1998 Martin Dunitz Ltd
InternationalJournal of psychiatry in Clinical Practice 1998 Volume 2 Pages 19-26
19
The serotonin paradox: Negative symptoms and SSRI augmentation
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DANIELE ZULLINO, GUIDO BONDOLFI AND PIERRE BAUMANN University Department of Adult Psychiatry, Biochemistry and Clinical Psychopharmacology Unit, Lausanne, Switzerland
Correspondence Address Daniele Zullino, MD, Dtpartement Universitaire de Psychiatrie Adulte, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland Tel: +41 21 643 64 04 F a : +41 21 643 64 69 E-mail: [email protected]
Received 19 June 1997; revised 18 November 1997; accepted for publication 23 November 1997
Negative symptoms of schizophrenia are often difficult to treat and may be associated with poorer long-term outcome. As depressive and negative symptoms show some overlap, augmentation of neuroleptics by antidepressants has repeatedly been investigatedfor efficacy against negative symptoms in schizophrenic patients. Studies on SSRI augmentation of neuroleptic medication reveal some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRls. Since no correlation could be found between improvement of negative symptoms on the one hand and positive, depressive or extrapyramidal motor symptoms on the other, a direct effect seems likely. SSRls may therefore be un alternative to clozapine, especially in patients for whom there are contraindicationsagainst clozapine treatment. As yet, there is 110 convincing rationalization for the paradox that both serotonergic and antiserotonergic substances, e.g. atypical antipsychotics, may improve negative symptoms. (Int J Psych Clin Pract 1998; 2: 19- 26)
Keywords selective serotonin re-uptake inhibitors antipsychotics combination treatment negative symptoms schizophrenia
chizophrenia is the ninth leading cause of disability in the world and the most costly psychiatric disorder,’ negative symptoms being one of the most debilitating aspects of this condition. Positive symptoms such as hallucinations, delusions and bizarre thoughts respond to treatment with standard antipsychotic drugs in a great proportion of patients. Negative symptoms, such as blunted affect, narrowing of ideation, alogia, anhedonia, avolition and social and emotional withdrawal are often difficult to treat and associated with poorer long-term outcome.2 Clozapine, an agent with low Dz receptor affinity, but higher 5HTzNc affinity, compared to standard neuroleptics, is often effective in the treatment of previously neuroleptic refractory patient^.^ The advantage of clozapine is, however, limited by the risk of agranulocytosi~.~*~
S
THE RATIONALE FOR SSRI AUGMENTATION IN (REFRACTORY) SCHIZOPHRENIA WITH NEGATIVE SYMPTOMS As depressive and negative symptoms such as anhedonia, lack of interest, motor retardation and social withdrawal
show some overlap, it may be difficult to distinguish these two syndromal dirnensiom6 They seem, however, to represent two different dimensions of psychopathoIogy with different time courses.’ Because of the similarities between negative and depressive symptoms in schizophrenic patients and the success of antidepressants in the treatment of depressive symptoms in schizophrenic disorders:’ combinations of neuroleptics with antidepressants of the tricyclic type (TCA) have also been evaluated in the treatment of negative syndromes, and found to be effective.”.” Selectiveserotonin re-uptake inhibitors (SSRIs) are safer and better tolerated than TCAs,” which is an important feature when considering the already high side-effect burden of neuroleptic treatment. A second reason for testing SSRIs as a treatment in schizophrenia is the socalled ‘serotonin hypothesis’. One of the earliest biochemical hypotheses was based on the observation of symptoms occurring during intoxication with lysergic acid diethylamide (ISD), such as distorted perception, derealization, depersonalization and possible hallucinations: symptoms clearly similar to those of schizophrenia. As LSD was found to act on the serotonergic system, partly as agonist, partly as antagonist, schizophrenic symptoms have been considered to be related, at least
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D Zullino et al
partly, to serotonergic dysfun~tion.’~ Furthermore, the 2. serotonergic dysfunction may be involved in the selective 5HTu-receptor blocker ritanserin was found to pathophysiology of schizophrenic psychoses; and counteract the psychotic effects of LSD, substantiating 3. serotonergic lesions may contribute to the occurrence of the serotonin appr~ach.’~ schizophrenic psychopathology, either directly, or After the introduction of dopamine antagonists in the indirectly via alterations in the dopaminergic system. 1950s the serotonin hypothesis of schizophrenia became progressively neglected. However, interest in serotonin SSRI AUGMENTATION OF CLASSICAL function in schizophrenia, and especially in negative NEUROLEPTIC TREATMENT symptomatology, has been restimulated by the efficacy Controlled studies and widespread use of clozapine in the treatment of To our knowledge, five controlled studies of the effect of patients with previously refractory schizophrenia.’ Clozathe addition of SSRIs to current. treatment with classic pine has been shown to be a 5HTmc-receptor neuroleptic agents have been published (Table 1). antagonist, but serotonin - dopamine interactions may In a double-blind study of 30 chronic schizophrenic be essential for its efficacy.” The relationship between patients (DSM-111-R), selected for their predominantly strong 5HT2and weak D2affinities has been shown to be negative symptomatology, Silver and Nassal15 added related to the therapeutic profile of the so-called fluvoxamine (up to 100 mg/day) to a fixed dose of ‘atypical’ antipsychotics,” i.e. antipsychotic agents with little induction of extrapyramidal side-effects (EPS). antipsychotic medication. After 5 weeks of combined Several new drugs with similar receptor-binding profiles, treatment, the fluvoxamine was reduced to 50 mg and then stopped. The total scores on the Scale for the including risperidone, sertindole and olanzapine, have Assessment of Negative Symptoms (SANS) improved, been introduced and shown to have similar efficacy in significantly more in the fluvoxamine group, and relieving negative and/or depressive symptoms in improvement persisted one week after fluvoxamine schizophrenia.16-23 While 5HTlA-autoreceptorsinhibit the release of 5HT, withdrawal. Significantly greater improvements in the active group were seen for affective blunting and for and have therefore been proposed to be related to alogia factors. There was no evidence of exacerbation of reduction of anxiety and aggression, other post-synaptic positive symptoms, as recorded by the Scale for the 5HT1 receptors have excitatory effects on hypothalamic- pituitary adrenal function. 5HTlD receptors act as Assessment of Positive Symptoms (SAPS). No significant difference between active and control groups was noted autoreceptors, inhibiting the release of 5HT, and could in regard to depressive features or EPS. Hence the be related to the pathophysiology of migraine. The 5HTa and 5HT3 receptors are post-synaptic, mainly authors deduced that improvement of negative symptoms could not be due to improvement in depressive or located in the frontal cortex and caudate nucleus, and features. have been associated with psychotic p h e n ~ m e n a . ’ ~ . ~extrapyramidal ~ In a randomized double-blind placebo-controIled study, Ritanserin, a selective 5HTu-receptor blocking agent, neuroleptic doses measured by chlorpromazine equivalents has antipsychotic activity and may improve extrapyrwere similar in both groups. Spina et a126investigated the amidal symptoms. effect of adding fluoxetine 20 mg/day on negative While positive symptoms are correlated with hypersymptoms in 34 chronic schizophrenic (DSM-111-R) function of the dopamine system, diminished dopaminergic inpatients receiving maintenance therapy with neuroneurotransmission in mesocortical projections from the leptics (haloperidol, fluphenazine, thioridazine, chlorventral tegmental area may be responsible for negative promazine, clotiapin). Patients with a Hamilton symptoms. This would also explain secondary negative (HAM-D) score 2 2 0 were not Depression Rating symptoms resulting from antidopaminergic neuroleptic 12 weeks of treatment, negative sympincluded. After treatment. A9 and A10 dopamine effects are counteracted toms (SANS) were significantly improved in the by serotonergic effects transmitted through the 5HTu in the placebo group. fluoxetine-treated patients, but not receptor, although this effect is less certain at some A10 Improvement was evident in affective flattening, alogia, cortical terminals. As reviewed by Iqbal and van Praag,13 there are many avolition and anhedonia, but not in impairment of attention. There was no evidence of any influence of inconsistencies between studies investigating the involfluoxetine on positive schizophrenic symptoms, but the vement of serotonin in schizophrenia and the mechanpatients had been selected specifically for predominantly ism of action of antipsychotic drugs. It is therefore not negative symptoms in the absence of significant positive possible to state that increasing 5HT function will invariably induce psychosis or that reducing 5HT symptoms. A statistically significant decrease in depressive symptoms (I-kM-D) was noted at the end of the function will necessarily have an antipsychotic effect. study. Nevertheless, three provisional conclusions can be drawn: In a further in~estigation~~ involving a 6-week doubleblind, placebo-controlled trial of fluoxetine 20 mg/day 1. interruption of certain serotonergic circuits may represent an antipsychotic principle; added to depot neuroleptics (haloperidol, fluphenazine)
II
The serotonin paradox
21
Table 1 SSRI augmentation of antipsychotic treatment in Schizophrenic patients: controlled studies
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n Silver & Nassar, 199225
30
spina et al, 1994*
34
Goff et al, 19%jz7 Vartiainen et al, 1995= Salokangas et al, 199629 Taiminen et al, 199730
41 19 90 75
SSRI (dose)
Antipsychotic agent
fluvoxamine (100 mg)
notspecified
rmprovement Depressive Negative Positive symptoms symptoms symptoms symptoms
Global
-a
fluoxetine butyrophenones (20mg) phenothiazines fluoxetine (20 mg) citalopram (20-60 mg) citalopram (40 mg) citalopram (40 mg)
depot
-a
-f
+c
-d
Patients selected for predominantly negative symptoms Chronic schizophrenia Major depression excluded Schizophrenia and schizoaffective disorder
not specified butyrophenones phenothiazines butyrophenones phenothiazines
-' -'
aggressive behaviour
Significant improve,ment for depression/ anxiety factor PANS, not sigru€icant for
HAMD Buchanan et al, 1996%
33
fluoxetine (SO mg)
clozapine
Patients resistant clozapine
- no efficacy;"Brief Psychiatric Raiing Scale (BPRS); bClinical Global Impression (CGI); Scale for the Assessment of Negative Symptoms (SANS); %ale for the Assessment of Positve Symptoms (SAPS); 'Positive and Negative Syndrome Scale (PANSS); 'Hamilton Depression Rating Scale (HAMD) .
+ efficacy
in 41 patients with schizophrenia or schizoaffective disorder, depressed type, serum fluphenazine levels rose by a mean of 65% and serum haloperidol concentrations by a mean of 20%, after 6 weeks of fluoxetine addition. Despite the substantial elevation in serum concentrations of neuroleptics, fluoxetine did not worsen EPS. Scores on the negative symptom sub-scale of the Brief Psychiatric Rating Scale (BPRS) were significantly lower in patients receiving fluoxetine than in patients taking placebo. The reduction in negative symptoms did not correlate with changes in depression or EPS, and remained significant after controlling for the change in neuroleptic serum concentrations. The large-although not statistically significant-improvement in the depression sub-scale of BPRS did not correlate with the improvement in negative symptoms. In a double-blind cross-over study Vartiainen et alz8 treated 19 schizophrenic patients (DSM-III-R), selected for chronic violent behaviour. Each was treated for 24 weeks with placebo and 24 weeks with citalopram (20 60 mg/day), in addition to previous neuroleptic medication. Although there was a reduction in the frequency of aggressive incidents with citalopram treatment, there was no improvement in schizophrenic symptomatology, as determined by BPRS total scores or Clinical Global Impression (CGI) scores. Salokangas et a129added up to 40 mg citalopram to a
stable regimen of neuroleptic medication (haloperidol, chlorpromazine, levomepromazine, zuclopenthixol, thioridazine) in a double-blind, placebo-controlled 12week study of 90 patients suffering from schizophrenic disorder (DSM-II-R). Neuroleptic doses were comparable in both treatment groups. There was a significantly greater number of responders in terms of severity of illness (CGI) and subjective well-being (Visual Analogy ScalefVAS) in the citalopram group than in those patients receiving placebo. Nevertheless, no statistically significant effect on positive and negative symptoms (PANSS) was detected. There were no changes in neuroleptic plasma levels during the study. The same group" reported a further analysis, using data from the 75 patients who completed the trial. Of the five factors of the PANSS entered in the repeated analysis of variance (ANOVA), only the factor for depression/ anxiety showed a significant effect by time interaction during the whole 12-week investigation. This interaction was significant only between week 3 and week 6 of the study. In addition, the HAM-D showed no improvement during the study. Open trials Goff et aP1 reported a 6-week open trial of fluoxetine 20 mg added to neuroleptics in nine treatment-resistant schizophrenic or schizoaffectivepatients (DSM-III-R). At
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D Zullino et al
week 6 , mean scores were significantly lower than at baseline on the BPRS, the HAM-Dand the SANS.31 Syvalahti et a132used citalopram up to 60 mdday in addition to a previous constant neuroleptic medication (chlorpromazine, haloperidol, perphenazine, thioridazine, zuclopenthixol). Among the 36 patients, suffering either from a psychosis or a personality disorder (DSMIII-R) and not responding satisfactorily to neuroleptic treatment, 24 were considered to be responders. The total mean BPRS score of all patients decreased significantly, as did the mean CGI score. In an open exploratory study in severely disabled chronic schizophrenic (DSM-III-R) inpatients, Silver et aP3 added fluvoxamine in doses ranging from 25 to 200 mg/ day to their neuroleptic medication, which was kept constant; 14 out of 19 patients improved, as indicated by a 15% change in SANS score or CGI improvement of at least 1 point. The symptom constellation appeared to influence the rate and timing of response: of six patients with only negative symptoms, three improved, all in the late period (6-8 weeks after starting fluvoxamine). By contrast, of the 13 patients who exhibited mixed symptoms, 11 improved, eight in the early period (the first 6 weeks). Exacerbation of psychotic symptoms was noted in 10 patients. Bacher and Ruskin3‘ added fluoxetine 20 mg/day to neuroleptic medication in 21 chronic, treatment-resistant schizophrenic or schizoaffective, male outpatients (DSM-111-R). They found mild to moderate improvements in energy, anxiety, and mood in 11 patients after fluoxetine addition. In a 12-week open study, Thakore et a135 added sertraline 50 mg to depot neuroleptic medication in chronic schizophrenic patients. There was a significant reduction in the magnitude of negative symptoms, as indicated by a decrease in the BPRS scores of emotional withdrawal, conceptual disorganization, unusual thought content and affective blunting. The SANS scores also improved significantly, but among the negative symptoms only the dimension of affective blunting showed significant improvement. As depression was an exclusion criterion for this study, the authors concluded that the beneficial effect of adjuvant sertraline was unlikely to have been due to a nonspecific anti-depressant effect. No significant EPS were detected. Unfortunately an important limitation of most published studies is their short duration of treatment, since improvement may continue or even begm beyond 6 weeks, as has been shown for treatment with cl~zapine.’~”~
refractory schizophrenic patients has been the addition of fluoxetine or fluvoxamine. In the only published double-blind placebo-controlled study, Buchanan et aP8 added fluoxetine up to 80 mg/day for 8 weeks to clozapine in treatment-refractory schizophrenic patients. Using the HAM-D, BPRS and SANS, they found no significant differences in positive, negative, depressive, or obsessive- compulsive symptoms between the adjunctive fluoxetine or placebo groups. Silver et a13’ reported an open trial of fluvoxamine augmentation in a clozapine-resistant schizophrenic patient with prominent negative symptoms, who responded after 8 weeks of combined treatment. However, no data relative to clozapine plasma levels were given.39 In a further 6-week open study, the same workers added fluvoxamine up to 100 mg/day to clozapine in schizophrenic (DSM-III-R) patients who showed persistent negative symptoms after no less than 4 months of continuous clozapine treatment. There were few extrapyramidal side-effects before fluvoxamine was given, and , no increase was noted during treatment. Improvement of at least 1 CGI improvement item was observed in 7/11 patients, although 4/11 patients improved by more than 20% in BPRS.%
SSRI AUGMENTATION OF CLOZAPINE TREATMENT
ARE SSRIS EFFECTIVE IN TREATING POSITIVE SYMPTOMS?
Though clozapine is a ‘gold standard’ in the pharmacological treatment of refractory schizophrenia, it is not always effe~tive.~’One strategy used in treating clozapine-
Neither placebo-controlled studies nor open trials have revealed evidence for additional efficacy of antipsychotid SSRI combination in comparison with antipsychotic
ARE SSRIS EFFECTIVE IN TREATING RESISTANT SCHIZOPHRENIA? In open trials, the addition of fluvoxamine, fluoxetine, sertraline or citalopram resulted in some response in chronic and neuroleptic-resistant schizophrenic patients. However, in placebo-controlled trials, only one study6 found a significantly greater global improvement after introduction of an SSRI (fluoxetine), as assessed by the BPRS and CGI.For citalopram this effect (assessment by CGI) could only be determined between week 3 and week 6 of treatment, being no longer present at week 112’ Further placebo-controlled studies showed no differences between placebo and fluv0xamine,2~fluoxetine2’ or ~ i t a l o p r a mN. ~o ~controlled studies have been reported for sertraline, and no study at all for paroxetine. In summary, fluoxetine or citalopram augmentation in neuroleptic-resistant patients can result in promising improvements but the efficacy of fluvoxamine could not be confirmed by controlled trials. Sertraline has not been tested in placebo-controlled studies and paroxetine has not been investigated. A s such, SSRI augmentation seems to be a poor alternative to the use of clozapine or other atypical antipsychotics in treating neuroleptic-resistant patients.
The serotonin paradox
treatment alone. As however the patients were generally selected on the basis of prominent negative symptoms, their neuroleptic resistance or their chronicity, inferences relating to the efficacy of the antipsychotidSSR1combination as a first-line treatment for schizophrenic patients with prominent positive symptoms cannot be drawn at present.
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ARE SSRIS EFFECTIVE IN TREATING DEPRESSIVE SYMPTOMS IN SCHIZOPHRENIA? Of controlled trials using a depression scale (HAM-D), only the study of Spina et alZ6showed a slight, but statistically significant, decrease in depressive symptoms after addition of fluoxetine. The improvement of depression and anxiety described by Taiminen et aI3’ with citalopram augmentation was only temporarily significant compared to placebo, and was not reflected by an improvement on the HAM-D.30 On the other hand, Goff et a12’ included three patients with schizoaffective disorder, depressive type, in a sample of 41 patients, jvithout reporting the score improvement for the depressive patients alone. There is therefore little to support the efficacy of SSRI treatment of depressive symptoms in chronic or neuroleptic-resistant schizophrenic patients with predominantly negative symptoms. While the antidepressant efficacy of older antidepressants has been ascertained: the antidepressant effect of SSRIs in schizophrenic patients selected for their depressive symptoms has yet to be determined.
ARE SSRIS EFFECTIVE IN TREATING NEGATIVE SYMPTOMS? The best evidence for the efficacy of antipsychotidSSR1 combinations has been found for negative symptoms. In the trial reported by Silver and Nassar?’ as well as in the study of Spina et a1,26 improvement in negative symptoms has been documented by SANS. In a further controlled study, Goff et al” recorded an improvement of symptoms as rated by the BPRS Withdrawal Subscale. Moreover, Goff et a131 and Thakore et a135 found significant improvements after addition of an SSRI, as measured by SANS. In conclusion, there seems to be some evidence supporting the efficacy of fluvoxamine or fluoxetine augmentation in the treatment of negative schizophrenic symptoms, and a little evidence for citalopram and sertraline.
IS THE EFFICACYOF SSRlS IN NEGATIVE SYMPTOMS DUE TO EFFICACY IN THE
TREATMENTOF OTHER SYMPTOMS? Negative symptoms in schizophrenic patients have been classified as either primary or secondary. Primary symptom may be part of the basic psychopathology of some, but not necessarily of all, forms of schizophrenic disorder. Their existence has been corroborated by observation of
23
their occurrence even in first psychotic episodes, and the tendency to persist throughout the further course of d i s e a ~ e .Secondary ~ ~ . ~ ~ symptoms, on the other hand, are thought to be a reaction to the psychotic experience (such as dysphoric mood), to be secondary to treatment (adverse effects of neuroleptic drugs), or to treatment circumstances (psychosocial understimulation). A drug treatment which improves psychosis, reduces dysphoria, has fewer side-effects and facilitates better psychosocial interactions would therefore be expected to improve secondary negative symptoms, whereas primary negative symptoms are expected to respond mainly to therapeutic interventions that modify the underlying core pathophy~iology.~~ Negative and depressive symptoms may be the same psychopathological dimension, or at least share similar pathophysiological pathways. Differentiation by available measuring techniques, i.e. rating scales, would therefore be artificial. According to this assumption, the effect of SSRIs would consequently be ‘purely antidepressive’. As depressive dimensions have not only been distinguished from negative dimensions,’ but have also been found to have a different course,44 a shared pathogenetic background would seem at best to only partially account for the efficacy of SSRIs in negative symptoms. Path analysis allows an estimate of whether, and to what degree, the effect of a treatment on a symptom is mediated by effects on other symptoms. For example, the negative symptoms of schizophrenia may be directly responsive to olanzapine treatment, but not to haloperidol treatment?’ To our knowledge, no analogous path analysis has been reported for antipsychotidSSR1 combinations. However, as the efficacy on positive or depressive symptoms seems to be supported by rather little evidence from published controlled trials, a correlation of negative symptom improvement with changes in these symptom dimensions seems unlikely. Whereas some SSRIs may induce akathisia, parkinsonism, neuroleptic malignant syndrome and tardive dyskine~ia,*-~lonly a few patients treated with a SSRI neuroleptic combination show a worsening of neurological side-effects, most studies reporting no differences from placebo treatment. Several case reports have, however, linked a k a t h i ~ i a , ~parkin~onism~~ ~,’~ and tardive dyskinesia with the addition of fluoxetine to hal~peridol.’~ As fluoxetine, fluvoxamine, paroxetine and sertraline are potent inhibitors of cytochrome P450 (CYP) enzymes, they may play an important role in determining a patient’s response to pharmacotherapy. P450 inhibition produces the potential for specific pharmacokinetic drug interactions between SSRIs and concomitantly administered drugs, which are dependent on the role of these particular CYF’ enzymes for their elimination. Only two controlled studies have been published reporting plasma levels during combined SSRYantipsychotic treatment. Goff et alZ7 described plasma level augmentations of haloperidol
24
D Zullino et a1
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and fluphenazine after fluoxetine augmentation, though no correlation could be found with clinical efficacy. In the study of Salokangas et al?’ no significant changes in neuroleptic plasma levels (haloperidol, chlorpromazine, levomepromazine, zuclopenthixol, thioridazine) were detected. Summarizing, SSRI augmentation in the treatment of schizophrenia seems to aqt directly, has only limited efficacy in treating depressive symptoms, and seems to have no effect on positive symptoms or EPS. Up till now, there has been no evidence for an increased efficacy due to increased plasma levels of typical neuroleptics.
THE SEROTONIN PARADOX As there is evidence for direct effects of an SSRVneuroleptic combination in the treatment of negative symptoms, the question arises as to whether it is a consequence of a pharmacodynamic interaction between the two combined agents, or whether it is due to a direct effect of SSRIs. As SSRIs have not been reported to have intrinsic antipsychotic efficacy, this supports the hypothesis of interaction. The therapeutic efficacy of atypical antipsychotics has been suggested to be related to the combination of Dzblocking and 5HT2-blocking pr~perties.‘~SSRIs have been developed to selectively inhibit serotonin re-uptake without having affinities for either uptake pumps of other monoamines, or for receptors, such as the 5HTz re~eptor.’~ The principal effect of the SSRIs and their active metabolites is therefore to enhance serotonergic neurotransmission. A paradox therefore exists, as the effects of serotonin agonists in combination with dopamine blockade are similar to those of serotonin antagonists. Several reasons for this have been proposed. The paradox could reflect the complexity of multiple 5HT-receptor types, their differing distribution, their different serotonin affinity and their partly divergent post-synaptic effects.” The receptors of the 5-HT1 class (5HT1,,, 5HTlB, 5HTlD, 5HTlE, 5HTlF) have a high affinity for 5HT, whereas the 5HT2 (5HTu, 5HTZB, 5HTlc) and the 5HT4 receptors bind serotonin with a lower affinity. In the central nervous system, 5HT receptors are located not only post-synaptically but also pre-synaptically, as demonstrated for 5HT1,,,, 5HTlBand 5HTID. Post-synaptic 5HT2-blockade by atypical antipsychotics may increase the availability of serotonin in the synaptic space, enhancing the occupancy of other serotonergic receptors (5HTlA, 5HTlc or 2c, 5HT4) suggested to be involved in the modulation of limbic functions related to mood and anxiety.% In this context, the antidepressant efficacy described for clozapine5’ could be related to an agonistic effect on 5HT receptors other than 5HT2. While in schizophrenia research interest has mainly focused on the dopaminergic and serotonergic systems, further neurotransmitters may be implicated in aetiology,
pathophysiology and pharmacological re~ponse.~’-~’ While SSRIs are selective in terms of affecting the neuronal uptake pump for serotonin, they may act on a number of other additional sites. Therefore the possibility of action by as yet undiscovered pathways cannot be excluded. Considering the complexity of the neural network and its functions, it is likely that effects on known sites of action are only the first phase of a presumed therapeutic cascade (e.g. adaptive changes after chronic or at least repeated administration), as is suggested by the delayed onset of action.
THE PLACE OF SSRIs IN THE TREATMENT OF SCHIZOPHRENIA Despite the limitations of the data, some inferences can be drawn. There seems to be some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRIs (best ascertained for fluoxetine and fluvoxamine). Since no correlation could be found between improvement of negative symptoms on the one hand and positive, depressive or extrapyamidal motor symptoms on the other, a direct effect seems likely, but this should be confirmed by path analytical studies. Clozapine remains the pharmacological treatment of choice for neuroleptic-resistant and, especially, negative schizophrenic symptoms. Due to the risk of agranulocytosis and the fact that a considerable proportion of patients do not respond to clozapine, it seems reasonable to develop further treatment strategies, e.g. combining different substances. Based on the data reviewed, two possible indications for SSRls in treatment of schizophrenia can be suggested.
(a) PATIENTS WITH POSITIVE SYMPTOMS RESPONSIVE TO TYPICAL NEUROLEPTICS, BUT NEGATIVESYMPTOMS RESISTANT TO THIS TREATMENT SSRIs may be an alternative to clozapine, especially for patients with contraindications for clozapine treatment. Fluoxetine and fluvoxamine are the best candidates for such a treatment, since sertraline and citalopram have only been tested in open studies and paroxetine has not been investigated at all.
(b) NEUROLEPTIC RESISTANCE DUE TO LOW PLASMA LEVELS The improvement of neuroleptic efficacy after SSRI augmentation in treatment-refractory patients remains unproven. Further research is needed in treatment-resistant patients with subnormal neuroleptic plasma levels, who are ultra-rapid metabolizers of CYP2D6 substrates due to gene amplification.60”’ Moreover, CYPlA2, the principal en-
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The serotonin paradox
zyme for clozapine metabolism, is known to be induced by cigarette smoking, leading to reduced clozapine plasma levels.62 By contrast, fluvoxamine, a CYPlA2 inhibitor, has been consistently reported to increase clozapine plasma levels.63As there is a great comorbidity between schizophrenia and tobacco dependence,@ alteration of clozapine metabolism in this population may be a major problem. Fluvoxamine may be a method of correcting accelerated clozapine metabolism. Though toxic antipsychotic levels may be reached after inhibition of cytochrome P450 isoenzymes with SSRIs,6I drug monitoring should be considered before introduction of the SSRI, and after signs of augmented neuroleptic sideeffects.
paradox that both serotonergic and antiserotonergic substances may improve negative symptoms.
KEY POINTS 0 0
Poor effic tipsychotics in treatment Augmentation by SSRI seems to increase the efficacy of conventional antipsychotics t of depressive symptoms or
EPS 0
SSRI augmentation may be an alternative to tients for whom there are conua-
CONCLUSION In conclusion, there is evidence that SSRI augmentation of antipsychotic medication can produce some benefit in schizophrenic patients with predominantly negative symptoms. As yet, there is no convincing rationalization for the
25
0
Fluvoxamine augmentation may be useful in patients resistant to clozapine due to low plasma levels
REFERENCES 1. World Health Organisation (1995) World Health Report 1995. WHO, Geneva. 2. Kane JM (1996) Factors which can make patients difficult to treat. Br J Psychiatry 169(Suppl. 31): 10-14. 3. Kane J, Honigfeld G, Singer J et a1 (1988) Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry 45: 789-96. 4. Krupp P, Barnes P (1989) Leponex-associated granulocytopenia: a review of the situation. Psychopharmacology 99: 118- 21. 5. Amsler HA, Teerenhovi L, Banh E et a1 (1977) Agranulocytosis in patients treated with clozapine-A study of the Finnish epidemic. Acta Psychiatr Scand 56: 241 - 8. 6. Gaebel W, Wolwer W (1994) Probleme der Abgrenzung von Depression, Akinesie und Minussymptomatik mittels Beurteilungsskalen und Verhaltensbeobachtung: Messmethodisches Artefakt oder Ausdruck pathogenetischer Identiat? In: Fortschritte in der Diagnostik und Therapie schieophrener Minwssymptomatik, (eds HJ Mbller and G Laux) 27 - 38. Springer-Verlag, Wien. 7. Newcomer JW, Faustman WO, Yeh W et a1 (1990) Distinguishing depression and negative symptoms in unmedicated patients with schizophrenia. Psycho1 Rep 31: 243 - 50. 8. Plasky P (1991) Antidepressant usage in schizophrenia. Schizophr Bull 17: 649-57. 9. Siris SG (1993) Adjunctive medication in the maintenance treatment of schizophrenia and its conceptual implications. Br j Psychiatry 163: 66- 78. 10. Evans AE, Goff DC (1996) Adjunctive antidepressant drug therapies in the treatment of negative symptoms of schizophrenia. CNS Drugs 6: 130-47. 11. Siris S, Bermanzohn PC, Gonzales A et a1 (1991) The use of antidepressants for negative symptoms in a subset of schizophrenic patients. Psychopharmacol Bull 27: 331 -5.
12. Boyer WF, Feighner JP (1996) Safety and tolerability of selective serotonin re-uptake inhibitors. In: Selective serotonin re-uptake inhibitors (eds JP Feighner and WF Boyer) J Wiley, Chichester. 13. Iqbal N, van Praag M (1995) The role of serotonin in schizophrenia. Eur Neuropsychophannacol (Suppl. 5) 11- 23. 14. Meltzer HY (1992) The importance of serotonin-dopamine interactions in the action of clozapine. Br J Psychiatry 160: 22 - 9. 15. Richelson E (1996) Predinical pharmacology of neuroleptics: focus on new generation compounds.J Clin Psychiatry 57: 4-11. 16. Marder SR, Meibach RC (1994) Risperidone in the treatment of schizophrenia. Am j Psychiatry 151: 825-35. 17. C a m n J, Peuskens J, Vangeneugen A (1995) Risperidone in the treatment of negative symptoms of schKophrenia: a metaanalysis. Int Clin Psychopharmacol 10: 207- 13. 18. Rossi A, Mancini F, Stratta P et a1 (1997) Risperidone, negative symptoms and cognitive deficit in schizophrenia: an open study. Acta Psychiatr Scand 95: 40-3. 19. Azorin JM (1995) Long-term treatment of mood disorders in schizophrenia. Acta Psychiatr Scand 91: 20-3. 20. Fleischhacker WW (1995) New drugs for the treatment of schizophrenic patients. Acta Psychiatr Scand 91: 24-30. 21. Smith RC, Chua JW, Lipetsker B et al (1996) Efficacy of risperidone in reducing positive and negative symptoms in medication-refractov schizophrenia: An open prospective study. J Clin Psychiatry 57: 460-66. 22. Borison RL (1995) Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics.J Clin P ~ ~ c h ~ p h ~ r m a15: c o 245 I - 295. 23. Hillert A, Maier W, Wetzel H et a1 (1992) Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome-A functional approach. Pharmacopsychiatry 25: 213- 7.
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24. Hamon M (1995) S~rotonind5-hydroxytryptamine(5-HT). In: Neuropeptides et ncncromtdiateurs (ed. J Epelbaum), pp. 261 70. b e r m , Paris. 25. Silver H, Nassar A (1992) Fluvoxamine improves negative symptoms in treated chronic schizophrenia: An add-on doubleblind, placebo-controlled sntdy. Biol Psychiatry 31: 698- 704. 26. Spina E, De Domenico P, Ruello C et a1 (1994) Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients. Int Clin Psychopharmacol 9: 281 - 5. 27. Goff DC, Midha KK, Sand-Segal 0 et a1 (1995) A placebocontrolled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology 117: 417-23. 28. Vartiainen H, Tiihonen J, Putkonen A et a1 (1995) Citalopram, a selective serotonin reuptake inhibitor, in the treatment of aggression in schizophrenia. Acta Psychiatr Scand 91: 348-51. 29. Salokangas RKR, Saarijani 5, Taiminen T et a1 (1996) Citalopram as an adjuvant in chronic schizophrenia: a doubleblind placebo-controlled study. Acta Psychiatr Scund 9 4 175 80. 30. Taiminen T. Syvalathi E, Saarijarvi S et a1 (1997) Citalopram as an adjuvant in schizophrenia: further evidence for a serotonergic dimension in schizophrenia. Int Clin Psychopharmacol 12: 31 - 5. 31. Goff DC, Brotman AW, Waits M et a1 (1990) Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients. Am Psychiatry 147: 492 - 4. 32. Syvalathi EKG, Kallioniemi H, Lehto H (1994) Citalopram in patients with unsatisfactory response to neuroleptics: An open follow-up study. Meth Find Exp Clin Pharmacol 1 6 49-55. 33. Silver H, Kaplan A, Kushnir M (1995) Fluvoxamine augmentation in chronic schizophrenia: An open exploratory study. Hum Psychopharmacol 1 0 59-63. 34. Bacher NM, Ruskin P (1991) Addition of fluoxetine to treatment of schizophrenic patients. Am J Psychiatry 148: 2745.
35. Thakore JH, Berti C, Dinan TG (1996) An open trial of adjunctive sertraline in the treatment of chronic schizophrenia. Acta Psychiatr Scand 94: 194-7. 36. Baldessarini RJ, Frankenburg FR (1991) Clozapine. A novel antipsychotic agent. N Engl J Med 324: 746-54. 37. Barnes TRE,McEvedy CJB, Nelson HE (1996) Management of treatment resistant schizophrenia unresponsive to clozapine. Br J Psychiatry 169: 31 - 40. 38. Buchanan RW. Kirkpavick B, Bryant N et a1 (1996) Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am j Psychiatry 153: 1625-7. 39. Silver H, Kaplan A, Jahjah N (1995) Fluvoxamine augmentation for clozapine-resistant schizophrenia. Am J Psychiatry 1 5 2 1098. 40. Silver H, Kushnir M, Kaplan A (1996) Fluvoxamine augmentation in clozapine-resistant schizophrenia: An open pilot study. Biol Psychiatry 40: 671 -4. 41. Arndt S, Andreasen NC, Flaum M et a1 (1995) A longitudinal study of symptoms dimensions in schizophrenia. Arch Gen Psychiatry 52: 352-60. 42. Salokagas RKR (1997) Structure of schizophrenic symptomatology and its changes over time: Prospective factoranalytical study. Acta Psychiatr Scand 95: 32-9. 43. Carpenter WT (1995) Serotonindopamine antagonists and treatment of negative symptoms. J Clin Psychopharmacol 15: 305 - 35s. 44. Czobon P, Volavka J (1996) Positive and negative symptoms: Is their change related? Schizophr Bull 22: 577 - 90.
45. ToUefson GD, Sanger TM (1997) Negative symptoms: A path analytic approach to a double-blind, placebo- and haloperidolcontrolled clinical trial with olanzapine. Am J Psychiatry 1 5 4 466 - 74. 46. Lipinski JF, Mallya G, Zimmermann P et a1 (1989) Fluoxetineinduced akathisia: Clinical and theoretical implications. J Clin Psychiatry 50: 339-42. 47. Bouchard RH, Pourcher E, Vincent P (1989) Fluoxetine and extrapyramidal side effects. Am J Psychiatry 146: 1352-3. 48. Halman M, Goldbloom DS (1990) Fluoxetine and neuroleptic malignant syndrome. Biol Psychiatry 28: 518- 21. 49. Leo RJ (1996) Movement disorders associated with the serotonin selective reuptake inhibitors. J Clin Psychiatry 57: 449 - 54. 50. Hamilton MS, Opler LA (1992) Akathiiia, suicidality, and fiuoxetine. J Clin Psychiatry 53: 401 - 6. 51. Sanz-Fuentenebro FJ, Huidobro A, Tejadas-Rivas A (1996) Restless legs syndrome and paroxetine. Acta Psychiatr S a n d 94: 482 - 4. 52. Balant-Gorgia AE, Ries C, Balant LP (1996) Metabolic interaction between fluoxetine and clomipramine: A case report. Pharmacopsychintry 29: 38 - 41. 53. Tate JL (1989) Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine. Am J Psychiatry 146: 399-400. 54. Stein MH (1991) Tardive dysknesia in a patient taking haloperidol and fluoxetine. Am J Psychiatry 1 4 8 683. 55. Preskorn SH (1996) Clinical pharmacology of selective serotonin reuptake inhibitors. Professional Communications Inc, Caddo, OH, USA. 56. Dubovsky SL,Thomas M (1995) Serotonergic mechanisms and current and future psychiatric practice. J Clin Psychiatry 56: 38 -48. 57. Meltzer HY, Okaly G (1995) Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: Impact on risk-benefit assessment. Am J Psychiatry 1 5 2 18390. 58. Tamminga CA,Holcomb HH, Gao WM et a1 (1995) Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. Int Clin Psychopharmncof 10: 2937. 59. Mtiller-Spahn F, Eich P, Hock C (1996) The psychobiology of the acute schizophrenic episode. Int Clin Psychopharmacol 11: 19-28. 60. Jerling M,Dahl ML, Aberg-Wistedt A (1996) The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther 5 9 423 - 8. 61. Linnet K, Wiborg 0 (1996) lnfluence of CYP2D6 polymorphism on ratios of steady-state serum concentration to dose of the neuroleptic zuclopenthixol. Ther Drug Monit 18: 629 - 34. 62. Haring C, Meise U, Humpel C et a1 (1989) Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacol99: 538-540. 63. Hiemke C, Weigman H, Hartter S et a1 (1994) Elevated levels of clozapine in serum after addition of fluvoxamine. Clin Psychopharmacol 1 4 279-81. 64. Brunette MF, Muesner KT, Haiyi X et a1 (1997) Relationships between symptoms of schizophrenia and substance abuse. J Nerv Ment Dis 185: 13 - 20. 65. Llerena A, Kilvet RA (1994) Fixed combinations of neuroleptics with antidepressants: potential risks and estimation of use. B r j Clin Pharmacol 37: 531-2.
InternationalJournal of psychiatry in Clinical Practice 1998 Volume 2 Pages 19-26
19
The serotonin paradox: Negative symptoms and SSRI augmentation
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DANIELE ZULLINO, GUIDO BONDOLFI AND PIERRE BAUMANN University Department of Adult Psychiatry, Biochemistry and Clinical Psychopharmacology Unit, Lausanne, Switzerland
Correspondence Address Daniele Zullino, MD, Dtpartement Universitaire de Psychiatrie Adulte, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland Tel: +41 21 643 64 04 F a : +41 21 643 64 69 E-mail: [email protected]
Received 19 June 1997; revised 18 November 1997; accepted for publication 23 November 1997
Negative symptoms of schizophrenia are often difficult to treat and may be associated with poorer long-term outcome. As depressive and negative symptoms show some overlap, augmentation of neuroleptics by antidepressants has repeatedly been investigatedfor efficacy against negative symptoms in schizophrenic patients. Studies on SSRI augmentation of neuroleptic medication reveal some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRls. Since no correlation could be found between improvement of negative symptoms on the one hand and positive, depressive or extrapyramidal motor symptoms on the other, a direct effect seems likely. SSRls may therefore be un alternative to clozapine, especially in patients for whom there are contraindicationsagainst clozapine treatment. As yet, there is 110 convincing rationalization for the paradox that both serotonergic and antiserotonergic substances, e.g. atypical antipsychotics, may improve negative symptoms. (Int J Psych Clin Pract 1998; 2: 19- 26)
Keywords selective serotonin re-uptake inhibitors antipsychotics combination treatment negative symptoms schizophrenia
chizophrenia is the ninth leading cause of disability in the world and the most costly psychiatric disorder,’ negative symptoms being one of the most debilitating aspects of this condition. Positive symptoms such as hallucinations, delusions and bizarre thoughts respond to treatment with standard antipsychotic drugs in a great proportion of patients. Negative symptoms, such as blunted affect, narrowing of ideation, alogia, anhedonia, avolition and social and emotional withdrawal are often difficult to treat and associated with poorer long-term outcome.2 Clozapine, an agent with low Dz receptor affinity, but higher 5HTzNc affinity, compared to standard neuroleptics, is often effective in the treatment of previously neuroleptic refractory patient^.^ The advantage of clozapine is, however, limited by the risk of agranulocytosi~.~*~
S
THE RATIONALE FOR SSRI AUGMENTATION IN (REFRACTORY) SCHIZOPHRENIA WITH NEGATIVE SYMPTOMS As depressive and negative symptoms such as anhedonia, lack of interest, motor retardation and social withdrawal
show some overlap, it may be difficult to distinguish these two syndromal dirnensiom6 They seem, however, to represent two different dimensions of psychopathoIogy with different time courses.’ Because of the similarities between negative and depressive symptoms in schizophrenic patients and the success of antidepressants in the treatment of depressive symptoms in schizophrenic disorders:’ combinations of neuroleptics with antidepressants of the tricyclic type (TCA) have also been evaluated in the treatment of negative syndromes, and found to be effective.”.” Selectiveserotonin re-uptake inhibitors (SSRIs) are safer and better tolerated than TCAs,” which is an important feature when considering the already high side-effect burden of neuroleptic treatment. A second reason for testing SSRIs as a treatment in schizophrenia is the socalled ‘serotonin hypothesis’. One of the earliest biochemical hypotheses was based on the observation of symptoms occurring during intoxication with lysergic acid diethylamide (ISD), such as distorted perception, derealization, depersonalization and possible hallucinations: symptoms clearly similar to those of schizophrenia. As LSD was found to act on the serotonergic system, partly as agonist, partly as antagonist, schizophrenic symptoms have been considered to be related, at least
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D Zullino et al
partly, to serotonergic dysfun~tion.’~ Furthermore, the 2. serotonergic dysfunction may be involved in the selective 5HTu-receptor blocker ritanserin was found to pathophysiology of schizophrenic psychoses; and counteract the psychotic effects of LSD, substantiating 3. serotonergic lesions may contribute to the occurrence of the serotonin appr~ach.’~ schizophrenic psychopathology, either directly, or After the introduction of dopamine antagonists in the indirectly via alterations in the dopaminergic system. 1950s the serotonin hypothesis of schizophrenia became progressively neglected. However, interest in serotonin SSRI AUGMENTATION OF CLASSICAL function in schizophrenia, and especially in negative NEUROLEPTIC TREATMENT symptomatology, has been restimulated by the efficacy Controlled studies and widespread use of clozapine in the treatment of To our knowledge, five controlled studies of the effect of patients with previously refractory schizophrenia.’ Clozathe addition of SSRIs to current. treatment with classic pine has been shown to be a 5HTmc-receptor neuroleptic agents have been published (Table 1). antagonist, but serotonin - dopamine interactions may In a double-blind study of 30 chronic schizophrenic be essential for its efficacy.” The relationship between patients (DSM-111-R), selected for their predominantly strong 5HT2and weak D2affinities has been shown to be negative symptomatology, Silver and Nassal15 added related to the therapeutic profile of the so-called fluvoxamine (up to 100 mg/day) to a fixed dose of ‘atypical’ antipsychotics,” i.e. antipsychotic agents with little induction of extrapyramidal side-effects (EPS). antipsychotic medication. After 5 weeks of combined Several new drugs with similar receptor-binding profiles, treatment, the fluvoxamine was reduced to 50 mg and then stopped. The total scores on the Scale for the including risperidone, sertindole and olanzapine, have Assessment of Negative Symptoms (SANS) improved, been introduced and shown to have similar efficacy in significantly more in the fluvoxamine group, and relieving negative and/or depressive symptoms in improvement persisted one week after fluvoxamine schizophrenia.16-23 While 5HTlA-autoreceptorsinhibit the release of 5HT, withdrawal. Significantly greater improvements in the active group were seen for affective blunting and for and have therefore been proposed to be related to alogia factors. There was no evidence of exacerbation of reduction of anxiety and aggression, other post-synaptic positive symptoms, as recorded by the Scale for the 5HT1 receptors have excitatory effects on hypothalamic- pituitary adrenal function. 5HTlD receptors act as Assessment of Positive Symptoms (SAPS). No significant difference between active and control groups was noted autoreceptors, inhibiting the release of 5HT, and could in regard to depressive features or EPS. Hence the be related to the pathophysiology of migraine. The 5HTa and 5HT3 receptors are post-synaptic, mainly authors deduced that improvement of negative symptoms could not be due to improvement in depressive or located in the frontal cortex and caudate nucleus, and features. have been associated with psychotic p h e n ~ m e n a . ’ ~ . ~extrapyramidal ~ In a randomized double-blind placebo-controIled study, Ritanserin, a selective 5HTu-receptor blocking agent, neuroleptic doses measured by chlorpromazine equivalents has antipsychotic activity and may improve extrapyrwere similar in both groups. Spina et a126investigated the amidal symptoms. effect of adding fluoxetine 20 mg/day on negative While positive symptoms are correlated with hypersymptoms in 34 chronic schizophrenic (DSM-111-R) function of the dopamine system, diminished dopaminergic inpatients receiving maintenance therapy with neuroneurotransmission in mesocortical projections from the leptics (haloperidol, fluphenazine, thioridazine, chlorventral tegmental area may be responsible for negative promazine, clotiapin). Patients with a Hamilton symptoms. This would also explain secondary negative (HAM-D) score 2 2 0 were not Depression Rating symptoms resulting from antidopaminergic neuroleptic 12 weeks of treatment, negative sympincluded. After treatment. A9 and A10 dopamine effects are counteracted toms (SANS) were significantly improved in the by serotonergic effects transmitted through the 5HTu in the placebo group. fluoxetine-treated patients, but not receptor, although this effect is less certain at some A10 Improvement was evident in affective flattening, alogia, cortical terminals. As reviewed by Iqbal and van Praag,13 there are many avolition and anhedonia, but not in impairment of attention. There was no evidence of any influence of inconsistencies between studies investigating the involfluoxetine on positive schizophrenic symptoms, but the vement of serotonin in schizophrenia and the mechanpatients had been selected specifically for predominantly ism of action of antipsychotic drugs. It is therefore not negative symptoms in the absence of significant positive possible to state that increasing 5HT function will invariably induce psychosis or that reducing 5HT symptoms. A statistically significant decrease in depressive symptoms (I-kM-D) was noted at the end of the function will necessarily have an antipsychotic effect. study. Nevertheless, three provisional conclusions can be drawn: In a further in~estigation~~ involving a 6-week doubleblind, placebo-controlled trial of fluoxetine 20 mg/day 1. interruption of certain serotonergic circuits may represent an antipsychotic principle; added to depot neuroleptics (haloperidol, fluphenazine)
II
The serotonin paradox
21
Table 1 SSRI augmentation of antipsychotic treatment in Schizophrenic patients: controlled studies
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n Silver & Nassar, 199225
30
spina et al, 1994*
34
Goff et al, 19%jz7 Vartiainen et al, 1995= Salokangas et al, 199629 Taiminen et al, 199730
41 19 90 75
SSRI (dose)
Antipsychotic agent
fluvoxamine (100 mg)
notspecified
rmprovement Depressive Negative Positive symptoms symptoms symptoms symptoms
Global
-a
fluoxetine butyrophenones (20mg) phenothiazines fluoxetine (20 mg) citalopram (20-60 mg) citalopram (40 mg) citalopram (40 mg)
depot
-a
-f
+c
-d
Patients selected for predominantly negative symptoms Chronic schizophrenia Major depression excluded Schizophrenia and schizoaffective disorder
not specified butyrophenones phenothiazines butyrophenones phenothiazines
-' -'
aggressive behaviour
Significant improve,ment for depression/ anxiety factor PANS, not sigru€icant for
HAMD Buchanan et al, 1996%
33
fluoxetine (SO mg)
clozapine
Patients resistant clozapine
- no efficacy;"Brief Psychiatric Raiing Scale (BPRS); bClinical Global Impression (CGI); Scale for the Assessment of Negative Symptoms (SANS); %ale for the Assessment of Positve Symptoms (SAPS); 'Positive and Negative Syndrome Scale (PANSS); 'Hamilton Depression Rating Scale (HAMD) .
+ efficacy
in 41 patients with schizophrenia or schizoaffective disorder, depressed type, serum fluphenazine levels rose by a mean of 65% and serum haloperidol concentrations by a mean of 20%, after 6 weeks of fluoxetine addition. Despite the substantial elevation in serum concentrations of neuroleptics, fluoxetine did not worsen EPS. Scores on the negative symptom sub-scale of the Brief Psychiatric Rating Scale (BPRS) were significantly lower in patients receiving fluoxetine than in patients taking placebo. The reduction in negative symptoms did not correlate with changes in depression or EPS, and remained significant after controlling for the change in neuroleptic serum concentrations. The large-although not statistically significant-improvement in the depression sub-scale of BPRS did not correlate with the improvement in negative symptoms. In a double-blind cross-over study Vartiainen et alz8 treated 19 schizophrenic patients (DSM-III-R), selected for chronic violent behaviour. Each was treated for 24 weeks with placebo and 24 weeks with citalopram (20 60 mg/day), in addition to previous neuroleptic medication. Although there was a reduction in the frequency of aggressive incidents with citalopram treatment, there was no improvement in schizophrenic symptomatology, as determined by BPRS total scores or Clinical Global Impression (CGI) scores. Salokangas et a129added up to 40 mg citalopram to a
stable regimen of neuroleptic medication (haloperidol, chlorpromazine, levomepromazine, zuclopenthixol, thioridazine) in a double-blind, placebo-controlled 12week study of 90 patients suffering from schizophrenic disorder (DSM-II-R). Neuroleptic doses were comparable in both treatment groups. There was a significantly greater number of responders in terms of severity of illness (CGI) and subjective well-being (Visual Analogy ScalefVAS) in the citalopram group than in those patients receiving placebo. Nevertheless, no statistically significant effect on positive and negative symptoms (PANSS) was detected. There were no changes in neuroleptic plasma levels during the study. The same group" reported a further analysis, using data from the 75 patients who completed the trial. Of the five factors of the PANSS entered in the repeated analysis of variance (ANOVA), only the factor for depression/ anxiety showed a significant effect by time interaction during the whole 12-week investigation. This interaction was significant only between week 3 and week 6 of the study. In addition, the HAM-D showed no improvement during the study. Open trials Goff et aP1 reported a 6-week open trial of fluoxetine 20 mg added to neuroleptics in nine treatment-resistant schizophrenic or schizoaffectivepatients (DSM-III-R). At
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D Zullino et al
week 6 , mean scores were significantly lower than at baseline on the BPRS, the HAM-Dand the SANS.31 Syvalahti et a132used citalopram up to 60 mdday in addition to a previous constant neuroleptic medication (chlorpromazine, haloperidol, perphenazine, thioridazine, zuclopenthixol). Among the 36 patients, suffering either from a psychosis or a personality disorder (DSMIII-R) and not responding satisfactorily to neuroleptic treatment, 24 were considered to be responders. The total mean BPRS score of all patients decreased significantly, as did the mean CGI score. In an open exploratory study in severely disabled chronic schizophrenic (DSM-III-R) inpatients, Silver et aP3 added fluvoxamine in doses ranging from 25 to 200 mg/ day to their neuroleptic medication, which was kept constant; 14 out of 19 patients improved, as indicated by a 15% change in SANS score or CGI improvement of at least 1 point. The symptom constellation appeared to influence the rate and timing of response: of six patients with only negative symptoms, three improved, all in the late period (6-8 weeks after starting fluvoxamine). By contrast, of the 13 patients who exhibited mixed symptoms, 11 improved, eight in the early period (the first 6 weeks). Exacerbation of psychotic symptoms was noted in 10 patients. Bacher and Ruskin3‘ added fluoxetine 20 mg/day to neuroleptic medication in 21 chronic, treatment-resistant schizophrenic or schizoaffective, male outpatients (DSM-111-R). They found mild to moderate improvements in energy, anxiety, and mood in 11 patients after fluoxetine addition. In a 12-week open study, Thakore et a135 added sertraline 50 mg to depot neuroleptic medication in chronic schizophrenic patients. There was a significant reduction in the magnitude of negative symptoms, as indicated by a decrease in the BPRS scores of emotional withdrawal, conceptual disorganization, unusual thought content and affective blunting. The SANS scores also improved significantly, but among the negative symptoms only the dimension of affective blunting showed significant improvement. As depression was an exclusion criterion for this study, the authors concluded that the beneficial effect of adjuvant sertraline was unlikely to have been due to a nonspecific anti-depressant effect. No significant EPS were detected. Unfortunately an important limitation of most published studies is their short duration of treatment, since improvement may continue or even begm beyond 6 weeks, as has been shown for treatment with cl~zapine.’~”~
refractory schizophrenic patients has been the addition of fluoxetine or fluvoxamine. In the only published double-blind placebo-controlled study, Buchanan et aP8 added fluoxetine up to 80 mg/day for 8 weeks to clozapine in treatment-refractory schizophrenic patients. Using the HAM-D, BPRS and SANS, they found no significant differences in positive, negative, depressive, or obsessive- compulsive symptoms between the adjunctive fluoxetine or placebo groups. Silver et a13’ reported an open trial of fluvoxamine augmentation in a clozapine-resistant schizophrenic patient with prominent negative symptoms, who responded after 8 weeks of combined treatment. However, no data relative to clozapine plasma levels were given.39 In a further 6-week open study, the same workers added fluvoxamine up to 100 mg/day to clozapine in schizophrenic (DSM-III-R) patients who showed persistent negative symptoms after no less than 4 months of continuous clozapine treatment. There were few extrapyramidal side-effects before fluvoxamine was given, and , no increase was noted during treatment. Improvement of at least 1 CGI improvement item was observed in 7/11 patients, although 4/11 patients improved by more than 20% in BPRS.%
SSRI AUGMENTATION OF CLOZAPINE TREATMENT
ARE SSRIS EFFECTIVE IN TREATING POSITIVE SYMPTOMS?
Though clozapine is a ‘gold standard’ in the pharmacological treatment of refractory schizophrenia, it is not always effe~tive.~’One strategy used in treating clozapine-
Neither placebo-controlled studies nor open trials have revealed evidence for additional efficacy of antipsychotid SSRI combination in comparison with antipsychotic
ARE SSRIS EFFECTIVE IN TREATING RESISTANT SCHIZOPHRENIA? In open trials, the addition of fluvoxamine, fluoxetine, sertraline or citalopram resulted in some response in chronic and neuroleptic-resistant schizophrenic patients. However, in placebo-controlled trials, only one study6 found a significantly greater global improvement after introduction of an SSRI (fluoxetine), as assessed by the BPRS and CGI.For citalopram this effect (assessment by CGI) could only be determined between week 3 and week 6 of treatment, being no longer present at week 112’ Further placebo-controlled studies showed no differences between placebo and fluv0xamine,2~fluoxetine2’ or ~ i t a l o p r a mN. ~o ~controlled studies have been reported for sertraline, and no study at all for paroxetine. In summary, fluoxetine or citalopram augmentation in neuroleptic-resistant patients can result in promising improvements but the efficacy of fluvoxamine could not be confirmed by controlled trials. Sertraline has not been tested in placebo-controlled studies and paroxetine has not been investigated. A s such, SSRI augmentation seems to be a poor alternative to the use of clozapine or other atypical antipsychotics in treating neuroleptic-resistant patients.
The serotonin paradox
treatment alone. As however the patients were generally selected on the basis of prominent negative symptoms, their neuroleptic resistance or their chronicity, inferences relating to the efficacy of the antipsychotidSSR1combination as a first-line treatment for schizophrenic patients with prominent positive symptoms cannot be drawn at present.
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ARE SSRIS EFFECTIVE IN TREATING DEPRESSIVE SYMPTOMS IN SCHIZOPHRENIA? Of controlled trials using a depression scale (HAM-D), only the study of Spina et alZ6showed a slight, but statistically significant, decrease in depressive symptoms after addition of fluoxetine. The improvement of depression and anxiety described by Taiminen et aI3’ with citalopram augmentation was only temporarily significant compared to placebo, and was not reflected by an improvement on the HAM-D.30 On the other hand, Goff et a12’ included three patients with schizoaffective disorder, depressive type, in a sample of 41 patients, jvithout reporting the score improvement for the depressive patients alone. There is therefore little to support the efficacy of SSRI treatment of depressive symptoms in chronic or neuroleptic-resistant schizophrenic patients with predominantly negative symptoms. While the antidepressant efficacy of older antidepressants has been ascertained: the antidepressant effect of SSRIs in schizophrenic patients selected for their depressive symptoms has yet to be determined.
ARE SSRIS EFFECTIVE IN TREATING NEGATIVE SYMPTOMS? The best evidence for the efficacy of antipsychotidSSR1 combinations has been found for negative symptoms. In the trial reported by Silver and Nassar?’ as well as in the study of Spina et a1,26 improvement in negative symptoms has been documented by SANS. In a further controlled study, Goff et al” recorded an improvement of symptoms as rated by the BPRS Withdrawal Subscale. Moreover, Goff et a131 and Thakore et a135 found significant improvements after addition of an SSRI, as measured by SANS. In conclusion, there seems to be some evidence supporting the efficacy of fluvoxamine or fluoxetine augmentation in the treatment of negative schizophrenic symptoms, and a little evidence for citalopram and sertraline.
IS THE EFFICACYOF SSRlS IN NEGATIVE SYMPTOMS DUE TO EFFICACY IN THE
TREATMENTOF OTHER SYMPTOMS? Negative symptoms in schizophrenic patients have been classified as either primary or secondary. Primary symptom may be part of the basic psychopathology of some, but not necessarily of all, forms of schizophrenic disorder. Their existence has been corroborated by observation of
23
their occurrence even in first psychotic episodes, and the tendency to persist throughout the further course of d i s e a ~ e .Secondary ~ ~ . ~ ~ symptoms, on the other hand, are thought to be a reaction to the psychotic experience (such as dysphoric mood), to be secondary to treatment (adverse effects of neuroleptic drugs), or to treatment circumstances (psychosocial understimulation). A drug treatment which improves psychosis, reduces dysphoria, has fewer side-effects and facilitates better psychosocial interactions would therefore be expected to improve secondary negative symptoms, whereas primary negative symptoms are expected to respond mainly to therapeutic interventions that modify the underlying core pathophy~iology.~~ Negative and depressive symptoms may be the same psychopathological dimension, or at least share similar pathophysiological pathways. Differentiation by available measuring techniques, i.e. rating scales, would therefore be artificial. According to this assumption, the effect of SSRIs would consequently be ‘purely antidepressive’. As depressive dimensions have not only been distinguished from negative dimensions,’ but have also been found to have a different course,44 a shared pathogenetic background would seem at best to only partially account for the efficacy of SSRIs in negative symptoms. Path analysis allows an estimate of whether, and to what degree, the effect of a treatment on a symptom is mediated by effects on other symptoms. For example, the negative symptoms of schizophrenia may be directly responsive to olanzapine treatment, but not to haloperidol treatment?’ To our knowledge, no analogous path analysis has been reported for antipsychotidSSR1 combinations. However, as the efficacy on positive or depressive symptoms seems to be supported by rather little evidence from published controlled trials, a correlation of negative symptom improvement with changes in these symptom dimensions seems unlikely. Whereas some SSRIs may induce akathisia, parkinsonism, neuroleptic malignant syndrome and tardive dyskine~ia,*-~lonly a few patients treated with a SSRI neuroleptic combination show a worsening of neurological side-effects, most studies reporting no differences from placebo treatment. Several case reports have, however, linked a k a t h i ~ i a , ~parkin~onism~~ ~,’~ and tardive dyskinesia with the addition of fluoxetine to hal~peridol.’~ As fluoxetine, fluvoxamine, paroxetine and sertraline are potent inhibitors of cytochrome P450 (CYP) enzymes, they may play an important role in determining a patient’s response to pharmacotherapy. P450 inhibition produces the potential for specific pharmacokinetic drug interactions between SSRIs and concomitantly administered drugs, which are dependent on the role of these particular CYF’ enzymes for their elimination. Only two controlled studies have been published reporting plasma levels during combined SSRYantipsychotic treatment. Goff et alZ7 described plasma level augmentations of haloperidol
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and fluphenazine after fluoxetine augmentation, though no correlation could be found with clinical efficacy. In the study of Salokangas et al?’ no significant changes in neuroleptic plasma levels (haloperidol, chlorpromazine, levomepromazine, zuclopenthixol, thioridazine) were detected. Summarizing, SSRI augmentation in the treatment of schizophrenia seems to aqt directly, has only limited efficacy in treating depressive symptoms, and seems to have no effect on positive symptoms or EPS. Up till now, there has been no evidence for an increased efficacy due to increased plasma levels of typical neuroleptics.
THE SEROTONIN PARADOX As there is evidence for direct effects of an SSRVneuroleptic combination in the treatment of negative symptoms, the question arises as to whether it is a consequence of a pharmacodynamic interaction between the two combined agents, or whether it is due to a direct effect of SSRIs. As SSRIs have not been reported to have intrinsic antipsychotic efficacy, this supports the hypothesis of interaction. The therapeutic efficacy of atypical antipsychotics has been suggested to be related to the combination of Dzblocking and 5HT2-blocking pr~perties.‘~SSRIs have been developed to selectively inhibit serotonin re-uptake without having affinities for either uptake pumps of other monoamines, or for receptors, such as the 5HTz re~eptor.’~ The principal effect of the SSRIs and their active metabolites is therefore to enhance serotonergic neurotransmission. A paradox therefore exists, as the effects of serotonin agonists in combination with dopamine blockade are similar to those of serotonin antagonists. Several reasons for this have been proposed. The paradox could reflect the complexity of multiple 5HT-receptor types, their differing distribution, their different serotonin affinity and their partly divergent post-synaptic effects.” The receptors of the 5-HT1 class (5HT1,,, 5HTlB, 5HTlD, 5HTlE, 5HTlF) have a high affinity for 5HT, whereas the 5HT2 (5HTu, 5HTZB, 5HTlc) and the 5HT4 receptors bind serotonin with a lower affinity. In the central nervous system, 5HT receptors are located not only post-synaptically but also pre-synaptically, as demonstrated for 5HT1,,,, 5HTlBand 5HTID. Post-synaptic 5HT2-blockade by atypical antipsychotics may increase the availability of serotonin in the synaptic space, enhancing the occupancy of other serotonergic receptors (5HTlA, 5HTlc or 2c, 5HT4) suggested to be involved in the modulation of limbic functions related to mood and anxiety.% In this context, the antidepressant efficacy described for clozapine5’ could be related to an agonistic effect on 5HT receptors other than 5HT2. While in schizophrenia research interest has mainly focused on the dopaminergic and serotonergic systems, further neurotransmitters may be implicated in aetiology,
pathophysiology and pharmacological re~ponse.~’-~’ While SSRIs are selective in terms of affecting the neuronal uptake pump for serotonin, they may act on a number of other additional sites. Therefore the possibility of action by as yet undiscovered pathways cannot be excluded. Considering the complexity of the neural network and its functions, it is likely that effects on known sites of action are only the first phase of a presumed therapeutic cascade (e.g. adaptive changes after chronic or at least repeated administration), as is suggested by the delayed onset of action.
THE PLACE OF SSRIs IN THE TREATMENT OF SCHIZOPHRENIA Despite the limitations of the data, some inferences can be drawn. There seems to be some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRIs (best ascertained for fluoxetine and fluvoxamine). Since no correlation could be found between improvement of negative symptoms on the one hand and positive, depressive or extrapyamidal motor symptoms on the other, a direct effect seems likely, but this should be confirmed by path analytical studies. Clozapine remains the pharmacological treatment of choice for neuroleptic-resistant and, especially, negative schizophrenic symptoms. Due to the risk of agranulocytosis and the fact that a considerable proportion of patients do not respond to clozapine, it seems reasonable to develop further treatment strategies, e.g. combining different substances. Based on the data reviewed, two possible indications for SSRls in treatment of schizophrenia can be suggested.
(a) PATIENTS WITH POSITIVE SYMPTOMS RESPONSIVE TO TYPICAL NEUROLEPTICS, BUT NEGATIVESYMPTOMS RESISTANT TO THIS TREATMENT SSRIs may be an alternative to clozapine, especially for patients with contraindications for clozapine treatment. Fluoxetine and fluvoxamine are the best candidates for such a treatment, since sertraline and citalopram have only been tested in open studies and paroxetine has not been investigated at all.
(b) NEUROLEPTIC RESISTANCE DUE TO LOW PLASMA LEVELS The improvement of neuroleptic efficacy after SSRI augmentation in treatment-refractory patients remains unproven. Further research is needed in treatment-resistant patients with subnormal neuroleptic plasma levels, who are ultra-rapid metabolizers of CYP2D6 substrates due to gene amplification.60”’ Moreover, CYPlA2, the principal en-
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The serotonin paradox
zyme for clozapine metabolism, is known to be induced by cigarette smoking, leading to reduced clozapine plasma levels.62 By contrast, fluvoxamine, a CYPlA2 inhibitor, has been consistently reported to increase clozapine plasma levels.63As there is a great comorbidity between schizophrenia and tobacco dependence,@ alteration of clozapine metabolism in this population may be a major problem. Fluvoxamine may be a method of correcting accelerated clozapine metabolism. Though toxic antipsychotic levels may be reached after inhibition of cytochrome P450 isoenzymes with SSRIs,6I drug monitoring should be considered before introduction of the SSRI, and after signs of augmented neuroleptic sideeffects.
paradox that both serotonergic and antiserotonergic substances may improve negative symptoms.
KEY POINTS 0 0
Poor effic tipsychotics in treatment Augmentation by SSRI seems to increase the efficacy of conventional antipsychotics t of depressive symptoms or
EPS 0
SSRI augmentation may be an alternative to tients for whom there are conua-
CONCLUSION In conclusion, there is evidence that SSRI augmentation of antipsychotic medication can produce some benefit in schizophrenic patients with predominantly negative symptoms. As yet, there is no convincing rationalization for the
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0
Fluvoxamine augmentation may be useful in patients resistant to clozapine due to low plasma levels
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