Review article
Benzodiazepines in the treatment of schizophrenia: an updated survev Lingjade 0. Benzodiazepines in the treatment of schizophrenia: an updated survey. Acta Psychiatr Scand 1991: 84: 453-459.
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Reports on the effects of benzodiazepines in schizophrenia have appeared since the early 1960s. Conclusions drawn from these studies, most of which have been uncontrolled, have ranged from worse than placebo to better than neuroleptics. A critical appraisal of the literature seems to warrant the following main conclusions. Benzodiazepines alone, in conventional doses, have no convincing antipsychotic effect in schizophrenia, although they may reduce anxiety, tension and insomnia. However, very high doses of diazepam, and possibly other benzodiazepines, may have a symptomatic antipsychotic effect, especially in paranoid-hallucinatory schizophrenics, also when given alone. Benzodiazepines, in conventional doses, can enhance the antipsychotic effect of neuroleptics in schizophrenics who have not responded satisfactorily to neuroleptics alone. This effect may be most conspicuous against hallucinations, but improvement may also be obtained from delusions, thought disturbances, some negative symptoms, anxiety and tension. Some benzodiazepines may be more effective than others in schizophrenia, but this has been insufficiently elucidated.
Neuroleptics have long since been established as the most important drugs in the treatment of schizophrenia. However, there is often a need for alternative drugs when neuroleptics have unsatisfactory therapeutic effect or preduce too disturbing side effects. Alternative drugs can either be used alone - to replace neuroleptics - or in addition to continued neuroleptic medication. The first alternative would seem to be preferable, but unfortunately very few schizophrenics derive substantial benefit from alternative drugs given alone. The relevant alternative is therefore more often to give a non-neuroleptic drug in addition to continued neuroleptic medication. This combined medication may have 2 favorable effects: first, there may be a better therapeutic effect on such symptoms as hallucinations, delusions or aggressiveness than was obtained with neuroleptics alone. Second, even if the therapeutic effect is not definitely better, it may be obtained with a lower dose and therefore produce fewer side effects. As an example, this may be the result of adding carbamazepine to haloperidol in manic or acute schizophrenic states. The difference between this use of
0. Lingjade Gaustad Hospital, Oslo, Norway
Key words: benzodiazepines; schizophrenia
0. Lingjade, M.D., Department of Psychiatry, Gaustad Hospital, N-0320 Oslo 3, Norway Accepted for publication August 12, 199 1
adjunctive drugs and the use of drugs against side effects - such as anticholinergics against parkinsonism - is that the latter are purely aimed at reducing side effects, and not at potentiating the therapeutic effect of the neuroleptics. Through the years, many different drugs have been claimed to be useful alternatives to or adjuncts to neuroleptics in schizophrenia, but few have been firmly established as particularly useful. However, especially when given in addition to neuroleptics, such drugs as tricyclic antidepressants, lithium, carbamazepine and benzodiazepines may have favorable effects on schizophrenic symptoms in several patients. I will try to give an updated survey of published experiences with benzodiazepines in schizophrenia; I feel that this type of drug ought to be tried more often in this condition. Previous surveys, on which the present one is partly based, have been published in edited monographs appearing in 1983 (1) and 1985 (2). Generally speaking, benzodiazepines may be given to schizophrenic patients for 3 different purposes: (a) against anxiety, tension or insomnia, similar to 453
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non-psychotic patients; (b) against such neurolepticinduced side effects as akathisia or tardive dyskinesia; and (c) against psychotic symptoms, such as hallucinations, delusions, thought disorders and psychotic excitement. Only the effect on psychotic symptoms will be addressed here. Many clinicians doubt that benzodiazepines have a true antipsychotic effect - beyond that which might be explained as “only” secondary to the anxiolytic and sedative effects. However, besides many negative reports, over the years numerous reports of uncontrolled and controlled studies have appeared that seem to warrant the conclusion that some benzodiazepines may, at least in certain schizophrenic patients, exert a favorable effect on psychotic symptoms, especially when given as an adjunct to neuroleptics. Many of the studies on benzodiazepines in psychosis were published in the 1960s, and several of them do not quite satisfy modern standards for clinical trials. Also, during recent years there have been published many anecdotal reports and small, uncontrolled studies, but some controlled ones as well. However, more controlled studies are still needed in this field. In clinical studies with benzodiazepines in schizophrenia, the dosages have usually been within the conventional range used in nonpsychotic states. In some interesting recent studies, on the other hand, diazepam has been used alone in extremely high doses, which have been claimed to be remarkably effective in some patients. This has prompted a renewed interest in the possible antipsychotic effect of this drug class. In this survey, I first refer to studies with benzodiazepines in conventional doses in open and controlled studies before commenting on studies with high-dose diazepam. Uncontrolled studies
Already in the early 1960s, several reports appeared claiming that diazepam had an excellent symptomatic effect in schizophrenia, especially against hallucinations (3,4), but there were also many negative reports (2). There were also reports claiming that chlordiazepoxide enhanced the antipsychotic effect of neuroleptics ( 5 , 6 ) . Taken as a whole, these early reports on uncontrolled trials were rather inconsistent and not quite convincing, but still promising. In the 1980s, there has been a renewed interest in the effect of benzodiazepines in schizophrenia and other psychoses, and besides some controlled studies (see later), several case reports and small uncontrolled studies have been published, mainly on such newer benzodiazepines as lorazepam, clonazepam, estazolam and alprazolam.
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Ansari (1) reported that lorazepam, given intravenously, had a rapid effect on hallucinations, aggressiveness, social behavior and disturbed ego boundaries in 8 acutely schizophrenic patients. Cohen & Khan (8) and Saltzman et al. (9) have reported a good effect of lorazepam in addition to neuroleptics in schizophrenic patients. Clonazepam, which has been marketed mainly as an antiepileptic, is also said to give some remarkable effects in schizophrenics in addition to neuroleptics (lo), and may also have a marked effect given alone to schizoaffective patients (1 1) and to atypical psychoses (12). Alprazolam, a triazolobenzodiazepine shown to be effective especially in panic disorder, and also to have some antidepressant effect, has been reported to have a good effect in schizophrenic patients with panic attacks (13), and also, when given in a relatively high dose, in schizophrenic patients with more unspecific anxiety (14). In a small, uncontrolled study, Douyon et al. (15) found that alprazolam, given in addition to neuroleptics, reduced both positive and negative symptoms in schizophrenic patients, although with varying effect in different patients. Less satisfactory effect of alprazolam - again in addition to neuroleptics -in chronic schizophrenic patients was reported by Bacher et al. (16); in 3 patients, an acute paranoid delusional state developed during alprazolam treatment. This is in agreement with some controlled studies to be mentioned later. Another triazolobenzodiazepine, estazolam, seems to be especially effective against hallucinations (see below). These more recent uncontrolled studies with newer benzodiazepines in schizophrenia are again promising, but seen in isolation, they carry little weight as evidence for an antipsychotic effect of such drugs. However, some controlled studies also corroborate this antipsychotic effect of newer benzodiazepines, at least when given in addition to neuroleptics. Benzodiazepines alone compared with placebo
Holden et al. (17) compared chlordiazepoxide (1 mg/ kg) with thioridazine and placebo in 24 schizophrenic men, and found chlordiazepoxide to be inferior to thioridazine, but significantly better than placebo for such symptoms as negativism, euphoria, disturbance of life drive, confusion and increased appetite. However, Azima et al. (18) found no difference between chlordiazepoxide (20-200 mg) and placebo. In the 1960s several reports also appeared on studies comparing diazepam with placebo in hospitalized schizophrenics; several of them concluded that diazepam was not markedly superior (19-2 1).
Benzodiazepines in schizophrenia
One of these studies (21) even found that patients on diazepam more often developed suicidal or paranoid thoughts, prompting the authors to conclude that diazepam alone may be contraindicated in psychotic patients. On the other hand, Venkoba Rao (22) found that diazepam had a better effect than placebo in schizophrenic patients. In a more recent study, Karson et al. (23) did a placebo-controlled cross-over study with clonazepam in 13 chronic schizophrenics who had previously been stabilized on neuroleptics; there were no significant differences between placebo and active drug periods. Summing up, controlled trials of benzodiazepines in conventional doses against placebo have not given convincing indications of an antipsychotic effect in schizophrenia. Benzodiazepines alone compared with neuroleptics
Given the largely negative results in trials comparing benzodiazepines alone with placebo, one would not expect positive results from studies comparing benzodiazepines with neuroleptics in schizophrenia. Nevertheless, several controlled studies have reported that benzodiazepines appear to have had about the same effect as neuroleptics, or even somewhat better. However, since such studies have often been performed on a limited number of patients, one should always consider the possibility of a Type I1 error (the conclusion “no difference” is false) in interpreting the results of these studies. In a cross-over trial comparing diazepam (maximum 60 mg), chlorpromazine (maximum 600 mg) and chlorprothixene (maximum 600 mg), each given for 3 weeks with 1-week placebo intervals in 37 chronic schizophrenic patients, Maculans (24) reported an overall improvement rate of 53 yo on chlorprothizene, 46% on chlorpromazine and 59% on diazepam. The symptoms that seemed to respond best to diazepam included anxiety-tension, depression, somatization, emotional apathy, seclusiveness and confused behavior. It can be argued that these effects of diazepam, however valuable, were not the expression of a true antipsychotic effect. As mentioned above, Holden et al. (17) found chlordiazepoxide to be inferior to thioridazine in a cross-over trial in chronic schizophrenics. On the other hand, Hankoff et al. (25) found both chlordiazepoxide and chlorpromazine to be better than placebo in psychotic - mostly schizophrenic - outpatients, and chlordiazepoxide was in fact better than chlorpromazine in some respects. Smith (26) also has reported better effect of chlordiazepoxide, in the high dosage of 150-700 mg, than chlorpromazine in schizophrenic patients. In a more recent trial, Lerner et al. (27) randomly
gave intravenous haloperidol (20-35 mg) or diazepam (30-40mg) to 40 acutely psychotic patients, including schizophrenics, and found both drugs to give marked and rapid improvement, with no significant difference. No placebo group was included, but given the established effectiveness of haloperidol in such patients, the trial indicates a true effect of diazepam (but one should also be aware of the effectiveness of placebo in such a treatment situation!). In sum, the relatively few trials that have been performed comparing benzodiazepines alone with neuroleptics in schizophrenic patients, often with less than optimal definitions of patient groups and improvement criteria, do not seem to warrant firm conclusions. Together with other data presented in this survey, these trials indicate a certain effect against psychotic schizophrenic symptoms, but this effect is, in general, not as good as can be obtained with neuroleptics. Benzodiazepines vs placebo as an adjunct to neuroleptics
Several controlled trials seem to establish that benzodiazepines may enhance the antipsychotic effect of neuroleptics. However, also in this area there are some clearly negative reports. The negative studies mainly comprise 3 large trials carried out by Kurlan, Hanlon, Michaux et al. (28-32). In these trials, acutely disturbed, predominantly schizophrenic patients were treated with chlorpromazine, thioridazine or fluphenazine, either alone or in combination with chlordiazepoxide (3040mg), imipramine (not to be discussed here) or placebo. In all 3 studies, an attenuating effect of chlordiazepoxide on the antipsychotic effect of the phenothiazines was observed. Some of the inferior effect of the chlordiazepoxide-phenothiazinecombination, at least in the chlorpromazine trial, may have been caused by a lower dose of the phenothiazine in the combination group, but this cannot explain the overall results. The effect of adding chlordiazepoxide was not uniformly poor; thus, the combination of chlorpromazine and chlordiazepoxide was better than chlorpromazine alone in the most disturbed patients, and also in the highly agitated and the highly retarded patients. A weakness of these studies, which were performed in the 1960s and the 1970s, is an unsatisfactory definition of the patient groups. Others have reported more favorable effect of chlordiazepoxide as an adjunct to neuroleptics. Ulett et al. (33) added chlordiazepoxide (40 mg) or placebo to thioridazine, tetrabenazine or fluphenazine in chronic psychotic - mainly schizophrenic - patients, and observed a noticeable behavioral improvement with chlordiazepoxide. In a small multiple cross-over study, Kellner et al. (34) found that chlordiazepoxide in a dosage of up to 300mg in 455
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some patients had a better effect than placebo when added to neuroleptics in anxious schizophrenics. Only 2 controlled trials seem to have compared diazepine with placebo in addition to neuroleptics in schizophrenic patients. In a cross-over trial. Lingjaerde et al. (35) gave 15 mg diazepam or placebo, in 3-week periods, in addition to continued neuroleptic medication, to 23 chronic psychotic patients (19 schizophrenics). Diazepam was significantly better than placebo in improving the total score on the Brief Psychiatric Rating Scale, and on the symptoms suspiciousness and unusual thought content; the difference was nearly significant also for anxiety and hallucinatory behavior. In a more recent study, Csernansky et al. (36) treated 55 schizophrenic outpatients with predominantly negative symptoms for up to 6 weeks with diazepam (mean dose 40.4mg), alprazolam (mean dose 4.2 mg) or placebo in addition to neuroleptics. In the first week there was a somewhat lower symptom score in the alprazolam group, but later on there was no difference between the 3 groups, neither on negative nor positive symptoms. Lorazepam (6 mg) was compared with placebo in 60 haloperidol-treated acutely psychotic patients in a 4-week study by Guz et al. (37). A significant difference in favor of lorazepam was observed on the symptoms anxious mood, delusions-hallucinations and behavior. Clonazepam was compared with placebo as an adjunct to haloperidol in a 4-week trial in 24 schizophrenic patients by Altamura et al. (38). A significantly better and more rapid effect was observed with clonazepam (3 mg), especially on excitement, but not on typical psychotic symptoms. There were fewer extrapyramidal side effects in the clonazepam group. During recent years, the triazolobenzodiazepines have attracted considerable interest as possibly effective drugs against panic disorder, depression, and schizophrenia. The first to be tested against placebo in schizophrenia was estazolam, developed by Takeda Industries in Japan. Based on the clinical observation that this benzodiazepine seemed to have a remarkable antihallucinatory effect in some schizophrenic patients (39), estazolam was compared with placebo in a double-blind, double cross-over trial in 58 patients with auditory hallucinations (40). Fortynine of the patients were schizophrenics, and all except 5 were continued on previous neuroleptic medication throughout the three 3-week treatment periods. Estazolam (6 mg) was given either in the first and third periods or in the second period, and placebo in the other periods. Estazolam was found to have a significantly better effect than placebo on the global clinical state, frequency and attitude towards the auditory hallucinations and compulsive thoughts
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and visual hallucinations. The antihallucinatory effect of estazolam usually appears in a few days, and also disappears rather rapidly after terminating medication. Thus, this effect seems to be more superficially symptomatic than is the antipsychotic effect of neuroleptics. Another triazolobenzodiazepine, alprazolam, has shown promising results in several uncontrolled trials (see above), but has also been compared with placebo. Wolkowitz et al. (4 1) compared alprazolam with placebo in a multiple cross-over trial in 2 schizophrenic patients on stable neuroleptic medication, and reported a clear effect on both negative and positive symptoms, with worsening after terminating alprazolam medication. Later, the same group have reported on a placebo-controlled trial in 12 chronic schizophrenic patients, with alprazolam given in dosages up to 5 mg, in addition to fluphenazine (42). A significant effect of alprazolam was seen on positive symptoms, and on global psychosis rating, thought disorder and paranoia rating. Interestingly, responders showed more prefrontal cortical atrophy than the nonresponders, and were also more anxious and more psychotic pre-treatment. A recent article from the same group reports that schizophrenic patients given alprazolam in addition to neuroleptics fall into 2 groups: alprazolam responders, showing improvement of psychotic symptoms, depression and anxiety, and alprazolam nonresponders, showing no effect or an increase in anxiety and depression scores (43). This interesting observation may be of great clinical relevance, but so far it is difficult to predict the response from the patient’s clinical picture prior to adding alprazolam. Another recent observation, however, may indicate that schizophrenics who are reasonably well stabilized on neuroleptic medication may be destabilized and show deterioration when given alprazolam in addition (44). So far it is uncertain whether this is the case also for other benzodiazepines. As already mentioned, Csernansky et al. (36) found no marked effect of alprazolam when given in addition to neuroleptics in schizophrenic outpatients with negative symptoms. High-dose diazepam in schizophrenia
Some earlier uncontrolled studies indicated that chlordiazepoxide in high doses might have a salutary effect in schizophrenic patients (26, 34), but this has not been explored further. Later on, however, studies with high-dose diazepam monotherapy in schizophrenia have attracted more interest. Beckmann & Haas (45) treated 9 paranoidhallucinatory schizophrenic and 6 schizoaffective patients with diazepam in rapidly increasing dosage, up to 400 mg; most patients were given a maximum
Benzodiazepines in schizophrenia of 200 mg. The schizophrenic patients showed marked improvement of anxiety, hallucinations, conceptual disorganization, unusual thoughts and uncooperativeness, whereas 5 of the schizoaffective patients had to be withdrawn from the trial because of unmanageable hyperactivity, excitation and insomnia. As to side effects, little sedation was seen except after the first 50 mg dose. Above 60 mg, a stimulatory and euphoriant effect was observed in many patients, partly with loss of social and sexual inhibition. Initially some muscular weakness, dysarthria and ataxia were seen, mostly in elderly patients. Nestoros et al. (46) treated 12 paranoid schizophrenic patients for one week with either placebo or diazepam in rapidly increasing doses up to a maximum of 70-400 mg; nonresponders were subsequently given haloperidol in addition. Within a few hours to a few days from the onset of diazepam treatment, both such positive symptoms as hallucinations and delusions, and such negative symptoms as emotional withdrawal and blunted affect were dramatically eliminated in 5 of 6 patients, whereas placebo had no effect in 5 of 6 patients. All patients tolerated high doses of diazepam without sedation as long as they were actively psychotic, but sedation appeared when schizophrenic symptoms were no longer present. Some far less dramatic effects were seen in a preliminary trial on 5 schizophrenic and one schizoaffective patient to whom diazepam was given in doses up to 300mg (47). Likewise, Weizman et al. (48), treating 13 acute schizophrenic patients aged 14-18 years with diazepam up to 400 mg for 4 weeks, obtained only a sedative and no antipsychotic effect. High-dose diazepam has also been tried as an adjunct to neuroleptics. Nestoros et al. (49) gave up to 200mg diazepam to 10 hospitalized chronic schizophrenic patients resistant to standard neuroleptics. In this open trial, 3 patients showed marked improvement of such symptoms as anxiety, emotional withdrawal, conceptual disorganization, tension, mannerism-posturing, suspiciousness, hostility and hallucinosis. Moderate improvement was seen in 4 patients, slight improvement in 1, and no change in 2. All improved patients were of the paranoid type, whereas the unresponsive were of the undifferentiated type. Summing up, some schizophrenic (but not schizoaffective) patients, mainly with paranoidhallucinatory symptoms, seem to benefit from highdose diazepam, either alone or in addition to neuroleptics. In most schizophrenic patients, doses up to several hundred milligrams daily are remarkably well tolerated, but sedation and disinhibition may be bothersome in some patients.
Conclusion
It is not easy to draw firm conclusions from published studies on the effect of benzodiazepines in schizophrenia, since so many of the studies have been uncontrolled, and since the conclusions drawn varies from worse than placebo to better than neuroleptics. However, the following conclusions seem to be warranted: 0
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When given alone in conventional doses (such as those given in nonpsychotic states), benzodiazepines may have an anxiolytic and a general sedative effect, but no convincing antipsychotic effect, although there have been claims to the contrary. When given alone in high dosage (for example, 10 times higher than used in nonpsychotic states), such benzodiazepines as diazepam seem to have a therapeutic effect especially in paranoidhallucinatory schizophrenic patients. This effect includes improvement of anxiety and tension, but also of typically psychotic symptoms like hallucinations, delusions, and disturbed thought. However, some patients may react with loss of social and sexual inhibition on this high-dose treatment. Benzodiazepines, also in ordinary dosage, may enhance the antipsychotic effect of neuroleptics in some schizophrenic patients who have not responded satisfactorily to neuroleptics alone. This effect is most conspicuous against hallucinations, but improvement may also be seen in several other symptoms, such as delusion, suspiciousness, disturbed thought, compulsions and - of course - in anxiety and tension. These beneficial effects of benzodiazepines as an adjunct to neuroleptics usually appear rather quickly, often during the first day of treatment. However, on terminating benzodiazepine treatment in such patients, improved symptoms - such as auditory hallucinations - may also reappear in a few days. Continued treatment does not seem to give rise to tolerance to the antipsychotic effects. In patients responding satisfactorily to neuroleptics alone, adding benzodiazepines (at least alprazolam) may have a destabilizing effect. The various benzodiazepines probably differ in their ability to enhance the antipsychotic effect of neuroleptics, but practically no comparative trials address this question. My personal clinical impre s sion is that the tri az olobenz odi az epin e e st azolam has a better antihallucinatory effect than, for instance, diazepam. If so, the question arises whether triazolobenzodiazepines as a group, and perhaps also the nearly related clonazepam, has a better antipsychotic effect than the ordinary benzodiazepin es like diazepam and chlor diazep457
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oxide. Further studies are required to elucidate this question. References 1. LINGJERDE 0. Benzodiazepines in the treatment of schizophrenia. In: COSTAE, ed. The benzodiazepines: from molecular biology to clinical practice. New York: Raven Press, 1983: 369-381. 2. LINGJERDE 0 . Antipsychotic effect of the benzodiazepines. GD, NORMAN TR, DAVISB, ed. Drugs in In: BURROWS psychiatry, Vol3: Antipsychotics. Amsterdam: Elsevier, 1985: 163-1 72. W. Klinische Erfahrungen mit dem Benzodi3. POELDINGER azepinderivat Valium, einem neuen Psychopharmakon. Schweiz Med Wochenschr 1963: 93: 797-801. 4. VINAR0, TAUSSIGOVA D. Therapeutic effects of diazepam in psychotics. Activ Nerv Superior 1966: 8: 441-444. 5. DYEEN. Dual pharmacotherapy in grossly disturbed psychotic patients. Am J Psychiatry 1961: 118: 548-549. 6. MONROE RR, WISE SP. Combined phenthiazine, chlordiazepoxide and primidone therapy for uncontrolled psychotic patients. Am J Psychiatry 1965: 122: 694-698. 7. ANSARI JMA. Lorazepam in control of acute psychotic symptoms and its comparison with flupenthixol. In: USDINE, IS, ed. Phenothiazines and structurally ECKERT H, FORREST related drugs: basic and clinical studies. Amsterdam: Elsevier, 1980: 299-302. 8. COHENS, KHANA. Adjunctive benzodiazepines in acute schizophrenia. Neuropsychobiology 1987: 18: 9-12. 9. SALZMAN C, GREENAI, RODRIGUEZ-VILLA F, JASKIW GE. Lorazepam-neuroleptic combination for acute disruptive behavior. Poster presented at Ann Meeting of the Am Coll Neuropsychopharmacol, Maui, Dec 9-13, 1985. 10. RAINESJM, GREENSPAN D. Clonazepam in the treatment of chronic schizophrenia. Am J Psychiatry 1987: 144: 1510. 11. VICTORBS, LINKNA, BINDERRL, BELLIR. Use of clonazepam in mania and schizoaffective disorders. Am J Psychiatry 1984: 141: 1111-1112. 12. FRYKHOLM B. Clonazepam - antipsychotic effect in a case of schizophrenia-like psychosis with epilepsy and in three cases of atypical psychosis. Acta Psychiatr Scand 1985: 71: 539-542. 13. KAHN JP, PUERTOLLANO M, SHANEMD, KLEINDF. Schizophrenia, panic anxiety, and alprazolam. Am J Psychiatry 1987: 144: 527-528. 14. KULIKFA, WILBURR. High dose alprazolam in schizophrenia. J Clin Psychopharmacol 1986: 6: 191-192. 15. DOUYONR, ANGRISTB, PESELOW E, COOPERT, RoTROSEN J. Neuroleptic augmentation with alprazolam: clinical effects and pharmacokinetic correlates. Am J Psychiatry 1989: 146: 231-234. 16. BACHER NM, LEWISHA, FIELDPB. Combined alprazolam and neuroleptic drug in treating schizophrenia. Am J Psychiatry 1986: 143: 1311-1312. JMC, ITILTM, KESKINER A, FINKM. Thiorida17. HOLDEN zine and chlordiazepoxide, alone and combined, in the treatment of chronic schizophrenia. Compr Psychiatry 1968: 9: 633-643. D, SILVERA. The effects of chlordi18. AZIMAA, ARTHURS azepoxide (Librium) in anxiety states: a multi-blind study. Can Psychiatr Assoc J 1962: 7: 44-50. 19. MERLISS, TURNERWJ, KRUMHOLZ W. A double blind comparison of diazepam, chlordiazepoxide, and chlorpromazine in psychotic patients. J Neuropsychiatry 1962: 3: (suppl 11): 133-138. 20. HOLLISTER LE, BENNETTJL, KIMBELL I Jr, SAVAGE c, OVERALL JE. Diazepam in newly admitted schizophrenics. Dis Nerv Syst 1963: 24: 746-749.
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BE, SPEES RC, 46. NESTOROSJN, SURANYI-CADOTTE SCHWARTZG, NAIR NPV. Diazepam in high doses is effective in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 1982: 6: 513-516. 47. JIMERSON DC, VAN KAMMEN DP, POSTRM. DOCHERTY JP, BUNNEYWE Jr. Diazepam in schizophrenia: a preliminary double-blind trial. Am J Psychiatry 1982: 139: 489491. H, DAVIDMB. 48. WEIZMANAN, TYANOS, WIJSENBEEK High dose diazepam treatment and its effect on prolactin secretion in adolescent schizophrenic patients. Psychopharmacology 1984: 82: 382-385. 49. NESTOROSJN, NAIR NPV, PULMANJR, SCHWARTZG. BLOOMD. High dose of diazepam improve neurolepticresistant chronic schizophrenic patients. Psychopharmacology 1983: 81: 4 2 4 7 .
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Benzodiazepines in the treatment of schizophrenia: an updated survev Lingjade 0. Benzodiazepines in the treatment of schizophrenia: an updated survey. Acta Psychiatr Scand 1991: 84: 453-459.
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Reports on the effects of benzodiazepines in schizophrenia have appeared since the early 1960s. Conclusions drawn from these studies, most of which have been uncontrolled, have ranged from worse than placebo to better than neuroleptics. A critical appraisal of the literature seems to warrant the following main conclusions. Benzodiazepines alone, in conventional doses, have no convincing antipsychotic effect in schizophrenia, although they may reduce anxiety, tension and insomnia. However, very high doses of diazepam, and possibly other benzodiazepines, may have a symptomatic antipsychotic effect, especially in paranoid-hallucinatory schizophrenics, also when given alone. Benzodiazepines, in conventional doses, can enhance the antipsychotic effect of neuroleptics in schizophrenics who have not responded satisfactorily to neuroleptics alone. This effect may be most conspicuous against hallucinations, but improvement may also be obtained from delusions, thought disturbances, some negative symptoms, anxiety and tension. Some benzodiazepines may be more effective than others in schizophrenia, but this has been insufficiently elucidated.
Neuroleptics have long since been established as the most important drugs in the treatment of schizophrenia. However, there is often a need for alternative drugs when neuroleptics have unsatisfactory therapeutic effect or preduce too disturbing side effects. Alternative drugs can either be used alone - to replace neuroleptics - or in addition to continued neuroleptic medication. The first alternative would seem to be preferable, but unfortunately very few schizophrenics derive substantial benefit from alternative drugs given alone. The relevant alternative is therefore more often to give a non-neuroleptic drug in addition to continued neuroleptic medication. This combined medication may have 2 favorable effects: first, there may be a better therapeutic effect on such symptoms as hallucinations, delusions or aggressiveness than was obtained with neuroleptics alone. Second, even if the therapeutic effect is not definitely better, it may be obtained with a lower dose and therefore produce fewer side effects. As an example, this may be the result of adding carbamazepine to haloperidol in manic or acute schizophrenic states. The difference between this use of
0. Lingjade Gaustad Hospital, Oslo, Norway
Key words: benzodiazepines; schizophrenia
0. Lingjade, M.D., Department of Psychiatry, Gaustad Hospital, N-0320 Oslo 3, Norway Accepted for publication August 12, 199 1
adjunctive drugs and the use of drugs against side effects - such as anticholinergics against parkinsonism - is that the latter are purely aimed at reducing side effects, and not at potentiating the therapeutic effect of the neuroleptics. Through the years, many different drugs have been claimed to be useful alternatives to or adjuncts to neuroleptics in schizophrenia, but few have been firmly established as particularly useful. However, especially when given in addition to neuroleptics, such drugs as tricyclic antidepressants, lithium, carbamazepine and benzodiazepines may have favorable effects on schizophrenic symptoms in several patients. I will try to give an updated survey of published experiences with benzodiazepines in schizophrenia; I feel that this type of drug ought to be tried more often in this condition. Previous surveys, on which the present one is partly based, have been published in edited monographs appearing in 1983 (1) and 1985 (2). Generally speaking, benzodiazepines may be given to schizophrenic patients for 3 different purposes: (a) against anxiety, tension or insomnia, similar to 453
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non-psychotic patients; (b) against such neurolepticinduced side effects as akathisia or tardive dyskinesia; and (c) against psychotic symptoms, such as hallucinations, delusions, thought disorders and psychotic excitement. Only the effect on psychotic symptoms will be addressed here. Many clinicians doubt that benzodiazepines have a true antipsychotic effect - beyond that which might be explained as “only” secondary to the anxiolytic and sedative effects. However, besides many negative reports, over the years numerous reports of uncontrolled and controlled studies have appeared that seem to warrant the conclusion that some benzodiazepines may, at least in certain schizophrenic patients, exert a favorable effect on psychotic symptoms, especially when given as an adjunct to neuroleptics. Many of the studies on benzodiazepines in psychosis were published in the 1960s, and several of them do not quite satisfy modern standards for clinical trials. Also, during recent years there have been published many anecdotal reports and small, uncontrolled studies, but some controlled ones as well. However, more controlled studies are still needed in this field. In clinical studies with benzodiazepines in schizophrenia, the dosages have usually been within the conventional range used in nonpsychotic states. In some interesting recent studies, on the other hand, diazepam has been used alone in extremely high doses, which have been claimed to be remarkably effective in some patients. This has prompted a renewed interest in the possible antipsychotic effect of this drug class. In this survey, I first refer to studies with benzodiazepines in conventional doses in open and controlled studies before commenting on studies with high-dose diazepam. Uncontrolled studies
Already in the early 1960s, several reports appeared claiming that diazepam had an excellent symptomatic effect in schizophrenia, especially against hallucinations (3,4), but there were also many negative reports (2). There were also reports claiming that chlordiazepoxide enhanced the antipsychotic effect of neuroleptics ( 5 , 6 ) . Taken as a whole, these early reports on uncontrolled trials were rather inconsistent and not quite convincing, but still promising. In the 1980s, there has been a renewed interest in the effect of benzodiazepines in schizophrenia and other psychoses, and besides some controlled studies (see later), several case reports and small uncontrolled studies have been published, mainly on such newer benzodiazepines as lorazepam, clonazepam, estazolam and alprazolam.
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Ansari (1) reported that lorazepam, given intravenously, had a rapid effect on hallucinations, aggressiveness, social behavior and disturbed ego boundaries in 8 acutely schizophrenic patients. Cohen & Khan (8) and Saltzman et al. (9) have reported a good effect of lorazepam in addition to neuroleptics in schizophrenic patients. Clonazepam, which has been marketed mainly as an antiepileptic, is also said to give some remarkable effects in schizophrenics in addition to neuroleptics (lo), and may also have a marked effect given alone to schizoaffective patients (1 1) and to atypical psychoses (12). Alprazolam, a triazolobenzodiazepine shown to be effective especially in panic disorder, and also to have some antidepressant effect, has been reported to have a good effect in schizophrenic patients with panic attacks (13), and also, when given in a relatively high dose, in schizophrenic patients with more unspecific anxiety (14). In a small, uncontrolled study, Douyon et al. (15) found that alprazolam, given in addition to neuroleptics, reduced both positive and negative symptoms in schizophrenic patients, although with varying effect in different patients. Less satisfactory effect of alprazolam - again in addition to neuroleptics -in chronic schizophrenic patients was reported by Bacher et al. (16); in 3 patients, an acute paranoid delusional state developed during alprazolam treatment. This is in agreement with some controlled studies to be mentioned later. Another triazolobenzodiazepine, estazolam, seems to be especially effective against hallucinations (see below). These more recent uncontrolled studies with newer benzodiazepines in schizophrenia are again promising, but seen in isolation, they carry little weight as evidence for an antipsychotic effect of such drugs. However, some controlled studies also corroborate this antipsychotic effect of newer benzodiazepines, at least when given in addition to neuroleptics. Benzodiazepines alone compared with placebo
Holden et al. (17) compared chlordiazepoxide (1 mg/ kg) with thioridazine and placebo in 24 schizophrenic men, and found chlordiazepoxide to be inferior to thioridazine, but significantly better than placebo for such symptoms as negativism, euphoria, disturbance of life drive, confusion and increased appetite. However, Azima et al. (18) found no difference between chlordiazepoxide (20-200 mg) and placebo. In the 1960s several reports also appeared on studies comparing diazepam with placebo in hospitalized schizophrenics; several of them concluded that diazepam was not markedly superior (19-2 1).
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One of these studies (21) even found that patients on diazepam more often developed suicidal or paranoid thoughts, prompting the authors to conclude that diazepam alone may be contraindicated in psychotic patients. On the other hand, Venkoba Rao (22) found that diazepam had a better effect than placebo in schizophrenic patients. In a more recent study, Karson et al. (23) did a placebo-controlled cross-over study with clonazepam in 13 chronic schizophrenics who had previously been stabilized on neuroleptics; there were no significant differences between placebo and active drug periods. Summing up, controlled trials of benzodiazepines in conventional doses against placebo have not given convincing indications of an antipsychotic effect in schizophrenia. Benzodiazepines alone compared with neuroleptics
Given the largely negative results in trials comparing benzodiazepines alone with placebo, one would not expect positive results from studies comparing benzodiazepines with neuroleptics in schizophrenia. Nevertheless, several controlled studies have reported that benzodiazepines appear to have had about the same effect as neuroleptics, or even somewhat better. However, since such studies have often been performed on a limited number of patients, one should always consider the possibility of a Type I1 error (the conclusion “no difference” is false) in interpreting the results of these studies. In a cross-over trial comparing diazepam (maximum 60 mg), chlorpromazine (maximum 600 mg) and chlorprothixene (maximum 600 mg), each given for 3 weeks with 1-week placebo intervals in 37 chronic schizophrenic patients, Maculans (24) reported an overall improvement rate of 53 yo on chlorprothizene, 46% on chlorpromazine and 59% on diazepam. The symptoms that seemed to respond best to diazepam included anxiety-tension, depression, somatization, emotional apathy, seclusiveness and confused behavior. It can be argued that these effects of diazepam, however valuable, were not the expression of a true antipsychotic effect. As mentioned above, Holden et al. (17) found chlordiazepoxide to be inferior to thioridazine in a cross-over trial in chronic schizophrenics. On the other hand, Hankoff et al. (25) found both chlordiazepoxide and chlorpromazine to be better than placebo in psychotic - mostly schizophrenic - outpatients, and chlordiazepoxide was in fact better than chlorpromazine in some respects. Smith (26) also has reported better effect of chlordiazepoxide, in the high dosage of 150-700 mg, than chlorpromazine in schizophrenic patients. In a more recent trial, Lerner et al. (27) randomly
gave intravenous haloperidol (20-35 mg) or diazepam (30-40mg) to 40 acutely psychotic patients, including schizophrenics, and found both drugs to give marked and rapid improvement, with no significant difference. No placebo group was included, but given the established effectiveness of haloperidol in such patients, the trial indicates a true effect of diazepam (but one should also be aware of the effectiveness of placebo in such a treatment situation!). In sum, the relatively few trials that have been performed comparing benzodiazepines alone with neuroleptics in schizophrenic patients, often with less than optimal definitions of patient groups and improvement criteria, do not seem to warrant firm conclusions. Together with other data presented in this survey, these trials indicate a certain effect against psychotic schizophrenic symptoms, but this effect is, in general, not as good as can be obtained with neuroleptics. Benzodiazepines vs placebo as an adjunct to neuroleptics
Several controlled trials seem to establish that benzodiazepines may enhance the antipsychotic effect of neuroleptics. However, also in this area there are some clearly negative reports. The negative studies mainly comprise 3 large trials carried out by Kurlan, Hanlon, Michaux et al. (28-32). In these trials, acutely disturbed, predominantly schizophrenic patients were treated with chlorpromazine, thioridazine or fluphenazine, either alone or in combination with chlordiazepoxide (3040mg), imipramine (not to be discussed here) or placebo. In all 3 studies, an attenuating effect of chlordiazepoxide on the antipsychotic effect of the phenothiazines was observed. Some of the inferior effect of the chlordiazepoxide-phenothiazinecombination, at least in the chlorpromazine trial, may have been caused by a lower dose of the phenothiazine in the combination group, but this cannot explain the overall results. The effect of adding chlordiazepoxide was not uniformly poor; thus, the combination of chlorpromazine and chlordiazepoxide was better than chlorpromazine alone in the most disturbed patients, and also in the highly agitated and the highly retarded patients. A weakness of these studies, which were performed in the 1960s and the 1970s, is an unsatisfactory definition of the patient groups. Others have reported more favorable effect of chlordiazepoxide as an adjunct to neuroleptics. Ulett et al. (33) added chlordiazepoxide (40 mg) or placebo to thioridazine, tetrabenazine or fluphenazine in chronic psychotic - mainly schizophrenic - patients, and observed a noticeable behavioral improvement with chlordiazepoxide. In a small multiple cross-over study, Kellner et al. (34) found that chlordiazepoxide in a dosage of up to 300mg in 455
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some patients had a better effect than placebo when added to neuroleptics in anxious schizophrenics. Only 2 controlled trials seem to have compared diazepine with placebo in addition to neuroleptics in schizophrenic patients. In a cross-over trial. Lingjaerde et al. (35) gave 15 mg diazepam or placebo, in 3-week periods, in addition to continued neuroleptic medication, to 23 chronic psychotic patients (19 schizophrenics). Diazepam was significantly better than placebo in improving the total score on the Brief Psychiatric Rating Scale, and on the symptoms suspiciousness and unusual thought content; the difference was nearly significant also for anxiety and hallucinatory behavior. In a more recent study, Csernansky et al. (36) treated 55 schizophrenic outpatients with predominantly negative symptoms for up to 6 weeks with diazepam (mean dose 40.4mg), alprazolam (mean dose 4.2 mg) or placebo in addition to neuroleptics. In the first week there was a somewhat lower symptom score in the alprazolam group, but later on there was no difference between the 3 groups, neither on negative nor positive symptoms. Lorazepam (6 mg) was compared with placebo in 60 haloperidol-treated acutely psychotic patients in a 4-week study by Guz et al. (37). A significant difference in favor of lorazepam was observed on the symptoms anxious mood, delusions-hallucinations and behavior. Clonazepam was compared with placebo as an adjunct to haloperidol in a 4-week trial in 24 schizophrenic patients by Altamura et al. (38). A significantly better and more rapid effect was observed with clonazepam (3 mg), especially on excitement, but not on typical psychotic symptoms. There were fewer extrapyramidal side effects in the clonazepam group. During recent years, the triazolobenzodiazepines have attracted considerable interest as possibly effective drugs against panic disorder, depression, and schizophrenia. The first to be tested against placebo in schizophrenia was estazolam, developed by Takeda Industries in Japan. Based on the clinical observation that this benzodiazepine seemed to have a remarkable antihallucinatory effect in some schizophrenic patients (39), estazolam was compared with placebo in a double-blind, double cross-over trial in 58 patients with auditory hallucinations (40). Fortynine of the patients were schizophrenics, and all except 5 were continued on previous neuroleptic medication throughout the three 3-week treatment periods. Estazolam (6 mg) was given either in the first and third periods or in the second period, and placebo in the other periods. Estazolam was found to have a significantly better effect than placebo on the global clinical state, frequency and attitude towards the auditory hallucinations and compulsive thoughts
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and visual hallucinations. The antihallucinatory effect of estazolam usually appears in a few days, and also disappears rather rapidly after terminating medication. Thus, this effect seems to be more superficially symptomatic than is the antipsychotic effect of neuroleptics. Another triazolobenzodiazepine, alprazolam, has shown promising results in several uncontrolled trials (see above), but has also been compared with placebo. Wolkowitz et al. (4 1) compared alprazolam with placebo in a multiple cross-over trial in 2 schizophrenic patients on stable neuroleptic medication, and reported a clear effect on both negative and positive symptoms, with worsening after terminating alprazolam medication. Later, the same group have reported on a placebo-controlled trial in 12 chronic schizophrenic patients, with alprazolam given in dosages up to 5 mg, in addition to fluphenazine (42). A significant effect of alprazolam was seen on positive symptoms, and on global psychosis rating, thought disorder and paranoia rating. Interestingly, responders showed more prefrontal cortical atrophy than the nonresponders, and were also more anxious and more psychotic pre-treatment. A recent article from the same group reports that schizophrenic patients given alprazolam in addition to neuroleptics fall into 2 groups: alprazolam responders, showing improvement of psychotic symptoms, depression and anxiety, and alprazolam nonresponders, showing no effect or an increase in anxiety and depression scores (43). This interesting observation may be of great clinical relevance, but so far it is difficult to predict the response from the patient’s clinical picture prior to adding alprazolam. Another recent observation, however, may indicate that schizophrenics who are reasonably well stabilized on neuroleptic medication may be destabilized and show deterioration when given alprazolam in addition (44). So far it is uncertain whether this is the case also for other benzodiazepines. As already mentioned, Csernansky et al. (36) found no marked effect of alprazolam when given in addition to neuroleptics in schizophrenic outpatients with negative symptoms. High-dose diazepam in schizophrenia
Some earlier uncontrolled studies indicated that chlordiazepoxide in high doses might have a salutary effect in schizophrenic patients (26, 34), but this has not been explored further. Later on, however, studies with high-dose diazepam monotherapy in schizophrenia have attracted more interest. Beckmann & Haas (45) treated 9 paranoidhallucinatory schizophrenic and 6 schizoaffective patients with diazepam in rapidly increasing dosage, up to 400 mg; most patients were given a maximum
Benzodiazepines in schizophrenia of 200 mg. The schizophrenic patients showed marked improvement of anxiety, hallucinations, conceptual disorganization, unusual thoughts and uncooperativeness, whereas 5 of the schizoaffective patients had to be withdrawn from the trial because of unmanageable hyperactivity, excitation and insomnia. As to side effects, little sedation was seen except after the first 50 mg dose. Above 60 mg, a stimulatory and euphoriant effect was observed in many patients, partly with loss of social and sexual inhibition. Initially some muscular weakness, dysarthria and ataxia were seen, mostly in elderly patients. Nestoros et al. (46) treated 12 paranoid schizophrenic patients for one week with either placebo or diazepam in rapidly increasing doses up to a maximum of 70-400 mg; nonresponders were subsequently given haloperidol in addition. Within a few hours to a few days from the onset of diazepam treatment, both such positive symptoms as hallucinations and delusions, and such negative symptoms as emotional withdrawal and blunted affect were dramatically eliminated in 5 of 6 patients, whereas placebo had no effect in 5 of 6 patients. All patients tolerated high doses of diazepam without sedation as long as they were actively psychotic, but sedation appeared when schizophrenic symptoms were no longer present. Some far less dramatic effects were seen in a preliminary trial on 5 schizophrenic and one schizoaffective patient to whom diazepam was given in doses up to 300mg (47). Likewise, Weizman et al. (48), treating 13 acute schizophrenic patients aged 14-18 years with diazepam up to 400 mg for 4 weeks, obtained only a sedative and no antipsychotic effect. High-dose diazepam has also been tried as an adjunct to neuroleptics. Nestoros et al. (49) gave up to 200mg diazepam to 10 hospitalized chronic schizophrenic patients resistant to standard neuroleptics. In this open trial, 3 patients showed marked improvement of such symptoms as anxiety, emotional withdrawal, conceptual disorganization, tension, mannerism-posturing, suspiciousness, hostility and hallucinosis. Moderate improvement was seen in 4 patients, slight improvement in 1, and no change in 2. All improved patients were of the paranoid type, whereas the unresponsive were of the undifferentiated type. Summing up, some schizophrenic (but not schizoaffective) patients, mainly with paranoidhallucinatory symptoms, seem to benefit from highdose diazepam, either alone or in addition to neuroleptics. In most schizophrenic patients, doses up to several hundred milligrams daily are remarkably well tolerated, but sedation and disinhibition may be bothersome in some patients.
Conclusion
It is not easy to draw firm conclusions from published studies on the effect of benzodiazepines in schizophrenia, since so many of the studies have been uncontrolled, and since the conclusions drawn varies from worse than placebo to better than neuroleptics. However, the following conclusions seem to be warranted: 0
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When given alone in conventional doses (such as those given in nonpsychotic states), benzodiazepines may have an anxiolytic and a general sedative effect, but no convincing antipsychotic effect, although there have been claims to the contrary. When given alone in high dosage (for example, 10 times higher than used in nonpsychotic states), such benzodiazepines as diazepam seem to have a therapeutic effect especially in paranoidhallucinatory schizophrenic patients. This effect includes improvement of anxiety and tension, but also of typically psychotic symptoms like hallucinations, delusions, and disturbed thought. However, some patients may react with loss of social and sexual inhibition on this high-dose treatment. Benzodiazepines, also in ordinary dosage, may enhance the antipsychotic effect of neuroleptics in some schizophrenic patients who have not responded satisfactorily to neuroleptics alone. This effect is most conspicuous against hallucinations, but improvement may also be seen in several other symptoms, such as delusion, suspiciousness, disturbed thought, compulsions and - of course - in anxiety and tension. These beneficial effects of benzodiazepines as an adjunct to neuroleptics usually appear rather quickly, often during the first day of treatment. However, on terminating benzodiazepine treatment in such patients, improved symptoms - such as auditory hallucinations - may also reappear in a few days. Continued treatment does not seem to give rise to tolerance to the antipsychotic effects. In patients responding satisfactorily to neuroleptics alone, adding benzodiazepines (at least alprazolam) may have a destabilizing effect. The various benzodiazepines probably differ in their ability to enhance the antipsychotic effect of neuroleptics, but practically no comparative trials address this question. My personal clinical impre s sion is that the tri az olobenz odi az epin e e st azolam has a better antihallucinatory effect than, for instance, diazepam. If so, the question arises whether triazolobenzodiazepines as a group, and perhaps also the nearly related clonazepam, has a better antipsychotic effect than the ordinary benzodiazepin es like diazepam and chlor diazep457
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702-706. 39. LINGJBRDE0, ASTRUPC. Mulig antipsykotisk virkning av benzodiazepiner, med szrlig henblikk pB estazolam (Domnamid). Nord Psykiatr Tidsskr 1978: 32: 421424. 40. LINGJBRDE0. Effect of the benzodiazepine derivative estazolam in patients with auditory hallucinations. A multicentre double-blind, cross-over study. Acta Psychiatr Scand 1982: 65: 339-354. 41. WOLKOWITZ OM, PICKARD, DORANAR, BREIERA, TARELL,PAULSM. Combination alprazolam-neuroleptic
Benzodiazepines in schizophrenia treatment of the positive and negative symptoms of schizophrenia. Am J Psychiatry 1986: 143: 85-87. 42. WOLKOWITZ OM, BREIERA, DORAN A et al. Alprazolam augmentation of the antipsychotic effects of fluphenazine in schizophrenic patients. Arch Gen Psychiatry 1988: 45: 664671. 43. PATOCN, WOLKOWITZ OM, RAPAPORTM, SCHULZSC, PICKAR D. Benzodiazepine augmentation of neuroleptic treatment in patients with schizophrenia. Psychopharmacol Bull 1989: 25: 263-266. 44. DIXONL, WEIDENPJ, FRANCES AJ, SWEENEYJ. Alprazolam intolerance in stable schizophrenic outpatients. Psychopharmacol Bull 1989: 25: 213-214. H, HAASS. High-dose diazepam in schizophre45. BECKMANN nia. Psychopharmacology 1980: 71: 79-82.
BE, SPEES RC, 46. NESTOROSJN, SURANYI-CADOTTE SCHWARTZG, NAIR NPV. Diazepam in high doses is effective in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 1982: 6: 513-516. 47. JIMERSON DC, VAN KAMMEN DP, POSTRM. DOCHERTY JP, BUNNEYWE Jr. Diazepam in schizophrenia: a preliminary double-blind trial. Am J Psychiatry 1982: 139: 489491. H, DAVIDMB. 48. WEIZMANAN, TYANOS, WIJSENBEEK High dose diazepam treatment and its effect on prolactin secretion in adolescent schizophrenic patients. Psychopharmacology 1984: 82: 382-385. 49. NESTOROSJN, NAIR NPV, PULMANJR, SCHWARTZG. BLOOMD. High dose of diazepam improve neurolepticresistant chronic schizophrenic patients. Psychopharmacology 1983: 81: 4 2 4 7 .
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