficits, more “soft” neurological signs, poorer response to neuroleptics, and increased incidence of drug-induced abnormal involuntary movements (Weinberger et al., 1980; Weinberger & Wyatt, 1983; Owens et al., 1985; Kaufman et al., 1986). With respect to the association of lateral ventricular size with Parkinsonism, Luchins et al. (1983) reported enlarged lateral ventricals in a group of neuroleptic-treated schizophrenic patients who required antiparkinson treatment. The authors suggested that the former is associated with heightened risk of drug-induced Parkinsonism. Hoffman et al. (1987) found a significant association between the severity of drug-induced Parkinsonism and ventricular brain ratio (VBR) in elderly chronic schizophrenic patients. Increased VBR was reported also in patients with idiopathic Parkinson’s disease (PD)(Steiner et al., 1985). Selby (1968) found a 75% incidence of


20


cortical (sulcal) atrophy and 30% ventricular enlargement in 250 Parkinsonian patients, compared with 27% and 24%, respectively, in 56 nonparkinsonian, control neurologic patients. He noted a “greater incidence of ventricular dilatation in the Parkinsonian patients with an impaired mental state.” Gath et al. (1975) found cortical atrophy in 47% and ventricular atrophy in 78% of their Parkinsonian patients. Neither study showed any significant correlation between duration of the Parkinsonian symptoms and either cortical or ventricular atrophy. Becker et al. (1976) found that more than half (53.4%) of their Parkinsonian patients had internal and external hydrocephalus. Ventricular dilatation was observed earlier than cortical atrophy, and cerebral atrophic changes generally seemed to increase with increasing age of the patients. There is increasing evidence that P D is a heterogenous disorder with distinct underlying anatomical, biochemical, pathological and pathophysiological mechanisms (Bermheimer et al., 1973; Barbeau & Porcher, 1982; Mortimer et al., 1982; Roy et al., 1983; Zetusky et al., 1985). Based on clinical and neuropsychological evaluation of 69 patients, Mortimer et al. (1982) proposed two clinical forms of PD: one with predominant bradykinesia and cognitive impairment, and the other with predominant tremor and relatively less functional impairment, more benign progression and relative intact intellectual functions. Jankovic (1987) considered tremor and rigidity as “positive” signs of PD which d o not specifically indicate a dysfunction of the basal ganglia. In contrast, postural instability and bradykinesia, the two “negative” signs, more specifically reflect a basal ganglia dysfunction. We found recently that neuroleptic-induced akathisia correlated with cortical atrophy on CT scan (Sandyk & Kay, in press b), while Parkinsonian tremor was associated with CT scan measures of diffuse cortical atrophy (Sandyk & Kay, in press d). Since the pathophysiology of Parkinsonian bradykinesia may be distinct from that of akathisia and tremor (Marsden & Jenner, 1980; Zetusky et al., 1985), we investigated its association with CT scan measures of cortical atrophy (prefrontal cortical atrophy and parieto-occipital atrophy) and subcortical atrophy (ventricular brain ratio, VBR) in neuroleptic-treated chronic schizophrenic patients. We predicted that bradykinesia would be associated with a different CT scan pattern of cerebral atrophy as compared to those observed in the cases of akathisia and tremor. Specifically, since bradykinesia seems to be characteristic of negative schizophrenia (Rifkin et al., 1975; Luchins et al., 1983; Hoffman et al., 1987), we predicted that it would be associated with enlarged VBR. METHODS The study was conducted in a research unit of a university affiliated state psychiatric hospital. The sample comprised 28 randomly selected chronic schizophrenic inpatients, which included 21 men and 7 women. The sample characteristics are summarized in Table 4. All patients met DSM-111 criteria of schizophrenia (American Psychiatric Association, 1980) as established by two independent research psychiatrists. There was no case of diagnostic disagreement between the raters. Patients with past history of serious head injury, recent history of alcohol or substance abuse, serious medical problems, diagnostable neurological disorders and mental retardation were excluded. Although the precise cumulative duration of neuroleptic treatment could not be established, all patients had received continuous neuroleptic treatment for longer than three years and were currently receiving neuroleptics and anticholinergic drugs. Parkinsonism was evaluated by two independent research psychiatrists according


21

TABLE 4 Sample characteristics ( N = 28)


Demographic Age (yrs) Onset of illness (yrs) Duration of illness since onset (yrs) Years of education Full Scale IQ (WAIS) Neuroradiological Ventricular brain ratio (VBR) (%)

Prefrontal cortical atrophy (PFCA) Parieto-occipital atrophy (POCA)

Mean (SD)

Range

31.3 19.7 11.6 11.8 83.0

21-47 12-29 1-25 10-13 67-1 13

(7.21) (4.40) (6.12) (0.87) (11.8)

6.79 (2.86)

2.23-13.40

1.02 (0.73) 0.94 (0.82)

0-2.00 0-2.50

to the Simpson and Angus (1970) Neurological Scale. Interrater reliability had previously been established in independent samples of patients on three separate occasions and was consistently found to be high (intraclass r = > .85 on each occasion). Severity of Parkinsonism was assessed by the mean score obtained in the four items rated on a five point scale (0 = absent, 4 = severe impairment) pertaining to tremor, bradykinesia, rigidity, and postural instability. The presence of Parkinsonism was defined by a mean score of one or greater. CT scans were obtained as part of an ongoing study of clinical and biological correlates of morphological brain abnormalities in patients with schizophrenia and affective disorders. All CT scan measurements were performed on a GE Model 7800 scanner. Fast scans (250 ms/slice) were taken in 10 mm steps starting on from parallel to the orbitomeatal line. VBR was measured on the slice in which the body of the lateral ventricles appeared largest, as according to the method of Synek and Reuben (1976) modified for use with computerized planimetry (Andreasen et al., 1982). Interrater reliability was determined previously in 18 schizophrenic patients and found to be high (intraclass r = .87). Cortical atrophy was assessed independently by two investigators and rated separately for prefrontal cortical atrophy (PFCA) and parieto-occipital atrophy (POCA), utilizing the method described by Shelton et al. (1988). PFCA was assessed on the part of the brain anterior to the Sylvian fissures on the scan that showed the foramina of Monro. POCA was evaluated on the third slice from the apex to avoid image distortion due to apical artifact that occurs on the higher scans. Findings were rated on a scale of 0-3 with half-point intervals, higher scores reflecting greater sulcal prominence. All CT scan measurements were performed by two independent research psychiatrists who were blind to the patient’s clinical data and ratings of Parkinsonism. The interrater reliability was higher for both measures (intraclass r = .95 and .97 for POCA and PFCA, respectively). RESULTS Of the 28 patients, 7 (25%) had Parkinsonism with moderate to severe bradykinesia. Independent t-tests indicated no significant associations between bradykinesia and the patient’s age, age at onset of psychiatric illness, chronicity of psychiatric illness, years of education, IQ and current neuroleptic and anticholinergic medication. In addition, there was no significant association of bradykinesia with sex (x’ = .66).


22

TABLE 5 Mean (SD) of neuroradiological measures in relation to bradykinesia Bradykinesia

Neuroradiological variables


Ventricular brain ratio (VBR)(%) Prefrontal cortical atrophy (PFCA) Parieto-occipital atrophy (POCA)

Independent 1-test (two-tailed)

Present (N = 7) Mean (SD)

Absent (N = 21) Mean (SD)

9.03(3.61)

6.00(2.14)

2.67*

I .3 l(0.70)

0.91(0.73)

1.29

1.28(0.85)

0.8 l(0.79)

1.28

The means (SD) of the neuroradiological measures for the group appear in Table 4, and these values in relation to bradykinesia are presented in Table 5. An indepen-

dent t-test, two-tailed, revealed that patients with bradykinesia had significantly greater VBR’s in comparison to those without bradykinesia (t = 2.67, p < .05). These groups did not differ significantly, however, with respect to the two measures of cortical atrophy (PFCA and POCA, respectively). DISCUSSION In this study we found a significant association between bradykinesia and VBR in neuroleptic-treated chronic schizophrenic patients with Parkinsonism. This observation could not be attributed to differences in patient’s age, age at onset of psychiatric illness, chronicity of psychiatric illness, years of education, IQ or neuroleptic and anticholinergic treatment. Our findings suggest, therefore, that the pathophysiology of Parkinsonian bradykinesia may be associated with the pathological process leading to enlargement of the cerebral ventricles in schizophrenia. It has been argued that schizophrenic patients with enlarged VBR represent a subgroup of patients whose core pathology may lie in the third ventricle-diencephalic region (Nieto & Escobar, 1972; Stevens 1982; Pandurangi et al., 1984; Lesch & Bogerts, 1984). Stevens (1982) found patchy primarily diencephalic, periventricular fibrillary gliosis in postmortem chronic schizophrenic patients, and suggested that destructive lesions in these areas may lead to enlargement of the lateral ventricles. Lesch and Bogerts (1984) found decreased thickness of the peri-third ventricular gray matter in chronic schizophrenics and suggested also that these lesions may cause enlargement of the ventricular system in some patients. The association of VBR with bradykinesia raises the possibility that its pathophysiology may be related primarily to damage of periventricular structures involving, among others, dopaminergic projections. Indeed, in patients with PD, enlarged VBR and mesial frontal atrophy have been related to mesocortical and mesolimbic dopaminergic degeneration (Javoy-Agid & Agid, 1980; Steiner et al., 1985). In a previous study, we have found that Parkinsonian tremor in schizophrenic patients was associated with CT scan measures of cortical atrophy, but not with VBR (Sandyk & Kay, in press d). The present findings suggest, therefore, that the motor symptom of Parkinsonism are related to different morphological pattern of cerebral atrophy and support the notion that Parkinsonism is a heterogenous disorder with



23

distinct underlying pathophysiological mechanisms (Zetusky et al., 1985). The results also may have implications for understanding the pathophysiology of negative schizophrenia and for newer treatment strategies. Several studies have suggested an association between large VBR and dopamine (DA) metabolism in schizophrenic patients. Van Kammen et al. (1983; 1986) and Nyback et al. (1984) found that cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) correlated negatively with VBR in drug-free chronic schizophrenic patients. Thus, enlarged VBR was associated with decreased DA metabolism, suggesting that it may predispose a subgroup of schizophrenic patients to develop Parkinsonism. The association of VBR with bradykinesia, which is the core feature of Parkinsonism, is not surprising in view of its intimate relationship with decreased striatal DA activity (Bernheimer et al., 1973). In a subset of chronic schizophrenics a large VBR has been associated with relatively poor prognosis, neuroleptic resistancy, greater degree of cognitive functions and preponderance of negative symptoms (Weinberger et al., 1980; Andreasen et al., 1982a; Weinberger & Wyatt, 1983; Andreasen, 1985; Carpenter et al., 1985). Several independent lines of evidence suggest that negative schizophrenia is related to decreased DA functions (MacKay, 1980; van Kammen et al., 1986; Weinberger, 1987): (a) CSF HVA is decreased in schizophrenics who are characterized by emotional blunting, poor premorbid social adjustment, and a schizoid personality (Bowers, 1974); (b) Neuroleptics, which block DA activity, frequently enhance negative symptoms (see Carpenter et al., 1985); (c) PD, which is characterized by decreased cerebral DA activity, is commonly associated with flat affect and other negative symptoms of schizophrenia (Alpert & Rush, 1983; Carpenter et al., 1985); (d) Postencephalitic TABLE 6 Comparison of Negative Schizophrenia with Parkinsonism Areas of study

Features in common

Symptoms

reduced motor activity blunted affect poverty of speech anhedonia intellectual impairment visuo-spatial deficits “soft neurological signs” extrapyramidal symptoms

Neurochemistry

reduced dopamine functions increased cholinergic activity

Endocrinology

glucose intolerance DST non-suppression

Pharmacology

neuroleptic resistancy response to dopaminergic drugs response to anticholinergics

Pathology

diencephalic, basal ganglia ? Lewy bodies

Radiology

Source: Sandyk & Kay (see above).

cortical atrophy ventricular enlargement


24


Parkinsonism leads to emotional deterioration and “psychic torpor” similar to that found in negative schizophrenia (Economo, 1931); and (e) DA agonists, such as L-dopa and amphetamines tend to improve negative symptoms (Gerlach & Luhdorf, 1975; Angrist et al., 1980; Alpert & Rush, 1983; Friedhoff, 1983; Desai et al., 1984). In addition, there is recent evidence that excessive cholinergic activity may underlie negative schizophrenia (Tandon & Greden, 1989). Since Parkinsonism is characterized by striatal DA underactivity and cholinergic overactivity (Jankovic, 1987), it appears from the above that negative schizophrenia may be a variant of Parkinsonism (Sandyk & Kay, see above; Sandyk & Kay, in press a)(Table 6). Our findings of a significant association between bradykinesia and enlarged VBR, which is a feature of negative schizophrenia (Weinberger & Wyatt, 1983; Andreasen, 1985), supports this hypothesis. We suggest, therefore, that neuroleptic refractory chronic schizophrenic patients with enlarged lateral ventricles and negative symptoms might be effectively treated with dopaminergic drugs, such as levodopa and bromocriptine, rather than with neuroleptics. Further, since deprenyl (a MAO-B inhibitor) may halt the progression of aging (Knoll et al., 1989) and PD (Tetrud & Langston, 1989), it might also be of benefit for the negative features of schizophrenia.

HABITUATION OF THE GLABELLAR TAP REFLEX AS A MARKER OF NEGATIVE SCHIZOPHRENIA Reduced facial expression and decreased blinking are among the early signs of Parkinson’s disease (PD)(Dening, 1987). In PD, the glabellar tap reflex characteristically fails to habituate. Whereas, in normal subjects, tapping on the glabella produces a blinking response that ceases after the first few taps, in Parkinsonian patients the blinking continues for as long as the stimulus is applied (Hall, 1945). It has been reported that the glabellar tap is positive in almost 100% of patients with PD (Pearce et al., 1968), characterizing it as an excellent marker. There is evidence that spontaneous blinking is connected with central dopaminergic activity (Karson, 1983). Animals given apomorphine or bromocriptine display increased spontaneous blinking, and neuroleptics, conversely, diminish the blink rate (Dening, 1987). Thus, reduced blink rate and failure of the glabellar tap reflex to habituate in Parkinsonism seem to reflect reduced striatal dopaminergic functions. It has been suggested that negative or deficit features of schizophrenia, such as flat affect and poverty of speech (Krawiecka et al., 1977), may constitute a neurolepticresistant aspect of the disorder associated with structural brain deficit (Crow, 1980), ventricular enlargement (Andreasen et al., 1982), and/or reduced dopaminergic functions (Mackay, 1980). More recently, on the basis of clinical, biochemical, pharmacological, neuroradiological, and pathological evidence, we have proposed that negative schizophrenia may in fact be a variant of Parkinsonism (see above). The following observations point to a clinical and biochemical overlap between negative schizophrenia and Parkinsonism: (a) the various features of negative schizophrenia (i.e., motor retardation, blunted affect, poverty of speech, anhedonia, cognitive deficit) are also characteristic of Parkinsonism (Alpert & Rush, 1983); (b) negative schizophrenia is associated with reduced central dopaminergic and noradrenergic functions (MacKay, 1980; van Kammen et al., 1986; Wise & Stein, 1973; Markianos & Tripodianakis, 1985) and increased cholinergic functions (Tandon &



25

Greden, 1989); (c) L-dopa and amphetamines tend to improve negative symptoms (Alpert & Rush, 1983; Friedhoff, 1983; Desai et al., 1984); (d) the basal ganglia have an unusual degree of involvement in diseases which resemble schizophrenia (Bowman & Lewis, 1980); and (e) there is an increased prevalence of Lewy body formation in schizophrenic patients with Parkinsonism (Woodard, 1962). Since, as discussed above, habituation of the glabellar tap reflex (positive glabellar tap) is a characteristic sign of Parkinsonism, we set out to investigate its relationship to the two major features of the negative syndrome described by Krawiecka et al. (1977) and Johnstone et al. (1978), namely, flat affect and poverty of speech as presented in neuroleptic-treated chronic schizophrenic patients. Based on our hypothesis, we predicted a significant association between positive glabellar tap and these features of negative schizophrenia.

METHODS The sample comprised 78 chronic schizophrenic patients (60 men, 18 women) of mean age 64.1 years (SD = 7.6)(range = 46-84), who were receiving treatment in a chronic psychiatric facility. The diagnosis of schizophrenia was established according to DSM-I11 criteria (American Psychiatric Association, 1980) by two independent research psychiatrists, for whom there was no case of diagnostic disagreement in this sample. All patients had undergone a continuous neuroleptic therapy for at least one year prior to assessment. Those with diagnosable neurological disorders or mental retardation and those currently treated with antidepressants on a lithium carbonate were excluded. Records of the patients were reviewed to determine the following demographic and treatment variables: age, sex, age at first hospitalization, duration of hospitalization since onset, age of first neuroleptic treatment, duration of neuroleptic treatment, average daily dosage of neuroleptics in chlorpromazine equivalents (CPZ-eq)(Davis, 1976) during the month prior to assessment, and presence or absence of anticholinergic treatment on the day of assessment. Flat affect was rated by two independent research psychiatrists using the Brief Psychiatric Rating Scale (BPRS)(Overall & Gorham, 1962). Poverty of speech was assessed on a scale of 0-10 as according to Waddington et al. (1987) on the basis of neuropsychological evaluation of the patients for cognitive functions. The interrater reliability for these two parameters was in the range of .92. The glabellar reflex was elicited independently by tapping between the eyebrows with the finger and looking for eyelid movements, avoiding a visual threat response, and asking the patient not to blink. Responses persisting after 10 taps were scored as abnormal. Interrate reliability has been previously established and found to be in the range of .85 (Mukherjee et al., 1982).

RESULTS Of the 78 patients, 12 (15.4%) had a positive glabellar tap response. As shown in Table 7, patients with a positive glabellar tap response did not differ significantly from those with a negative response on any of the demographic and treatment variables.


26

TABLE 7 Sample characteristics ( N = 78) Variables

Glabellar tap reflex Absent (N = 66) (Mean (SD)


Present ( N = 12) Mean (SD)

Independent t-test (two-tailed) f

Age (yrs)

65.4(7.72)

62.8(8.73)

1.05

Age at first hospitalization (Yrs)

28.0(5.76)

27.8(6.50)

.I1

Years of hospitalization

32.0(6.98)

30.9(7.65)

.54

Age of first neuroleptic treatment (Yrs)

30.0(6.38)

29.4(7.79)

.29

Duration of neuroleptic treatment (Yrs)

27.2(6.46)

26.2(6.71)

.49

Mean past month neuroleptic dosage (CPZ-eq)

172.0(135.7)

21 0.9(187.5)

.86

Current neuroleptic dosage (CPZ-eq)

130.4(104.4)

202.3(207.9)

1.82

Note: None of the 1-tests was significant.

TABLE 8 Mean (SD) of flat affect and poverty of speech in relation to the response of the glabellar tap reflex Negative symptoms

Fiat affect Poverty of speech

Glabellar tap reflex

Independent t-test (two-tailed)

Positive (n = 12) Mean (SD)

Negative ( N = 66) Mean (SD)

t

P

5.25(0.96) 5.08( I .08)

4.44(1.28) 3.85( 1.61)

2.54 3.33

< .02 < ,002

The glabellar tap response also was not associated with sex (x2 = .38) nor anticholinergic therapy (x’ = .01). The association of the glabellar tap response with the severity of flat affect and poverty of speech, analyzed by independent t-tests, two-tailed, is presented in Table 8. It can be seen that patients with positive glabellar tap response had significantly more severe symptoms of flat affect ( p < .02) and impoverished speech ( p < .002). In these respects, this group was more representative of negative schizophrenia. DISCUSSION As predicted, we found a significant association between positive glabellar tap reflex with severity of flat affect and poverty of speech. Thus, a positive glabellar tap reflex, which is a characteristic sign of Parkinsonism, could also be a useful clinical sign of negative schizophrenia. Insofar as patients with and those without positive glabellar



21

tap responses did not differ in neuroleptic and anticholinergic exposure or dose, their drug treatment could not account for the differences in the glabellar tap reflexes. Positive glabellar tap reflex is a clinically sensitive sign of Parkinsonism (Hall, 1945; Pearce et al., 1968), which is related to decreased striatal dipaminergic activity (Karson et al., 1981). Accordingly, the present findings support the notion that the pathophysiology of negative schizophrenia is associated with reduced dopaminergic functions (Chouinard &Jones, 1978; MacKay, 1980; Alpert & Friedhoff, 1982; van Kammen et al., 1986). This may explain the coexistence of both negative and Parkinsonian symptoms in the same patient and resolve the seeming paradox (Crow et al., 1976; Friedman & Lannon, 1989) that Parkinsonism (dopamine deficiency) prevails in schizophrenia (usually thought to reflect dopamine excess). In addition, prior observation in demented patients that positive glabellar tap reflex strongly correlates with CT scan measures of ventricular dilatation (Tweedy et al., 1982), which is a putative feature of negative schizophrenia (Weinberger et al., 1980; Andreasen et al., 1982), further intimates a pathophysiological relationship between negative schizophrenia and Parkinsonism. Thus, taken together, these findings provide added support for the concept that negative schizophrenia may be a variant of Parkinsonism (Sandyk & Kay, see above). This position is enhanced further by neuropathological studies that demonstrate neuronal loss and other degenerative changes in the basal ganglia of patients with schizophrenia (Stevens, 1982; Bogerts et al., 1985), and by the findings of Bowman and Lewis (1980), who observed an unusually high degree of basal ganglia disorders in patients presenting with schizophrenia-like symptoms. The glabellar tap reflex is considered, along with other “primitive reflexes” (i.e., head retraction, palmomental, snout, grasp), a sign of cortical disinhibition (Paulson & Gottleib, 1968; Tweedy et al., 1982; Sandyk et al., 1982). Elicitation of these reflexes requires only the participation of neuronal structures at the brainstem level or below, and it can be demonstrated in hydranencephalic infants without cerebral tissue above the basal ganglia (cf. Tweedy et al., 1982). In normal infants, these reflexes are most prominent in the neonatal period when the dendritic arbor and subcortical myelination are still incomplete. As these structures mature, these signs usually disappear. Damage of the cortex, subcortical white matter, or the basal ganglia can lead to the reappearance of these reflexes in adults (Tweedy et al., 1982). The emergence of these signs has been interpreted as a “release” effect, attributed to dissolution of cortical inhibition of brainstem activity (Jenkyn et al., 1977). In adults, these “primitive reflexes” have traditionally been associated with dementia (Jenkyn et al., 1977; Moylan & Saldias, 1979; Huber & Paulson, 1986; Keshavan & Yergani, 1987). Indeed, Pearce et al. (1968) found an 80% prevalence of positive glabellar tap reflex in patients with presenile dementia. There is increasing evidence that negative schizophrenia is associated with cognitive impairment. Computed tomographic (CT) scan studies have demonstrated in patients with a prominent negative syndrome a higher rate of structural brain abnormalities, which included ventricular enlargement, cortical atrophy, and cerebellar atrophy (Johnstone et al., 1976; Andreasen et al., 1982; Weinberger, 1984; Andreasen, 1985). Patients with prominent negative symptoms also tend to have impaired performance on various neuropsychological tests and lower educational achievement than do patients with prominent positive symptoms (Rieder et al., 1979); Opler et al., 1984). Thus, the association of positive glabellar tap, which reflects some degree of cortical damage, with features of negative schizophrenia adds to the data that implicates cerebral damage in the pathophysiology of the negative syndrome. The clinical and biochemical overlap of negative schizophrenia and Parkinsonism

28



is not only of theoretical interest, but also of potential therapeutic consequence. As indicated above, several studies have reported improvement of negative schizophrenia with dopaminergic drugs (Gerlach & Luhdorf, 1975; Alpert & Rush, 1983; Friedhoff, 1983; Desai et al., 1984). In addition, the recent studies demonstrating that LDeprenyl (a MAO-B inhibitor) may halt the progression of Parkinson’s disease (PD)(Birkmayer et al., 1985; Tetrud & Langston, 1989) and that adrenal medullary tissue transplantation may improve the motor symptoms of therapy resistant patients with PD (Madrazo et al., 987), lend hope that future management of therapy resistant negative schizophrenics would improve with further development of antiparkinsonian treatment. NEGATIVE SCHIZOPHRENIA AND THE COEXISTENCE OF PARKINSONISM AND TARDIVE DYSKINESIA Neuroleptic drug-induced Parkinsonism (DIP) and tardive dyskinesia (TD) are two iatrogenic movement disorders commonly seen in schizophrenia. DIP is an extrapyramidal syndrome that purportedly results from blockade of striatal dopamine receptors (Rajput et al., 1982). Prevalence estimates for DIP range from 5% to 50% of schizophrenic patients (Ayd, 1961; Sheppard & Merlis, 1967), with higher rates in elderly patients and in women (Ayd, 1961; Stephen & Williamson, 1984). Possible risk factors include history of previous extrapyramidal reactions, presence of organic brain damage and underlying idiopathic Parkinson’s disease (Holden et al., 1969; Donlon & Stenson, 1976; Rajput et al., 1982; Goetz, 1983; Luchins et al., 1983; Hoffman et al., 1987).TD is a hyperkinetic movement disorder thought to result from dopaminergic supersensitivity induced by chronic neuroleptic therapy (Klawans, 1973).It develops in about 30% of neuroleptic-treated chronic schizophrenicpatients (Kane et al., 1988) and is manifested usually later in the course of therapy. Several authors have reported that these two conditions can coexist in the same patient (DeFraites et al., 1977; Crane, 1971; Fann & Lake, 1974; Fahn & Mayeux, 1980; Richardson & Craig, 1982; Bitton & Melamed, 1984; Sandyk & Kay, in press f). Crane (1972) found that in a group of 180 psychiatric inpatients, 12.5% demonstrated both disorders, while Richardson and Craig (1982) found that both conditions coexisted in 17.4% of 132 psychiatric inpatients. Of the 86 patients demonstrating drug-induced neurological symptoms in the latter study, as many as 26.7% manifested Parkinsonism and TD simultaneously. Neuroleptic dosage, anticholinergic use, and antiparkinson medication did not differ significantlyamong those with TD alone, DIP alone, those who had both disorders, and those who exhibited neither disorder. These findings suggest that the occurrence of Parkinsonism and TD in the same patient may reflect an idiosyncratic response in susceptible individuals. The coexistence of Parkinsonism and TD seems paradoxical, since Parkinsonism is associated with decreased dopaminergic activity and TD with increased dopaminergic functions. Clinically, as well, it poses a serious dilemma, since pharmacological treatments that improve Parkinsonism, such as dopaminergic and anticholinergic drugs, may worsen TD, while those potentially beneficial for TD may aggravate Parkinsonism (DeFraites et al., 1977; Fann & Lake, 1974). At present, virtually nothing is known about the biological substrates that predispose some patients to manifest Parkinsonism and TD simultaneously. It has been suggested that their coexistence may result from the blockade of different dopaminergic pathways, with inhibition of nigro-striatal dopaminergic activity causing Parkinsonism and blockade of mesolimbic and mesocortical dopaminergic activity account-



29

ing for the development of TD (Bitton & Melamed, 1984). Others have proposed that blockade of different dopaminergic receptors (Costal1 & Naylor, 1981) or systems within the striatum (Gerlach, 1985) may account for the development of hypokinetic and hyperkinetic movement disorders in the same patient. However, the question as to why a particular subgroup of patients develops coexisting Parkinsonism and TD is not explained by these hypotheses. One possible clue to understanding the occurrence of these movement disorders comes from phenomenological studies of schizophrenia. There is evidence that negative symptoms may be a risk factor for DIP (Luchins et al., 1983; Hoffman et al., 1987; van Kammen et al., 1986; Sandyk & Kay, see above). By contrast, TD appears to be a feature of positive schizophrenia (Gureje, 1988; Sandyk & Kay, in press e; Sandyk & Kay, in press g). Since positive symptoms have been thought to reflect variable, “accessory” features of schizophrenia, while the negative syndrome represents the fundamental deficiency of the schizophrenic illness (Bleuler, 1911/ 1950), we predict that patients with coexisting Parkinsonism and T D will exhibit predominant negative symptoms. Thus, we postulate that negative schizophrenia may be a risk factor not only for the development of a pure Parkinsonian syndrome, but also for the emergence of coexisting Parkinsonism with TD. We therefore set out to examine the relationship of negative syndrome to pure Parkinsonism and to Parkinsonism coexisting with TD. METHODS The data were derived from a study conducted on a long-term unit of a state psychiatric hospital. The sample comprised 20 randomly selected neuroleptic-treated patients (10 men, 10 women) who met DSM-I11 criteria of schizophrenia (American Psychiatric Association, 1980). Patients with diagnosable neurological illnesses, organic mental disorders and mental retardation and those currently being treated with antidepressants or lithium salts were excluded. Records of the patients were reviewed to determine the following demographic and treatment variables: age, sex, age of first hospitalization, duration of hospitalization, duration of neuroleptic treatment, mean neuroleptic dosage over the month prior to assessment in chlorpromazine equivalents (CPZ-eq)(Davis, 1976), current neuroleptic dosage in CPZ-eq, and presence or absence of anticholinergic therapy on the day of assessment. All patients had received continuous neuroleptic therapy for the past year and were currently taking neuroleptics, with a proportion also receiving anticholinergics ( N = 5). The patients had a mean age of 62.8 years (SD = 8.5, range = 46-84), a mean age of first hospitalization of 27.4 years (SD = 6.4, range = 14-43) and a mean duration of hospitalization of 30.9 years (SD = 7.2, range = 8-49). The mean age of first neuroleptic therapy was 29.0 years (SD = 7.5, range = 14-52), and the mean duration of neuroleptic therapy was 26.7 years (SD = 6.3, range = 2.6-40). The mean past month neuroleptic dosage in CPZ-eq was 206.4mg (SD = 180.7mg, range = 10-900mg) and current neuroleptic dosage in CPZ-eq was 195.1mg (SD = 195.2mg, range = 10-1000mg). The patients were evaluated for the presence of Parkinsonism with a modified verison of the Simpson-Angus (1970) Scale for Extrapyramidal Effects. This was performed by the same rater, who was blind to each patient’s clinical data and medication history as well as to the research hypothesis. The interrater reliability has been previously established for this investigator and was found to be satisfactory


30


(intraclass r = .85)(Mukherjee et al., 1982). Severity of Parkinsonism was first assessed by the mean score obtained for the four items pertaining to tremor, bradykinesia, rigidity and postural instability, which were rated on a 5-point scale (0 = absent, 4 = severe impairment). The presence of Parkinsonism was defined by a mean score of more than one. T D was assessed on the Rockland T D Scale (Simpson et al., 1978) by two research psychiatrists for whom the interrater reliability had previously been established on independent samples of patients and found satisfactory (intraclass r = 35). A diagnosis of persistent T D was made according to Research Diagnoses for Tardive Dyskinesia criteria (RDTD; Schooler & Kane, 1982). To fulfil RDTD criteria for the diagnosis of TD, a patient was required to have abnormal involuntary movements of at least mild severity in two body areas, or else at least moderate severity in one body area for at least 3 months. Patients with dystonic movement were not included in the sample. In addition, to ensure sufficient neuroleptic exposure, they were required to have had a history of least one year of cumulative neuroleptic exposure. RDTD diagnoses were assigned following independent reviews of abnormal involuntary movements ratings and clinical records by two psychiatrists. There was no instance of diagnostic disagreement. Assessments of flat affect and poverty of speech were made independently on the Brief Psychiatric Rating Scale (BPRS)(Overall & Gorham, 1962) by two research psychiatrists who were blind to other measures and to the research hypothesis. Their interrater reliability on this scale was .90. These two items were taken as indices of negative schizophrenia, according to Crow (1980). Independent f-tests, two-tailed, were used in the analysis of continuous variables and chi-square analysis for the dichotomous variables. RESULTS Ten (50%) of the 20 patients had coexisting Parkinsonism and persistent TD, while the remaining patients had a pure Parkinsonian symdrome. As shown in Table 9, there were no significant differences on any of the demographic and treatment variables between the groups, including their global Parkinsonian scores and their neuroleptic and anticholinergic regimen. The only exception was that the patients with the pure Parkinsonian syndrome had a later age of initiating first neuroleptic therapy. The mean (SD) of flat affect and poverty of speech in relation to the presence of Parkinsonism and TD and Parkinsonism alone are summarized in Table 10. Independent t-test, two-tailed, revealed that patients with coexistent Parkinsonism and T D had significantly higher ratings of negative symptoms as compared to patients with a pure Parkinsonian syndrome. DISCUSSION As predicted, we found that patients with coexisting Parkinsonism and T D exhibited significantly more severe negative symptoms as compared to those who had a pure drug-induced Parkinsonian syndrome. Thus, negative schizophrenia may conceivably be a risk factor for the subgroup of patients who develop coexisting Parkinsonism and T D during neuroleptic therapy. Insofar as both groups of patients did not differ significantly with respect to any of the demographic and treatment variables, with the


31

TABLE 9 Sample characteristics as a function of Parkinsonism with and without tardive dyskinesia Parkinsonism + T D ( N = 10)

Parkinsonism ( N = 10)

Continuous Variables

Mean ( S D )

Mean (SD)

t

Age (yrs)

65.5(6.5)

66.5(8.3)

.30

Age at first hospitalization (yrs)

25.8(5.1)

29.9(6.9)

1.51

n.s.

Duration of hospitalization (yrs)

35.1(3.7)

32.0(7.3)

1.20

ns.

Age at first neuroleptic therapy (yrs)

26.7(4.5)

35.0(10.4)

2.32

< .05

Duration of neuroleptic therapy (yrs)

27.6(5.8)

29.4(3.4)

35

ns.

Mean past month neuroleptic dosage (CPZ-eq)

1 5 2 3 126.6)

218.0(225.5)

.80

ns.

Current neuroleptic dosage (CPZ-eq)

137.5(130.0)

222.0(295.6)

.83

ns.

Mean Parkinsonian score

1.62(.38)

1.57(.47)

.26

n.s.

Dichotomous variables

Percent

Percent

X2


Sample characteristics

Sex (male) Anticholinergic therapy

Statistical analysis

P ns.

P

70

30

3.20

< .I0

10.0

40

1.67

.I9

TABLE 10 Mean (SD) of flat affect and poverty of speech in relation to the Parkinsonian syndrome ~~~~~

Negative symptoms

Flat affect Poverty of speech

Parkinsonism + TD Mean (SD) ( N = 10) 5.80(.99) 5.75(.88)

~~

Parkinsonism Mean (SD) ( N = 10) 4.60( 1.07) 4.70(.94)

~

Independent 1-test (two- tailed) t

P

2.60 2.58

i .01

i .01

exception in age at first neuroleptic exposure, it seems unlikely that these variables accounted for our findings. Rather, it is possible that the Parkinsonism and TD may have predisposed patients to negative schizophrenia. Alternatively, it is possible that the combination of two severe movement disorders only made these patients appear more flat in affect and impoverished in speech. To our knowledge, this is the first study investigating the relationship of coexisting Parkinsonism and TD to negative


32


schizophrenia. In view of the relatively small size of the sample, our findings must be viewed as preliminary. We reported above a significant association of drug-induced Parkinsonism with negative schizophrenia. Similarly, Hoffman et al. (1987) found a significant relationship between increased ventricular brain ratio (VBR) on CT scan, drug-induced Parkinsonism, and negative symptoms of schizophrenia. Van Kammen et al. (1986) reported reduced cerebrospinal fluid (CSF) dopamine metabolites in drug-free schizophrenics with preponderant negative symptoms, and Tandon and Greden (1989) proposed that increased cholinergic activity may underlie the negative schizophrenic symptoms. Since decreased dopaminergic functions and increased cholinergic activity are known to be fundamental neurochemical features of Parkinsonism (Calne, 1970), we have proposed that negative schizophrenia may be a variant of Parkinsonism (see above), which thus accounts for its core deficit features. Alternatively, we have presented data to suggest that T D may be a feature of positive schizophrenia (Sandyk & Kay, in press e; Sandyk & Kay, in press g) and, as such could be viewed as an “accessory” motor symptom of the disease. Our present findings of a significant association of coexisting Parkinsonism and TD with negative symptoms highlights further the intimate association of Parkinsonism with the negative schizophrenic syndrome. There is evidence that Parkinsonism is associated with greater right, as opposed to left, hemispheric dysfunction (Proctor et al., 1964; ASSO,1969; De Lancy-Horne, 1971; Bowen et al., 1972; Horn, 1974; Bentin et al., 1981; Direnfeld et al., 1984). By contrast, TD may be associated with greater left hemispheric dysfunction (Waziri, 1980). These findings also suggest asymmetric vulnerability of the striatum to the dopamine blocking effects of neuroleptics (Waziri, 1980). Thus, while patients with a pure neuroleptic-induced Parkinsonian syndrome may have a greater right striatal and hemispheric dopaminergic dysfunction, those with coexisting Parkinsonism and T D may suffer a more extensive striatal damage associated with a global bihemispheric dysfunction, which reflects itself in greater severity of negative symptoms. As indicated above, patients with coexisting persistent Parkinsonism and TD may pose a therapeutic dilemma (Richardson & Craig, 1982). We suggest, based on our findings, that the primary approach to the management of these patients might include therapy of the Parkinsonian syndrome, which reflects the core motor symptom of the disorder and is associated with major functional disability. Consequently, their treatment would involve primarily antiparkinsonian drugs such as levodopa, anticholinergics, or agents with mixed dopaminergic, anticholinergic properties such as amantadine hydrochloride. The TD component of the syndrome may be viewed as an “accessory” motor symptom and, as such, to be managed only if it is associated with a major disability to the patient. In view of the observation that the majority of schizophrenic patients with T D are unaware of their involuntary movements (Alexopoulos, 1979; Rosen et al. 1982; Sandyk & Kay, in press f, and may not suffer major disability as a result of their TD, treatment of the involuntary movements should not be the primary goal in the management of patients with coexisting Parkinsonism and T D. THE EFFECTS OF ANTICHOLINERGIC THERAPY ON NEGATIVE SCHIZOPHRENIA Schizophrenia is generally considered as a heterogenous disorder characterized by psychotic symptoms, partial response to neuroleptics, chronic course, and a relatively



33

poor outcome (Andreasen, 1985). Current concepts suggest that schizophrenia includes two major syndromes, namely positive and negative schizophrenia (Andreasen, 1985; Crow, 1985). While positive symptoms are characterized by abnormal productions, such as delusions and hallucinations, negative symptoms include deficit symptoms such affective blunting, emotional withdrawal, impoverished thinking, passive social withdrawal and apathy. In addition, the negative presentation is associated with increased prevalence of extrapyramidal reactions and a relative poor response to neuroleptics (andreasen, 1985). Attempts to understand these apparently different profiles have led to suggestions that positive symptoms are associated with increased dopaminergic functions, while negative symptoms may be related to structural brain abnormalities (Andreasen, 1985; Crow, 1985). We have suggested recently that the covariation of negative and Parkinsonian symptoms may reflect their common pathophysiology and that negative schizophrenia may in fact be a variant of Parkinsonism (Sandyk & Kay, see above). Our hypothesis is supported by the observations that both conditions are associated with similar clinical symptomatology (i.e., blunted affect, motor retardation, cognitive dysfunction)(Alpert & Rush, 1983; Rifkin et al., 1979, decreased dopaminergic activity (MacKay, 1980; van Kammen et al., 1986) and increased cholinergic functions (Tandon & Greden, 1989; Hornykiewicz, 1982), favorable response to dopaminergic drugs (Alpert & Rush, 1983; Friedhoff, 1983; Gerlach & Luhdorf, 1975), computed tomographic (CT) scan evidence of cortical and subcortical atrophy (Andreasen, 1985), and common anatomic and pathologic sites of dysfunction (Stevens, 1982; Bogerts et al., 1985). If, indeed, negative schizophrenia shares common pathophysiological mechanisms with Parkinsonism, then one would predict that anticholinergics would improve negative symptoms. In addition, one would predict that schizophrenic patients who are treated with anticholinergics would display less severe negative symptoms as compared to those who are not treated with these agents. To test this possibility, we studied the effects of anticholinergics on the severity of negative schizophrenia using, as per Crow (1989, flat affect and poverty of speech as the main indicators of the syndrome. The study was conducted on a sample of 95 chronic schizophrenic inpatients (66 men; 19 women; mean age = 62.8 years, SD = 8.5; range = 46-84) who were hospitalized in a chronic psychiatric facility. The sample characteristics are summarized in Table 11. All patients met DSM-I11 criteria of schizophrenia (American Psychiatric Association, 1980) as established by two independent research psychiatrists, for whom there was no case of diagnostic disagreement in this sample. Patients with a past history of serious head injury, recent history of alcohol or substance abuse, mental retardation, and any diagnosable neurological disorder were excluded. In addition, patients were screened out if they were being currently treated with antidepressants or lithium salts. All patients had received continuous neuroleptic treatment for at least the past year. Records of the patients were reviewed to determine the following demographic and treatment variables: age, sex, age at first hospitalization, duration of hospitalization since onset, age at first neuroleptic treatment; duration of neuroleptic treatment; mean daily neuroleptic dosage during the past month prior to assessment in chlorpromazine equivalents; and presence or absence of anticholinergic treatment on the day of assessment. Assessment of flat affect was derived from the Brief Psychiatric Rating Scale (BPRS)(Overall & Gorham, 1962). Poverty of speech was assessed on a scale from 0-10 as according to Waddington et al. (1987) on the basis of a neuropsychological evaluation of the patients for cognitive functions. Both assessments were made


34

TABLE 11 Sample characteristics ( N = 85) Variable

Anticholinergic therapy



Independent f-test (two-tailed)

Absent ( N = 59) Mean (SD)

i

P

Age ( Y W

61.8(8.2)

63.6(8.4)

.93

n.s

Age at first hospitalization (yrs)

25.9(5.0)

28.2(6.8)

1.74

ns.


30.0(6.0)

31.6(7.6)

I .04

n.s.

Age at first neuroleptic treatment (yrs)

26.9(5.6)

30.0(8.0)

2.05

< .05

Duration of neuroleptic treatment (yrs)

22.6(4.9)

26.4(7.0)

2.87

< .10

Past month average neuroleptic dosage (CPZ-eq)

268.6(2 I 7.7)

172.6(150.3)

2.04

< .05

Current neuroleptic treatment (CPZ-eqj

269.0(252.3)

154.I( 150.0)

2.16

< .05

independently by two psychiatrists who demonstrated an interrater reliability in the range of .92. Of the 85 patients, 26 (31%) were currently taking anticholinergic drugs, such as trihexyphenidyl or benztropine mesylate, for the prophylaxis of neuroleptic-induced extrapyramidal reactions. Patients on anticholinergics did not differ significantly from those of anticholinergics with respect to age, age at onset of illness, and chronicity of psychiatric illness. There was a significant association of male sex with anticholinergics treatment (1’ = 10.78, p < .OOl), but not with negative symptoms. As shown in Table 11, those on anticholinergics also had begun neuroleptics at an earlier age, had a longer history of neuroleptic use, had greater neuroleptic exposure during the month prior to assessment, and were currently receiving significantly higher neuroleptic dosages. The association of present anticholinergic therapy with the severity of flat affect and poverty of speech, analyzed by independent t tests, two-tailed, is summarized in Table 12. It can be seen that, as predicted, patients on anticholinergics had significantly less TABLE 12 Mean (SD) of flat affect and poverty of speech in relation to anticholinergic therapy Anticholinergic therapy

Negative symptoms

Flat affect Poverty of speech


Absent ( N = 59) Mean (SD)

4.03(1.11j 3.53(1.39)

4.93( 1.29) 4.36(1.68)

Independent t-test (two-tailed) t

P

3.27 2.38

< ,002 < .02



35

severe symptoms of flat affect ( p < .002) and impoverished speech ( p < .02) as compared to those who were not taking anticholinergics. Insofar as the two groups did not differ with respect to age, age at onset of illness, and chronicity of psychiatric illness, these variables could not account for the differences in the severity of negative symptoms. According to some reports, neuroleptics may produce or exacerbate negative symptoms (Andreasen, 1985). Although patients who were taking anticholinergics had significantly greater neuroleptic exposure, they, nevertheless, displayed less severe negative symptoms. These findings suggest that increased cholinergic activity may underlie the pathophysiology of negative schizophrenia, thus supporting the theory of Tandon and Greden (1989). More direct experimental evidence from psychopharmacological manipulations is to be sought in future pursuit of this work. There is evidence that negative schizophrenia is associated with decreased cerebral dopaminergic activity (MacKay, 1980; Van Kammen et al., 1986). The present findings further implicate the role of cholinergic overactivity in negative schizophrenia. It is noteworthy that decreased dopaminergic and increased cholinergic activity are also major neurochemical features of Parkinson’s disease (Hornykiewicz, 1982), which supports our hypothesis that negative schizophrenia may be a variant of Parkinsonism (see above). On a pragmatic clinical level, the current observations suggest the testable proposition that patients with therapy resistant negative schizophrenia may benefit from the administration of dopaminergic and/or anticholinergic drugs. NEGATIVE SCHIZOPHRENIA AND SEBORRHEA: POSSIBLE ROLE OF HYPOTHALAMIC DYSFUNCTION IN THE PATHOPHYSIOLOGY OF THE NEGATIVE SYNDROME Positive and negative symptom dimensions of schizophrenia have figured prominently in current discussion on the pathogenesis and course of schizophrenia (Crow, 1985; Andreasen, 1985). Despite evidence in favor of this distinction (Andreasen, 1985), the neurochemical mechanisms underlying the positive-negative symptoms remain largely unknown. Crow (1980) and MacKay (1980) proposed that positive symptoms of schizophrenia are associated with increased dopaminergic functions. The pathophysiology of the negative symptoms, however, has been the subject of greater disagreement. Whereas Crow (1 980) related negative features to neurostructural impairment, MacKay (1980) thought that these reflect chronic dopaminergic underactivity. The latter concept is supported by the observations that some features of negative schizophrenia (e.g., blunted affect, poverty of speech and apathy) may be produced by neuroleptics (Andreasen, 1985), and that prolonged treatment with L-dopa and amphetamines was found to be effective in improving various negative symptoms (Alpert & Rush, 1983; Friedhoff, 1983; Angrist et al., 1980; Kay & Opler, 1985). In addition, several features of the negative syndrome, such as flat affect, emotional withdrawal, and loss of initiative, are found in patients with Parkinson’s disease (Alpert & Rush, 1983), which is characterized by decreased striatal dopaminergic activity. We have suggested above that negative schizophrenia may be a feature of Parkinsonism (Sandyk & Kay, see above). Seborrhea is a common clinical sign of Parkinson’s disease (Shuster et al., 1973; Burton et al., 1973; Flint, 1977), and the association of negative schizophrenia with Parkinsonism suggests that seborrhea may also be a feature of negative schizophrenia. We tested this hypothesis by investigating the


36

R. SANDYK A N D S . R . KAY

relationship of negative symptoms of schizophrenia (flat affect and poverty of speech)(Crow, 1985) to the presence of facial seborrhea in neuroleptic-treated chronic schizophrenic patients. We predicted that, in a sample of neuroleptic-treated chronic schizophrenic patients, those with seborrhea would demonstrate a more severe degree of negative features as compared to those without seborrhea. The sample consisted of 25 randomly selected chronic institutionalized elderly, female schizophrenic inpatients. Those with organic mental disorders and mental retardation as well as those treated with antidepressants on lithium salts were excluded from the study. The mean age of the sample was 62.6 years (SD = 8.5; range = 51-84); the mean age of first hospitalization was 31.8 years (SD = 8.3); the mean duration of hospitalization since onset of illness was 30.8 years (SD = 7.6); the mean neuroleptic dosage in chlorpromazine equivalents (CPZ-eq)(Davis, 1976) over the month prior to assessment was 149.3mg (SD = 102.9); and the mean current neuroleptic dosage in CPZ-eq was 147.0mg (SD = 116.2). All patients received continuous neuroleptic therapy for at least one year prior to assessment and a proportion ( N = 5) were currently treated with standard anticholinergic drugs. The diagnosis of schizophrenia was made according to DSM-111 criteria (American Psychiatric Association, 1980) by two independent research psychiatrists and was based on charge reviews and routine, semistructured clinical interviews. There was no case of diagnostic disagreement in this sample. Assessments of negative symptoms were made by two independent research psychiatrists. Evaluation of flat affect was derived from the Brief Psychiatric Rating Scale (BPRS)(Overall & Gorham, 1962). Poverty of speech was assessed on a scale from 0-10 according to Waddington et al. (1987) on the basis of a neuropsychological evaluation of the patients for cognitive functions. Interrater reliability was high (intraclass r = .92). Parkinsonism was evaluated using a modified version of the Simpson-Angus (1970) Scale for Extrapyramidal Effects by the same rater who was blind to the negative symptom ratings. Interrater reliability had been previously established and found to be satisfactory (intraclass r = .85)(Mukherjee et al., 1982). Severity of Parkinsonism was assessed by the mean score obtained on a five-point rating scale (0 = absent; 4 = severe impairment) for the four items pertaining to tremor, bradykinesia, rigidity, and postural instability. The presence of Parkinsonism was defined by a mean score of more than one. Presence of facial seborrhea was evaluated by two physicians who were blind to the clinical data and hypothesis of the study. There was no case of disagreement between the raters in this sample. Of the 25 patients, 9 (36%) had prominent facial seborrhea. With respect to sample characteristics, patients with seborrhea were significantly older ( t = 2.57, p < .01) and had longer duration of hospitalization ( t = 2.39, p < .025). Seborrhea was unrelated to current anticholinergic therapy (x’ = .05). The association of seborrhea with the severity of flat affect, poverty of speech, and Parkinsonism, analyzed by independent t tests, two-tailed, is presented in Table 13. It can be seen that patients with seborrhea had significantly more severe symptoms of flat affect ( p < .005) and impoverished speech ( p < .Ol), and they rated more than twice as high on Parkinsonian symptoms ( p < .lo). As predicted, we found a significant association of seborrhea with severity of flat affect and poverty of speech, while the results for Parkinsonism approached significance. Insofar as patients with and without seborrhea did not differ in neuroleptic and anticholinergic exposure or dose, their drug treatment could not account for the difference in the incidence of seborrhea. In addition, since there is no significant relationship between age, chronicity of illness and negative symptoms (Kay et al.,


37

TABLE 13 Mean (SD) of flat affect, poverty of speech and Parkinsonism in relation to seborrhea ( N = 25) Symptoms

Patients without seborrhea

Patients with seborrhea

Mean (SD) ( N = 16)

Mean (SD) ( N = 9)

Independent r-test (two-tailed) I

P


~~

Flat affect

3.11(0.92)

4.50(1.09)

3.39

< ,005

Poverty of speech

3.1 l(0.78)

4.37(1.36)

2.94

< .01

Parkinsonism

0.44(0.57)

0.98(0.75)

1.88

c .I0

1986), differences in age and duration of illness between the groups could not account for the greater severity of flat affect and poverty of speech in the patients with seborrhea. Rather, seborrhea is a feature of Parkinson’s disease (Shuster et al., 1973; Burton et al., 1973; Flint, 1977), which is related to decreased striatal and hypothalamic dopaminergic activity (Javoy-Agid et al., 1984), these findings support the notion that the pathophysiology of negative symptoms of schizophrenia is associated with reduced dopaminergic functions. In addition, these findings support the notion that negative schizophrenia may be a variant of Parkinsonism (see above). Finally, since seborrhea may be produced by a hypothalamic disease which leads to an overproduction of a “sebotrophic factor” (see Flint, 1977), our findings may support the notion that the pathophysiology of negative schizophrenia is associated with hypothalamic dysfunction (Sandyk & Kay, see above). FACIAL SEBORRHEA AND ITS RELATIONSHIP TO AGE AT ONSET AND THE PATHOGENESIS O F SCHIZOPHRENIA Facial seborrhea is a common accompanying feature of Parkinson’s disease, postencephalitic Parkinsonism, and drug-induced Parkinsonism (Burton & Shuster, 1970; Burton et al., 1973; Flint, 1977; Sandyk et al., in press). Although several studies have shown that the secretion of sebum in patients with Parkinson’s disease is significantly increased in comparison to control samples of similar age and sex (Kvorning, 1952; Grasset & Brun, 1959), the mechanisms underlying this phenomenon remain elusive (Flint, 1977). Testicular and adrenal androgens stimulate the sebaceous glands (Flint, 1977), but urinary excretion of 17-ketosteroids in Parkinsonian men was not different from that of either normal controls or controls with other neurologic disorders (Pochi et al., 1962). These findings suggest that factors other than androgens may contribute to the development of seborrhea in Parkinsonism. Serrati et al. (1938) observed that in postencephalitic Parkinsonism, the sebaceous secretion is increased, more so on the side corresponding to the brain lesion. This led him to conclude that the sebaceous glands are under autonomic control, with the parasympathetic system playing the major role. Krestin (1927) suggested that the excessive sebaceous gland secretion in postencephalitic Parkinsonism resulted from damage to centers connected with the autonomic nervous system in the region of the substantia nigra, or to the base of the third ventricle adjoining it. Bettley and Marten (1956) reported a case of temporal meningioma with fifth nerve and sympathetic damage that was associated with seborrheic dermatitis confined to the denervated


38


area. With recovery of the sympathetic lesion, the skin returned to normal. The authors concluded that the sympathetic lesion in the brainstem caused the seborrhea. Rothman, commented on the article of Pochi et al. (1962), that the best explanation is that hypothalamic disease leads to an overproduction of a “sebotrophic factor,” which would potentiate the action of androgens in these patients (cf. Flint, 1977). Indeed, pathological lesions in the hypothalamus have consistently been found in schizophrenia (Dide, 1934; Morgan & Gregory, 1935; Von Buttlar-Brentano, 1952; Nieto & Escobar, 1972; Stevens, 1982). While in rats beta-melanocyte stimulating hormone (beta-MSH) has been shown to be seborotrophic (cf. Shuster et al., 1973), the role of MSH peptides in the pathophysiology of human seborrhea requires further investigation (Sandyk, in press). Undoubtedly, the pituitary gland influences sebum secretion in man, since hypophysectomy reduces sebum secretion (cf. Sandyk, 1990). Pharmacologically, there is indication that seborrhea in Parkinson’s disease is related to decreased dopaminergic functions, since levodopa therapy decreases the severity of seborrhea (Burton & Shuster, 1970). Thus, dopamine may be involved in the inhibition of the hypothalamic “sebotrophic factor.” Since damage to the midbrain increases sebum production in rabbits (Perutz & Lustig, 1933), it is possible that dopaminergic neurons originating from the substantia nigra normally inhibit sebum production. In fact, Kizer et al. (1976) presented evidence for a nigral-hypothalamicmedian eminence dopaminergic pathways, which may be involved in the pathogenesis of endocrine abnormalities in Parkinson’s disease. The prevalence of seborrhea among patients with Parkinson’s disease is unknown. Burton and Shuster (1970) found a greater incidence of seborrhea among female Parkinsonian patients who had a more severe Parkinsonism. With respect to druginduced Parkinsonism in schizophrenic patients, there are presently no data pertaining to the incidence of seborrhea in these patients, although our clinical experience suggests that seborrhea is present in only a segment of these patients. A central question, therefore, is why does only a certain subpopulation of schizophrenic patients with drug-induced Parkinsonism develop seborrhea? Do these patients constitute a recognizable subgroup with specific unifying characteristics for which seborrhea may be an outward biological marker? Indeed, more fundamentally, is the presence of seborrhea in these patients related to the underlying schizophrenic illness? In a previous study (see above), we found that schizophrenic patients with seborrhea were characterized by more severe negative symptoms as compared to those without seborrhea. This suggested to us that the presence of seborrhea in neuroleptictreated schizophrenic patients may indicate a more deficit-ridden clinical profile which, according to the literature (cf. reviews by Pogue-Geile & Zubin, 1988; Kay, in press), is associated with more severe organic brain syndrome, poor premorbid history, poorer response to neuroleptics, and, in the chronic stage, a generally poorer outcome. To explore the significance of seborrhea in schizophrenic patients with druginduced Parkinsonism further, we investigated its association with historical, demographic, and treatment variables. In addition, we investigated whether patients with and without seborrhea differed with respect to the current severity of Parkinsonism and its major motor symptoms such as akinesia, rigidity, and tremor. Since cigarette smoking has been shown to reduce the risk of Parkinsonism (Baron, 1986), we also included this factor in our analysis. In view of the evidence that seborrhea is more likely to be found in female patients with Parkinson’s disease (Burton & Shuster, 1970), we chose to study only female schizophrenic patients. Based on the association of seborrhea with negative schizophrenia (see above), we hypothesized that patients with coexisting Parkinsonism and seborrhea might have not only a more ominous


39

outcome, but also an earlier age of onset of psychiatric illness as compared to those with Parkinsonism without seborrhea.


METHODS The sample comprised 37 randomly selected elderly, female schizophrenic patients with drug-induced Parkinsonism who were hospitalized in a long-term psychiatric facility, and met all study criteria of schizophrenia according to DSM-I11 criteria (American Psychiatric Association, 1980). All patients older than 45 years of age, and free of diagnosable neurological illness, organic mental disorders, and mental retardation were selected for the study. In addition, patients were excluded if they were being currently treated with antidepressants or lithium salts. The patients were evaluated with a modified version of the Simpson-Angus Scale for Extrapyramidal Effects (Simpson & Angus, 1970) by the same rater, who was blind to the study hypothesis. Interrater reliability on the scale has been previously established and found to be satisfactory (Mukherjee et al., 1982). Severity of Parkinsonism was assessed by the mean score obtained across the four items pertaining to tremor, bradykinesia, rigidity, and postural instability. Each item was rated according to a 5-point scale in which 0 = absent and 4 = severe impairment. The presence of Parkinsonism was defined by a mean score of one or greater. The presence of facial seborrhea was assessed independently by two staff psychiatrists who were blind to the Parkinsonian ratings and the historical and treatment data as well as to the research hypothesis. Patients were considered to have seborrhea only if they showed clear evidence of oily skin of the face that was unrelated to sweating. There was no case of disagreement between the raters on the presence or absence of seborrhea. Records of the patients were reviewed to determine the following demographic, historical, and treatment variables: age, age at onset of florid psychiatric symptoms, duration of hospitalization, age of first neuroleptic treatment, duration of neuroleptic treatment, current neuroleptic dose in chlorpromazine equivalents (CPZ-eq)(Davis, 1976), and presence or absence of anticholinergic treatment (e.g., benztropine mesyTABLE 14 Sample characteristics ( N

=

37)

Mean

S.D.

Range

Age (yrs)

66. I

10.8

46-92

Age at onset of psychiatric illness (yrs)

33.3

9.8

14-57

Duration of hospitalization (Yrs)

32.8

9.6

13-70

Age of first neuroleptic treatment (yrs)

38.5

12.5

19-91


24.0

8.8

0.5-40

Current neuroleptic dose (mg/d)

132.2

125.6

Variable

5-505

R.SANDYK AND S.R. KAY

40

late, trihexyphenidyl) on the day of assessment. These sample characteristics are summarized in Table 14.


RESULTS

In our sample of patients we found that 10 patients (27%) had coexisting Parkinsonism and seborrhea. Differences between the group with coexisting Parkinsonism and seborrhea and those with Parkinsonism alone were analyzed by independent t test, two-tailed, for the continuous variables and by chi-square test for the discrete variables. As shown in Table 15, there were no significant differences between the two groups on any of the demographic and treatment variables or with respect to cigarette smoking. In addition, the groups did not differ significantly in terms of the global TABLE 15 Comparison of neuroleptic-treated schizophrenic patients with Parkinsonism vs. coexisting Parkinsonism and seborrhea Sample characteristics

Parkinsonism (N = 27)

Parkinsonism + seborrhea ( N = 10)

Continuous variables

Mean (SD)

Mean (SD)

Age (yrs)

67.9(9.5)

63.5(9.3)

1.30

Age at onset of psychiatric illness (Yrd

35.4(10.3)

27.1(9.2)

2.28'


32.5(8.9)

36.4(15.5)

.95

Age of first neuroleptic treatment (yrs)

40.3(11.7)

38.I( 10.3)

.47


24.0t8.4)

27.0(7.4)

.89

Current neuroleptic dose (CPZ-eq) *

I 11.9(107.1)

207.5(171.O)

.07

Global Parkinsonian ratings

1.20(.62)

1.05(.53)

.63

Akinesia

1.78(1.19)

2.10(1.10)

.72

Rigidity

I .67(1.09)

1.22(.97)

1.11

Tremor

1.92(1.21)

l.SS(1.13)

.8 I

Dichotomous variables

Anticholinergic treatment Cigarette smoking

' p < 45.

Statistical analysis t

Percent

Percent

32.1

22.2

1.80

11.1

.75

3.5

x2


41

severity of Parkinsonism, including the major motor symptoms of the disease. The only significant group difference was in the age at onset of schizophrenia, which occurred earlier in the patients with coexisting Parkinsonism and seborrhea (see Table 15).


DISCUSSION As predicted, the present analysis revealed that female schizophrenic patients with drug-induced Parkinsonism and seborrhea were distinguished from those without seborrhea specifically on the basis of the age at onset of schizophrenia. Other historical and treatment variables such as age, duration of hospitalization, neuroleptic exposure, anticholinergic treatment, and history of cigarette smoking did not differentiate the groups. In addition, contrary to the findings in patients with Parkinson’s disease (Burton & Shuster, 1970), we found no significant differences between the seborreic and nonseborrheic patients in terms of the severity of Parkinsonism and its subsyndromes. To our knowledge, this is the first report suggesting that seborrhea may be a biological covariate of Parkinsonism in schizophrenia that is of significance for its timing of its onset; this, we believe, may shed important light on the pathogenesis of schizophrenia. Although several studies indicate similarities in the phenomenology, course, and treatment response between early and late-onset schizophrenia (Rother, 1955; Post, 1966; Eaton, 1985; Rabins et al., 1984), pharmacological and neuroradiological studies suggest that patients with early-onset schizophrenia are biologically distinct from others with the disease. For instance, MacKay et al. (1982) reported higher dopamine levels in the nucleus accumbens in patients with early-onset schizophrenia. Spokes et al. (1980) reported decreased gamma-aminobutyric acid (GABA) levels in the nucleus accumbens in cases of early-onset schizophrenia, and Arregui et al. (1979) found decreased angiotensin-converting enzyme activity in the substantia nigra of patients with young-onset schizophrenia. Rabins et al. (1978) found increased ventricle-to-brain ratio (VBR) in patients with late-onset schizophrenia as compared to normal controls. Since seborrhea may be related to hypothalamic damage, causing increased release of a pituitary “sebotrophic factor” (cf. Flint, 1977), our findings that seborrhea was present in schizophrenic patients with a significantly earlier age at onset of schizophrenia may indicate that hypothalamic dysfunction, which preceded or occurred at an early stage of the disease, may have predisposed these patients to develop seborrhea at a later age. These findings, therefore, raise the possibility that early versus lateonset schizophrenia may be distinguished also on the basis of hypothalamic dysfunction involving the regulatory systems which normally inhibit the development of seborrhea. Since levodopa diminishes the severity of seborrhea in patients with Parkinson’s disease (Burton & Shuster, 1970), it is possible that dopaminergic influences on hypothalamic centers which regulate sebum production may be specifically dysregulated in patients with early-onset schizophrenia. The significance of the hypothalamic dopaminergic system for schizophrenia is highlighted further by the findings that recent onset and chronic schizophrenics may differ with respect to the sensitivity of hypothalamic dopamine receptors (Meltzer et al., 1981). We recently reported a higher prevalence of PC in patients with early-onset schizophrenia as compared to those with onset at a later age (Sandyk & Kay, in press c) and suggested accordingly that disturbances in melatonin secretion, by reducing the protective effect of the pineal gland, could enhance the development of schizophrenia.


42


These findings may be relevant to the present study since there is evidence that melatonin may be involved in the pathogenesis of seborrhea. In experimental animals, beta-MSH is seborrotrophic (Shuster et al., 1972). Melatonin, by inhibiting pituitary beta-MSH release (Kastin et al., 1967), may act to suppress sebum production, and therefore decreased melatonin secretion could enhance the development of seborrhea. The observations that the incidence of seborrhea increases during puberty (cf. Flint, 1977), a period associated with decreased melatonin secretion (Silman et al., 1979; Waldhauser et al., 1986), seems to support this notion. It is, thus, possible that the presence of seborrhea in Parkinsonian schizophrenic patients with an earlier onset of the disease may reflect, in part, the result of disturbances in melatonin secretion which have occurred at an early phase of the disease. Our previous findings of an increased prevalence of PC in patients with early-onset schizophrenia (Sandyk & Kay, in press c) are congruent with the association of seborrhea with negative symptoms (see above) as well as the present observations of an increased prevalence of seborrhea in patients with early onset-schizophrenia. Taken together, these findings suggest that dysregulation of pineal-hypothalamic inferactions may characterize a subgroup of schizophrenic patients with Parkinsonism, negative symptoms and poor response to neuroleptics who, in addition, tend to manifest an early-onset of the disease. This hypothesis implies that dysregulation of pineal-hypothalamic functions that occurred at an early stage of the schizophrenic illness may underlie neuroleptic unresponsiveness in schizophrenia. Moreover, clinically, our findings suggest that the presence of seborrhea in neuroleptic-treated schizophrenic patients may be a biological marker of early onset of the disease, poor neuroleptic response, and generally poor prognosis. This hypothesis suggests that schizophrenics who develop seborrhea while on classic neuroleptics might be good candidates for clozapine or other atypical antipsychotics that have been shown to be efficacious for negative schizophrenic symptoms (Angst et al., 1989) or for patients who responded inadequately to classic neuroleptics. RELATIONSHIP OF THIRD VENTRICULAR WIDTH TO DRUGINDUCED PARKINSONISM: SUPPORT FOR THE ROLE OF THE HYPOTHALAMUS IN THE PATHOPHYSIOLOGY OF PARKINSON’S DISEASE Neuroleptic-induced Parkinsonism (DIP) is a common iatrogenic extrapyramidal syndrome thought to be caused from blockade of striatal dopamine receptors. There is increasing pathological and clinical evidence that underlying idiopathic Parkinson’s disease (PD) is a major risk factor for DIP (Rajput et al., 1982; Goetz, 1983). In addition, cognitive studies demonstrate that patients with DIP perform poorly on the same general subsets of psychometric tests (i.e., visual-motor) identified as deficient in PD (Hoffman et al., 1987). It is conceivable, therefore, that DIP and PD share common pathophysiological mechanisms and that investigations pertaining to DIP may be applicable also to PD. Despite intensive research, the pathophysiology of PD remains unknown. While degeneration of the nitrostriatal dopaminergic neurons is the neuropathological hallmark of the disease, there is no convincing evidence that the nitrostriatal system is the primary locus of pathology. On the contrary, we have suggested recently, that primary hypothalamic damage leading to impaired neuropeptidergic modulation of the striatum may be implicated in the pathophsyiology of PD (Sandyk & Iacono,



43

1986; Sandyk et al., 1987; Sandyk, 1988; Sandyk, 1989). Several lines of evidence support this position: (a) Beginning with Lewy (1923), a number of investigators have noted pathological changes in the hypothalamus in PD (Forno, 1966; de Hartog Jager & Bethlem, 1960; Ohama & Ikuta, 1976; Langston & Forno, 1978). Langston and Forno (1978) examined systematically the hypothalamus of 30 patients and observed nerve cell degeneration in each case. Of the 13 hypothalamic nuclei that could be individually identified, none were exempt from Lewy body degeneration. This was identified also in cases of postencephalitic Parkinsonism (Langston & Fonno, 1978) and in psychiatric patients who manifested Parkinsonian symptoms (Woodard, 1962). In addition, the hypothalamus is one of the major subcortical structures affected in von Economo’s encephalitis which leads to the development of Parkinsonism. (b) Autonomic impairment indicates the possibility of abnormal hypothalamic functions in PD. Gross et al. (1972) have demonstrated postural hypotension in patients with PD, and they concluded that the autonomic defect is central. Impaired peripheral vasodilatation (Appenzeller & Gross, 1971) and deficient sudomotor function (Appezeller & Gross, 1971) in response to heat have also been demonstrated in Parkinsonian patients. These findings could be explained on the basis of abnormal central regulation of temperature (Appenzeller & Gross, 1971), possibly at the hypothalamic level. Posterior hypothalamic damage may account for the apparent susceptibility of Parkinsonian patients to accidental hypothermia (Gubbay & Barwick, 1966), since the posterior hypothalamus is responsible for correcting body temperature when it drops below normal (Myers, 1969). (c) Endocrine studies provide additional evidence for hypothalamic involvement in PD. Lipman et al. (1974) found a 52.4% incidence of abnormal glucose tolerance in patients with PD and speculated that “hypothalamic involvement might be logically suspected as explaining the abnormal glucose metabolism in these cases.” Impaired glucose metabolism has also been suggested to increase the risk of Parkinsonism (Sandyk et al., in press h). Impairment of growth hormone release in response L-dopa administration (Malarkey et al., 1974) also might reflect hypothalamic deficit in PD. A final endocrine abnormality that might be related to hypothalamic damage in P D is the marked elevation of alpha-melanocyte stimulating hormone (MSH) in the hypothalamus (Pique et al., 1985) and cerebrospinal fluid (CSF)(Rainero et al., 1988) of patients with PD. (d) Postmortem biochemical studies found decreased dopamine and norepinephrine levels in the hypothalamus of patients with P D (Javoy-Agid et al., 1984; Ehringer & Hornykiewicz, 1960). To investigate further the role of hypothalamic dysfunction in the pathophysiology of Parkinsonism, we conducted a computerized tomographic (CT) scan study in 14 schizophrenic patients with DIP to ascertain the relationship of Parkinsonism to third ventricle width (TVW). Since the anterior hypothalamus surrounds the base of the third ventricle (Barr, 1979), its dilatation on CT scan could be a radiological marker of hypothalamic damage. In addition, since TVW correlates with reduced CSF dopamine metabolites in schizophrenic patients (Houston et al., 1986), third ventricle dilatation may indicate the presence of reduced dopaminergic functions which characterize the Parkinsonian syndrome. METHODS The study was conducted on a research unit of a state +ychiatric hospital. The sample


44

R. SANDYK AND S.R.KAY

comprised 14 schizophrenic patients who had been consecutively admitted to the research unit. All patients were medically healthy, and those with a history of serious head injury, or a recent history of substance abuse or dependence (i.e., within the past 6 months) were excluded from the study. All patients had received continuous neuroleptic therapy for the past three years and were currently treated with typical neuroleptics. The patients had a mean age of 33.6 years (SD = 7.6; range = 23-50), a mean age at onset of illness of 21.6 years (SD = 4.8; range = 12-29), a mean duration of illness of 12.0 years (SD = 7.4; range = 2-25), a mean duration of formal education of 11.7 years (SD = .80; range = 10-13), and a mean WAIS Full Scale IQ of 79.9 (SD = 10; range = 69-95). There were 9 men and 5 women, with no significant difference between the sexes on any of the foregoing sample characteristics. A diagnosis of schizophrenia was established according to DSM-I11 criteria (American Psychiatric Association, 1980) by two research psychiatrists, for whom there was no case of diagnostic disagreement in this sample. The patients were evaluated for the presence of Parkinsonism with a modified version of the Simpson-Angus (1970) Scale. This was performed by two raters, who were blind to the patient’s clinical data and medication history as well as to the research hypothesis. The interrator reliability had previously been established in independent samples of patients on three separate occasions and was consistently found to be satisfactory (intraclass r > .85 on each occasion). Severity of Parkinsonism was first assessed by the mean score obtained on the four items pertaining to tremor, akinesia, rigidity, and postural instability, which were rated on a 5-point scale (0 = absent, 4 = severe impairment). The presence of Parkinsonism was defined by a mean score of more than one. CT scans were obtained as part of an ongoing study of clinical and biological correlates of morphological brain abnormalities in patients with schizophrenia. CT scan measurements were performed on a GE Model 7800 scanner. Fast scans (250 ms/ slice) were taken in 10 mm steps starting from parallel to the orbitomeatal line. TVW was measured using a magnifying ruler (Standlupe Desk Magnifier), with a 10 x magnification, on the slice below that showing the foramina of Monro. Third ventricle size was measured at its greatest width to the nearest tenth of a millimeter. This was performed by two independent researchers who were blind to the patient’s clinical data and hypothesis of the study. Interrater reliability on TVW measurements was high (intraclass r = .96).

RESULTS The mean of TVW was 3.9mm (SD = 1.40; range = 2.3-8.1). TVW was unrelated to any of the foregoing demographic variables including sex. The distribution of TVW in the sample is summarized in Table 16. While in nonparkinsonian schizophrenics (Dewan et al., 1983) only 4% had a TVW greater than 3 mm, in our sample 5 patients (35.7%) had TVW greater than 3 mm, 5 patients (35.7%) had TVW greater than 4mm and one patient (7.1%) had TVW greater than 8 mm. Thus, 78.5% of the sample had TVW that is atypical in size for a schizophrenic population without Parkinsonism ( > 95th percentile). The relationship of TVW to the Parkinsonian symptoms is summarized in Table 17. As can be seen, TVW correlated significantly with akinesia ( p < .01) and rigidity ( p < .05), but not with tremor or postural instability. These findings implicate third ventricular dilatation in specific facets of drug-induced Parkinsonism.


45

TABLE 16 Distribution of TVW in 14 schizophrenic patients with drug-induced Parkinsonism ( N = 14) TVW (size in mm)

N


> 2mm >3mm >4mm > 5mm > 6mm >7mm > 8mm

TABLE 17 Pearson correlations ( r ) between third ventricle width and Parkinsonian symptoms Parkinsonian symptoms Akinesia Rigidity Tremor Postural instability

Pearson r with third ventricle width .59**

.45'

- .36

- .04

*p < .05. **p < .01.

DISCUSSION The present work indicated significant correlations between TVW and the severity of akinesia and rigidity in schizophrenic patients with DIP. By contrast, TVW was unrelated to tremor and postural instability, supporting the notion that Parkinsonism is a heterogenous disorder with more than one underlying pathophysiological mechanism (Zetusky et al., 1985). Since TVW may indicate degeneration of hypothalamic tissue (Cannon et al., 1988), these findings seem to implicate hypothalamic damage in the pathophysiology of Parkinsonism (Sandyk et al., 1987; Sandyk & Iacono, 1986; Sandyk, 1988; Sandyk, 1989). The correlation between TVW, which has been associated with reduced CSF dopamine metabolites (Houston et al., 1986) and akinesia and rigidity but not with tremor and postural instability, are in accord with postmortem neurochemical studies that link reduced striatal dopamine levels with akinesia and rigidity in patients with PD (Bernheimer et al., 1973). By contrast, tremor has been unrelated to lesions of the substantia nigra (Stern, 1966) and to decreased dopamine levels in the neostriatum (Bernheimer et al., 1973). The pathophysiology of postural instability in PD is unknown, but it is likely to result from more extensive degeneration of basal ganglia and brainstem motor nuclei (see Reichert et al., 1982). Prior studies in experimental animals suggest that hypothalamic damage may be implicated in the pathophysiology of Parkinsonism. Reduction in spontaneous locomotor activity, similar to Parkinsonian akinesia, has been shown to follow hypothalamic lesions. Destructive lesions at the level of the dorsomedial nuclei and periventricular system of the hypothalamus tended to decrease spontaneous locomotor activity without affecting the alertness of the rats (Poirier, 1971). Bilateral electrolytic lesions of the ascending dopaminergice fibers in the lateral hypothalamus produced akinesia accompanied by mild catalepsy in rats (Costal1& Taylor, 1973). Butterworth


46


et al. (1977) produced hypokinesia by anterolateral hypothalamic 6-hydroxydopamine lesions in rats. The hypokinesia was reversed by administration of dopamine receptor agonists, suggesting that interruption of hypothalamic dopaminergic functions may be implicated in the pathophysiology of Parkinsonian akinesia. The clinical observation of a higher prevalence of autonomic disturbances in bradykinetic versus nonbradykinetic Parkinsonian patients (Spiegel et al., 1968) supports involvement of the hypothalamus in the pathophysiology of Parkinsonian akinesia. The mechanisms by which hypothalamic damage may contribute to the pathophysiology of Parkinsonism are complex and not entirely understood. Elsewhere we have discussed the potential impact of hypothalamic damage on striatal dopaminergic activity (see Sandyk & Iacono, 1986; Sandyk et al., 1987; Sandyk, 1989). Damage to the lateral hypothalamus in animals results in changes in feeding, drinking, and motor behavior and in sensory and orienting functions equivalent to an akinetic state. These changes were initially attributed to direct damage to hypothalamic nuclei, but further studies demonstrated that the same behavioral deficits can be caused by unilateral or bilateral injections of 6-hydroxydopamine into either the substantia nigra, the ventral tegmentum, the nigrostriatal tract, within the medial forebrain bundle, or the far lateral hypothalamus (Ungerstedt, 1970; 1971; Marshall et al., 1974). In addition, these deficits, which have been attributed to akinesia, can be reversed by apomorphine, a direct dopamine agonist (Ungerstedt, 1976). The foregoing observations were supported anatomically with the discovery in the rat, initially by Lindvall et al. (1974), of two dopaminergic nigrocortical projections. One originates in the pars compacta of the substantia nigra (Area A8, 9), courses through the medial forebrain bundle, and ultimately ends in the anterior cingulate gyrus. The other projection originates in the area tegmentum ventralis of the nigral complex (AlO), courses through the medial forebrain bundle, and ends in the frontal cortex. Both of these projections have been observed in primates and exist also in man (Baldessarini et al., 1979). According to Ross and Stewart (1981) and Berger et al. (1985) damage to the lateral hypothalamus that is direct or indirect (through mechanical pressure such as seen with hydrocephalus) can cause akinesia by disrupting the activity of these projections. Support for this hypothesis comes from the demonstration that experimental hydrocephalus in rabbits causes a reduction of dopamine release in both the cerebral cortex and caudate nucleus (Miwa et al., 1982). In addition, important dopaminergic cell bodies with projections to the cerebral cortex may also exist in hypothalamic areas such as the group A13 lying dorsomedial and dorsal to the nucleus dorsomedialis hypothalami (Fuxe et al., 1974). It is likely that damage to these intrahypothalamic dopaminergic projections to the cortex may contribute also to the pathophysiology of Parkinsonism. Parkinsonian akinesia has been attributed to reduced nigrostriatal dopaminergic activity (Kanazawa, 1986). In addition, there is also evidence that reduced dopaminergic activity in the nucleus accumbens, the recipient of dopaminergic fibres from the ventral tegmenal area, is involved in the pathophysiology of akinesia (Javoy-Agid & Agid, 1980; Morris et al., 1989). Thus, damage to both nigrostriatal and mesolimbic dopaminergic pathways may contribute to the development of akinesia in PD and DIP (Kanazawa, 1986). Hypothalamic damage, by disrupting nigrocortical dopamine projections coursing through the lateral hypothalamus, may impair both nigrostriatal and mesolimbic dopaminergic activity and thus contribute to the development of Parkinsonism. We caution that our study included only 14 patients and that replications is required to confirm the association of TVW with DIP. Also, our study did not assess


47

the relationship of neuroleptic treatment to DIP and TVW, a factor that may be of significance in the interpretation of the relationship of third ventricular size to DIP.


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Is negative schizophrenia a variant of parkinsonism?

Akinesia: a syndrome common to parkinsonism, retarded depression, and negative symptoms of schizophrenia.

Insight in schizophrenia: relationship to positive, negative and neurocognitive dimensions.

The relationship between parkinsonism and tardive dyskinesia.

The relationship between ABO blood groups and schizophrenia. A report of negative findings.

The relationship of the vampire legend to schizophrenia.

Relationship between symptoms rated with the Positive and Negative Syndrome Scale and brain measures in schizophrenia.

Bromocriptine for "negative" schizophrenia.

Positive and negative symptoms of schizophrenia. Their course and relationship over time.

Positive and negative symptoms. Relation to familial transmission of schizophrenia.

Relationship between negative symptoms and neurocognitive functions in adolescent and adult patients with first-episode schizophrenia.

Naltrexone in chronic negative schizophrenia.

Heterogeneity of schizophrenia: relationship to latency of neuroleptic response.

The relationship between Positive and Negative Syndrome Scale (PANSS) schizophrenia severity scores and risk for hospitalization: an analysis of the CATIE Schizophrenia Trial.

Stability of negative symptoms of schizophrenia.

The new challenge in identifying the negative syndrome of schizophrenia.

Pharmacological treatment of negative symptoms in schizophrenia.

Tackling negative symptoms of schizophrenia with memantine.

Schizophrenia drug gets negative results for negative symptoms.

Olfactory acuity in the positive and negative syndromes of schizophrenia.

Primitive drive-dominated thinking: relationship to acute schizophrenia and sociopathy.

Relationship of maternal to neonatal colonization with coagulase-negative staphylococci.

The current conceptualization of negative symptoms in schizophrenia.

Pineal calcification and its relationship to hallucinations in schizophrenia.