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USE OF BENZODIAZEPINES IN SCHIZOPHRENIA
S. Thirumalai, DPM, MRCPsych, Stephen D. Martin
Middleton St. George Hospital
Darlington
DL2 1TS
Introduction
There is often a need for pharmacological agents when neuroleptics have failed to deliver an immediate therapeutic effect, or when they produce disturbing side effects. Schizophrenia heterogeneity may be behind the difficulties in treating it solely with one drug. Several medications have been tried as alternatives (e.g. Clozapine) or adjuncts (e.g. antidepressants, mood stabilisers and benzodiazepines). Our paper will focus on the role of benzodiazepines in the treatment of schizophrenia.
GABA nergic dysfunction in Schizophrenia
The pharmacological properties of virtually all known antipsychotic medications seems to include the blockade of Dopamine receptors, hence supporting the over-active Dopamine system theory in schizophrenic illness. Benzodiazepine interacts with GABA-nergic systems which modulate dopaminergic systems in the brain. (1Van Kammen, 1977). The stress response in mesocortical dopaminergic systems is also blocked by the benzodiazepines (2*Bunny et al 1987). Interconnections between dopamine and GABA-glutamate have been implicated in the aetiopathogenesis of schizophrenia. (3 Squires et al 1991). Direct acting GABA agonists such as muscimol produce psychotomimetic and cataleptic side effects, which probably suggest that schizophrenia may be related to increased GABA activity. Partial GABA - A receptor agonist Bretazemil, an imidazobenzodiazepine has shown moderate antipsychotic efficacy in schizophrenic patients. (4 A Delini-Stula et al 1996). A reduced GABAnergic tone in limbic cortical regions may correlate with psychotic symptoms in schizophrenia. (5 Busatto et al 1977).
Current Benzodiazepine Use in Schizophrenia
Reports about the use of benzodiazepines in schizophrenia date back to the 1960's. Initial reports were largely based upon uncontrolled trials and the results were inconsistent. In practice Benzodiazepines may be given to the schizophrenic patient for: a) insomnia and anxiety reduction; b) control of florid psychotic symptoms such as hallucinations, delusions, aggression and psychotic excitement; c) reduction of neuroleptic induced side effects such as akathisia or tardive dyskinesia. (6O. Lingjaerde et al 1991). The possible situations warranting review are when there is a delay in the onset of actions by neuroleptics or later response of negative symptoms to neuroleptics.
Efficacy of Benzodiazepines in schizophrenia
Benzodiazepines have been investigated either as a sole agent or adjunct to neuroleptic. There are fifteen double-blind studies reporting the use of benzodiazepines as sole agents in the treatment of schizophrenia. (7 Smith 1961; 8 Hankoff LD et al 1962; 9 Azima et al 1962; 10 Merlis et al 1962; 11 Rao. V.K. 1964; 12 Maculans 1964; 13 Stonehill et al 1966; 14 Gudlach et al 1966; 15 Wekimian et al 1967; 16 Holden 1968; 17 Lerner et al 1979; 18 Nishikawa et al 1982; 19 Nestros et al 1982; 20 Jimerson et al 1982; 21 Carpenter W.T. et al 1999). Two thirds of these studies reported positive results using benzodiazepine. One third reported either no difference or a negative response. It is difficult to interpret these studies especially those conducted in the 1960's and 1970's as there are several problems, e.g. inadequate sample size, poor diagnostic criterion used, short duration of trial periods, inconsistent drug dosing regimens and inconsistent outcome measurements used.
Studies using cross over design (12 Maculans 1964; 13 Stonehill et al 1966, 16 Holden et al 1968; 20 Jimerson et al 1982) state that some patients did show a beneficial response to benzodiazepines. Positive effects when seen ranged from "improved", "moderate" and "marked". These suggest that there could be a group of patients who respond to benzodiazepines. Diazepam was reported to be effective in treating prodromal and early signs of schizophrenia. (21 Carpenter WT et al 1999).
Placebo-crossover double-blind studies of benzodiazepines used an adjunct to neuroleptics (22 Ruskin et al 1979; 23 Lingjaerde et al 1979; 24 Lingjaerde et al 1982; 25 Karson et al 1982; 26 Nestros et al 1983) reported a positive response in three of them with the remaining two showing no response. Three crossover studies have reported favourable responses (27 Holden et al 1968; 28 Wolkowitz et al 1988; 29 Pato et al 1989), multiple crossover studies (30 Kelner et al 1975) reported significant improvement using chlordiazepoxide in three of six patients. Authors (31 Walkowitz et al 1991) found that when the effect did occur they helped to reduce anxiety levels along with symptoms such as hallucinations, delusions and negative symptoms. Interestingly, they also reported the response to be heterogenous with a response rate of about 49%. They suggested the possibility of identifying biological markers for Benzodiazepine responders and non-responders (32 Walkowitz et al 1990). Study (33 Pato et al 1989) reported the effect of alprazolam added to stable neuroleptic regimes, in which they found definite responders and non-responders. Others failed to show such responses (34 Wolkowitz et al 1993).
To date, demonstrable evidence of efficacy is seen when benzodiazepines have been augmented in the acute phase of illness, and hastened the response to neuroleptics and reduced their use to low doses. (35 Salzman et al 1986). Motor symptoms (e.g. akathisia, catatonia) may also be ameliorated with benzodiazepines (36 Menza et al 1989).
Clonazepam is reported to control manic symptoms (37 Chouinard et al 1983); control agitated schizoaffective patients (38 Victor et al 1984); have no effect in the chronic schizophrenic population (39 Karson et al 1982) and have a beneficial effect in the treatment of tardive dyskinesia (40 Thaker et al 1990) associated with neuroleptics. Case reports of behaviour disinhibition (41 Binder, 1987), paradoxical akathisia (42 Joseph et al 1993), withdrawal psychosis (43 Jaffe et al 1996) have been reported with the use of Clonazepam. Midazolam is cited to be effective in controlling agitated psychotic patients (44 Mendoza et al 1987). Alprazolam is reported to be effective against positive symptoms (46 Csernsky et al 1984). Alprazolam augmented with neuroleptics demonstrated a clinically significant antipsychotic response in long term follow up (47 Walkowitz et al 1992). Intolerance to Alprazolam in stable neuroleptic outpatients is reported (48 Dixon et al 1989). There is no consensus regarding the efficacy of benzodiazepines, as the results from various studies have major methodological problems and the outcomes measured were different between studies.
Onset, dose, duration response and choice of benzodiazepine
When a therapeutic response occurs for diminishing agitation it is seen within the initial few hours to a couple of weeks. Reports do suggest that if no response is seen in the reduction of target symptoms by two weeks, benzodiazepines should be gradually withdrawn. There appears to be no correlation between dose and response. If used as an adjunct to neuroleptics then the mean daily average dose is reported by (34 Wolkowitz et al 1991) is about 54 mg +/- 34 mgs per day of diazepam equivalent. In spite of early onset, benzodiazepine appears to lose efficacy in about four weeks (49 Sernansky et al 1999). Many other studies have not observed this pattern (47 Wolkowitz O.M. et al 1992). In spite of lack of consistent evidence, patients with high levels of agitation, prominent initial psychosis, anxiety and panic symptoms have been suggested to be suitable responders. The stable "neuroleptic responsive" outpatients, post-psychotic depression and long stay rehabilitation patients are poor responders. (24 Walkowitz et al 1983).
Potential problems with Benzodiazepines
| Short-term (3 - 4 weeks) |
Long term ( More than 4 weeks) |
|
|
Discussion
Benzodiazepines have gained popularity since the decline of barbiturates in use. There are fifteen benzodiazepines listed in the BNF (50 BNF, 2000). The use of benzodiazepine in an acute psychotic state is primarily to reduce hyperarousal and prevent further exhaustion and harm. Long term use of benzodiazepine has not been adequately researched. Only study (47 Wolkowitz et al 1992 reported the successful use of alprazolam combination to neuroleptic after 37 months of follow -up. The choice of benzodiazepines remains unresolved, although diazepam and lorazepam are the most frequently used benzodiazepines for rapid tranquilisation. (51 Pilowsky et al 1992). High potency benzodiazepines such as alprazolam and clonazepam have been reported to be more effective in neuroleptic augmentation (31 Walkowtiz et al 1991), however low potency is preferred for successful withdrawal in the long term (52 Christison et al1991). Diazepam has been shown to be superior to placebo and comparably effective to fluphenazine in treating early signs of relapse in schizophrenia. (21 Carpenter et al 1999). This study does state the lack of power to detect the difference between diazepam and fluphenazine. It is also difficult to ascertain what are the early signs of relapse or prodromal phase. It is known from evidence (53 Kane et al 1992) that nearly one third of patients with schizophrenia do not respond to conventional neuroleptics. These are the patients who occupy long stay rehabilitation wards. About 10% of these patients with a diagnosis of schizophrenia had received long term benzodiazepines (54 Paton et al 2000). Tolerance, rebound psychosis and withdrawal have been associated with the use of benzodiazepines (55 Petrusson et al 1981). Worsening baseline symptoms in these long term benzodiazepine users would mean increase in benzodiazepine dose, increase or change of the antipsychotic medication. Given these potential problems, is there a need for long term prescription? Is there conclusive evidence for short-term high potency and long-term potency benzodiazepine use in schizophrenia? Do benzodiazepines have an antipsychotic property? How does this work? What are the underlying neurobiological mechanisms?
Research evidence to these questions would probably help us to predict a favourable response, duration of treatment and frequency of dosage. The Committee on the Safety of Medicines and the Royal College of Psychiatrists statement recommend benzodiazepines only for short term relief of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia, short-term psychosomatic, organic or psychotic illness. (56 Priest et al 1988). The Royal College of Psychiatrists' consensus statement on the use of high dose antipsychotics states that benzodiazepines alone or in combination with standard doses of antipsychotic are the drug of choice in rapid tranquilisation. (57 Thompson 1994). It is important as a prescriber to establish clearly the rationale for long term use of benzodiazepines and also to explain and document the reasons for use beyond the CSM guidelines.
Conclusions
Benzodiazepines alone do not treat schizophrenia
Use in schizophrenia should be considered only as a short term adjunct therapy to neuroleptics
Long acting benzodiazepines should be the drugs of choice to reduce tolerance/addiction
Alternatives to benzodiazepines can be considered (e.g. Promethazine, Zopiclone)
Avoid intravenous benzodiazepine use
Avoid high doses
Avoid abrupt withdrawal
Intermittent use should be considered if benzodiazepine long term use is likely
Regular review of dose and duration
Avoid in patients with previous history of alcohol or drug misuse
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