Psychosis refers to a disturbance in reality testing as witnessed by hallucinations, delusions, and/or thought disorder. Hence, psychosis can occur for a variety7 of reasons including the effect of drugs, metabolic disturbances, structural brain lesions, or "functional" disorders such as schizophrenia, manic-depressive illness, and psychotic depressive disorders. In DSM-III-R. psychosis may be a component of clinical presentation in the following conditions: schizophrenia, delusional disorders, some organic mental conditions such as alcohol withdrawal delirium, some mood disorders, and psychotic disorders not elsewhere classified.1
Given the diverse pathology that can produce psychosis, drugs with different mechanisms can have "antipsychotic" effects in specific disorders. There is also a common misconception that the terms "antipsychotic" and "neuroleptic" are interchangeable. As the understanding of brain mechanisms relevant to psychiatry evolves, the advantage of thinking in terms of pathophysiology rather than in terms of syndromes becomes clearer.- It is from this perspective that this article reviews the role of benzodiazepines in treatment of psychosis.
Although benzodiazepines are not generally considered antipsychotic agents, clinical uses range from being the treatment of choice for some psychoses to ameliorative therapy for adverse effects resulting from use of neuroleptics (Table 1). As primary acute therapy, benzodiazepines can promptly and specifically reverse psychosis resulting from sedative-hypnotic drug withdrawal (Table 2). They can also be useful as solo agents for a wide variety of other- psychotic disorders, although their action in these conditions is less specific than in sedative-hypnotic withdrawal. An example of the latter is hallucinogeninduced psychosis. Benzodiazepines can sedate such patients and thus prevent them from harming themselves or others. During the period of sedation, the effect of the hallucinogen is likely to dissipate, leading to a successful resolution of the psychosis.
Use of Benzodiazepines in Psychotic Disorders
Use of Benzodiazepines as Primary Acute Drug Therapy
Benzodiazepines can also be useful in a variety of ways in "functional" psychoses such as manic-depressive illness and schizophrenia (Table 1 ). Reducing agitation and excitement is frequently an immediate goal in the treatment of an acute psychotic episode in such patients. Effective, safe sedation in this situation can be achieved with alternating doses of a high-potency, short-lived benzodiazepine such as lorazepam and a high-potency neuroleptic such as haloperidol. This approach has advantages over the use of either class alone. It reduces the likelihood of behavioral disinhibition that can occur when benzodiazepines are used alone. This alternating approach can also reduce the total dose of the neuroleptic needed to calm the patient and thus reduce the risk and severity of acute extrapyramidal effects. It also prevents the problems associated with the use of lowpotency neuroleptics (e.g., orthostatic hypotension, peripheral and central anticholinergic effects). With the use of shortlived benzodiazepines such as lorazepam, oversedation can be promptly reversed by stopping the benzodiazepine.
Benzodiazepines can also be used as ancillary therapy to ameliorate treatmentemergent adverse effects associated with neuroleptics (Table 2). Akathisia frequently responds better to benzodiazepines than to anticholinergic agents. Benzodiazepines are also frequently helpful in the treatment of tremors due to lithium or neuroleptics.
Psychotic decompensation in schizophrenia and manic-depressive illness is frequently preceded by complaints of insomnia. It is not clear whether such insomnia is simply the first sign of the impending psychotic relapse or is the provocative stressor that causes the relapse. Nevertheless, short-term treatment with a short-lived benzodiazepine can often manage the insomnia and perhaps prevent the psychotic decompensation.
Thus, benzodiazepines have a wide range of uses in psychotic disorders. Moreover, there has recently been a resurgence of interest in whether these agents have a primary role in the treatment of manic-depressive illness and schizophrenia. The literature pertinent to the role of benzodiazepines in these "functional" psychoses is reviewed below.
POSSIBLE MECHANISMS IN "FUNCTIONALPSYCHOSES
Ironically, benzodiazepines are now being re-evaluated for treatment of the conditions for which they were first developed but found to be ineffective. In the late 1950s, as the usefulness of chlorpromazine in the treatment of schizophrenia became known, many drug companies began programs to identify other chemical structures with similar activity. A young Roche chemist, Leo Sternbach, synthesized some benzodiazepine structures, one of which had potent "tranquilizing" activity. This compound (chlordiazepoxide) was tested for its influence on psychosis and found to be inactive (LO Randall, PhD, LH Sternbach, PhD, spoken communication, 1975). Eventually chlordiazepoxide was found to be a potent anxiolytic and the benzodiazepines achieved a prominent place in medicine.
Benzodiazepines exert their major pharmacological effects through the benzodiazepine receptor.3 By enhancing the effects of gamma-aminobutyric acid (GABA), the benzodiazepines reduce the turnover of several neurotransmitters in the brain, including dopamine.4 Neuroleptics have antipsychotic activity in a wide variety of conditions such as schizophrenia, manic-depressive illness, and druginduced psychosis. Antipsychotic activity by the traditional neuroleptics is presumably due to their ability to directly antagonize central dopamine activity at postsynaptic receptors.5,6 Thus, the benzodiazepines may have additive effects when combined with drugs that more directly antagonize central dopamine action such as neuroleptics or reserpine.
BENZODIAZEPINES IN SCHIZOPHRENIA
Benzodiazepines have been used as acute sedative therapy for agitation and excitement and as primary antipsychotic therapy either alone or in combination with neuroleptics. The efficacy of benzodiazepines for these uses has recently been reviewed.79 A summary is provided here.
Acute Sedative Therapy
Initiating drug therapy with an agitated, disruptive, or violent patient presents several problems. The use of high doses of sedative neuroleptics (e.g., thioridazine) may result in oversedation for a prolonged time and clinically significant orthostatic hypotension. The use of nonsedating antipsychotics at doses sufficient to calm and control a disruptive patient may produce a high level of extrapyramidal effects. Several workers have attempted to reduce these problems by using a combination of a short-acting benzodiazepine with a relatively nonsedating neuroleptic (e.g., haloperidol).
Arana et al,7 on the basis of a small, open-label study and a chart review of 380 patients, concluded that the combination of lorazepam and an antipsychotic required less antipsychotic to achieve the desired response than with the antipsychotic alone. Salzman et al10 also conducted a retrospective study of patients treated in a 24-hour psychiatric emergency clinic. These workers also concluded that lorazepam allowed the use of lower doses of antipsychotic to achieve patient control and cooperation.
Cohen and Khan11 conducted an open-label study in 17 patients suffering from acute exacerbation of chronic schizophrenia. Twelve of these patients were randomly assigned to receive less than 2 mg per day of lorazepam while the other five received more than 2 mg per day. The authors concluded that those patients who received more than 2 mg per day had greater improvement over four days of treatment than did those at the lower dose.
Garza-Trevino et al12 investigated the effects of lorazepam (IM, 4 mg) alone, haloperidol (IM, 5 mg) alone, and the combination of these two drugs in a randomized, open-label trial with acutely psychotic subjects. These workers concluded that the combination was superior to either drug alone because sedation was attained more quickly and with fewer repeated doses.
More recently, Barbee and colleagues13 conducted a double-blind trial with 28 acutely psychotic schizophrenia patients seen in an emergency psychiatric service. Subjects were randomly assigned haloperidol (PO, 5 mg) plus alprazolam (PO, 1 mg) or haloperidol (PO, 5 mg) plus placebo. The subjects were evaluated at regular intervals and given a dose of medication if the psychoticism ratings exceeded a predetermined level. Over a 72-hour follow-up period, both groups improved but the alprazolam group required significantly fewer doses of medication and had 56% fewer dystonic reactions. Alprazolam did not appear to treat any of the core psychotic symptoms, but was effective in reducing excitation and uncooperativeness.
Primary Antipsychotic Therapy
Since 1961. 14 double-blind trials have been conducted with benzodiazepines in schizophrenic patients.8 In addition, several other small, open-label trials have been reported.7 Diazepam and chlordiazepoxide have been the most frequently tested benzodiazepines, although clonazepam, lorazepam, alprazolam, and estazolam have also been included in a few trials.7
In spite of a substantial number of trials, the efficacy of the benzodiazepines as a primary treatment for the psychotic symptoms of schizophrenia remains equivocal and somewhat controversial. Individual study results range from "effective" to "ineffective" to exacerbation of symptoms. Wolkowitz and Pickar8 report that, in a review of those studies with positive results, the average dose (in diazepam equivalents) was 124 mg while the average dose for the studies with negative results was only 32 mg, suggesting that high doses are required to achieve antipsychotic activity. The maximum recommended therapeutic dose of diazepam for its labeled indications is 40 mg per day.
The large doses required to achieve antipsychotic activity may suggest that in psychosis the benzodiazepine receptor/ GABA complex is abnormal or that the benzodiazepines may exert antipsychotic activity through a mechanism other than the benzodiazepine receptor. Benzodiazepines are known to interact at several other sites such as adenosine uptake sites,14,15 enkephalin regulation,16,17 and prostaglandin receptors.18 For example, it is of particular interest to note that chronic benzodiazepine administration to animals produces the same reduction in brain enkephalin levels as does the chronic administration of either haloperidol or chlorpromazine.19,20
Although there is little evidence to suggest that benzodiazepines alone have specific antipsychotic activity, there is no question that a few patients treated with benzodiazepines have done remarkably well. The extent of improvement and duration of remission of psychotic symptoms suggest that this is not merely a placebo effect but that a small subgroup of psychotic patients may respond to benzodiazepines. Unfortunately, at this time, there is no known way to identify those patients who may respond to benzodiazepines.
If a selected few patients respond to benzodiazepines, the question arises as to whether these drugs should be considered as a second-line therapy for those who do not respond to standard antipsychotic therapy. In a study of six schizophrenic subjects, Jimerson21 reported that those subjects who had responded best to standard antipsychotic treatment also responded best to benzodiazepine treatment; however, this relationship was not observed in another study.22 A better understanding of the relationship between the responses to these two classes of drugs would be critical in considering the benzodiazepines as alternative therapy.
Adjunct Therapy with Standard Antipsychotics
Several investigators have tested the antipsychotic activity of benzodiazepines when given in combination with standard antipsychotics over several weeks. Nestoros et al23 have evaluated the influence of high doses (up to 200 mg per day) of diazepam in 10 antipsychotic-refractory patients and reported marked improvement in three, moderate improvement in four, a mild improvement in one. and no change in two patients.
Wolkowitz et al24 and Douyan et al25 studied the influence of alprazolam (up to 5 mg per day and 3 mg per day, respectively) on schizophrenic patients being treated concurrently with standard antipsychotics. Responses could best be described as modest, and not all subjects responded. Responses included a reduction in both positive and negative symptoms. Those patients who were most psychotic and anxious at the start of the study seemed to improve the most.24
Csernansky et al2fi compared alprazolam (up to 4.2 mg per day), diazepam (up to 44 mg per day), and placebo as adjunct therapies in schizophrenic patients receiving concurrent, standard antipsychotic therapy. Although alprazolam appeared to have a rapid influence in improving negative symptoms, this effect was not sustained for the six-week duration of the study. Also, neither of these benzodiazepines was demonstrated to have an influence on either negative or positive symptoms.
Altamura et al27 studied the effects of clonazepam in haloperidol-treated schizophrenic patients. Clonazepam (3 mg per day) provided a modest improvement in the Brief Psychiatric Rating Scale and the Extrapyramidal Side Effect Scale, but did not produce any changes in specific symptoms.
BENZODIAZEPINES IN MANIA
Lithium is the drug of choice for treating mania or bipolar affective disorders. Nevertheless, several limitations are associated with lithium. Approximately 20*% of patients with bipolar disorder are refractory to lithium. For those patients who do respond, its therapeutic effects require days to manifest themselves. Finally, there is the potential for severe toxicity due to lithium. Hence, several attempts have been made to find alternative drug therapies. 2S Benzodiazepines have been tried as acute sedative therapy and as longer-term primary antimanic therapy, principally in combination with a mood stabilizer.
Acute Sedative Therapy
To treat the acute excitement characteristic of mania, neuroleptics are often administered during therapy initiation because of their immediate tranquilizing influence. However, there are several disadvantages to such use, as described in the previous section on acute treatment of excitement in schizophrenia. Moreover, the use of neuroleptics on a long-term basis is particularly problematic in affective patients since they may be at special risk for the development of tardive dyskinesias.29,30 Hence, benzodiazepines have been tested as alternatives to the use of neuroleptics for this purpose.
Chouinard and his colleagues31,32 chose to study the influence of clonazepam on newly admitted, acutely manic patients because of its anticonvulsant and serotonin-enhancing activities. Six of 12 patients were treated with clonazepam for 10 days followed by 10 days of treatment with lithium. The other six patients were treated in reverse order. Haloperidol was given as needed to all subjects. Patients on clonazepam required less haloperidol because clonazepam had a rapid onset of action and was well tolerated. These results suggest that clonazepam may be useful in the treatment of acute episodes of mania.
Modell et al33 studied the effects of lorazepam on four manic patients who had been started on lithium treatment. Lorazepam was given as needed to control agitation and noncooperative behavior. Lorazepam was found to be effective in the control of agitation. It had a rapid onset and produced few troublesome adverse effects. Further observations by these authors in nearly 100 additional patients confirmed the usefulness of lorazepam as an adjunct treatment in controlling agitation.34
Recently, Bradwejn et al35 conducted a double-blind comparison of lorazepam and clonazepam in 24 acute manic patients. For two weeks patients received only lorazepam or clonazepam. The drugs were administered double-blind and doses were increased daily to achieve maximum therapeutic effect. As determined by the Inpatient Multidimensional Psychiatric Scale (IMPS) and a Clinical Global Impression of Severity and Improvement (administered by psychiatrists), lorazepam was judged to produce a marked reduction in symptoms. Sixty-one percent of the lorazepam patients responded, with 38% achieving remission. Only 189? of clonazepam-treated patients responded and none remitted. The authors suggest that starting therapy with lorazepam would be preferable to using antipsychotics.
Primary Antimanic Therapy
A number of types of drugs have been evaluated for their usefulness in long-term mania treatment (for lithium-refractory patients). Classes of drugs include agents with actions on central serotonin, dopamine, norepinephrine, and acetylcholine mechanisms.2' In addition, anticonvulsants, benzodiazepines, calcium channel blockers, and opiate antagonists have received trials in treating mania.28,36
Aronson et al87 attempted to use clonazepam as maintenance therapy in five lithium-refractory patients. All five patients relapsed, one within two weeks and four within 10 to 15 weeks. The study was therefore terminated prematurely.
Adjunct Therapy with Mood Stabilizers
Janicak et al3fi recently reviewed and evaluated a variety of treatments for mania. They recommend that lorazepam may be used concurrently with lithium for those patients who do not respond fully to lithium. Clonazepam was suggested for atypical manic patients who do not respond adequately to anticonvulsant treatment with or without lithium or antipsychotics. There is minimal information from systematic, appropriately controlled studies of the efficacy, safety, and tolerability of benzodiazepines used in combination with other mood stabilizers (i.e., valproate or carbamazepine) in the treatment of bipolar disorder.
DISCUSSION AND IMPLICATIONS
In an effort to eliminate or reduce the use of antipsychotics, benzodiazepines have been evaluated numerous times for their potential antipsychotic properties in a variety of disorders (Table 2). The studies in patients with schizophrenia and psychotic mood disorders have provided mixed and frequently conflicting results. The possible reasons are numerous.
First, benzodiazepine doses varied greatly among the protocols. In general, those protocols employing higher doses (above 100 mg) seem to have provided the most positive results. Second, the experimental endpoints varied and the definition of "improvement" has not been consistent. "Improvement" may be restricted to frank symptoms of psychosis or may include the absence of anxiety, agitation, or a reduction in akinesias. Third, the results may depend on the particular benzodiazepine employed. It. is often assumed that all benzodiazepine actions occur via the benzodiazepine receptors; however, benzodiazepines are known to interact at several other sites.14-19
Furthermore, the structure-activity relationship at each site is unique so that relative potencies among benzodiazepine structures would vary among the various sites of action. Benzodiazepines evaluated in psychosis include diazepam, chlordiazepoxide, clonazepam, lorazepam, estazolam, and alprazolam. Although these compounds all have potent activity at the central benzodiazepine receptor, some may have little or no activity at an as-yetunidentified site relevant to antipsychotic activity.
In spite of the lack of positive study results, there is no doubt that a few study subjects have shown a remarkable and clear improvement. Unfortunately, there is no known way of predicting which psychotic patients will respond to benzodiazepine therapy. Also, those patients who respond best to benzodiazepines may be good responders to traditional antipsychotics21 so that using benzodiazepines as a secondary treatment for antipsychotic nonresponders may not prove to be a useful strategy. Based on present knowledge, there is no compelling reason to use benzodiazepine therapy for the treatment of psychosis associated with schizophrenia, either as monotherapy or as an adjunct therapy with standard antipsychotics.
In contrast to the previous conclusion, benzodiazepines are useful in the acute treatment of patients with schizophrenia who are suffering from an acute psychotic episode and are anxious, agitated, or uncooperative.13 Benzodiazepines in these circumstances tend to be more effective and safer than antipsychotics. Although benzodiazepines are not effective as maintenance therapy for mania, they have proven useful in treating acute mania. Short-lived benzodiazepines have been recommended to reduce agitation and improve cooperation during the initial stages of drug therapy.
Any potential benefit derived from the use of benzodiazepines in treating psychosis must, of course, be weighed against the potential difficulties or risks that may result from such use. Table 3 lists several problems that should be considered when using benzodiazepines in psychotic disorders. While several of these problems are obvious, some deserve further comment.
One effect of benzodiazepines is behavioral disinhibition. This effect precedes overt sedation. Thus, the patient may paradoxically demonstrate increased excitement and psychomotor activity in response to initial exposure to benzodiazepines, rather than the reverse. Because the patient is already agitated, aggressive behavior may result from such disinhibition. Such a scenario can occur whether the patient is suffering from mania, schizophrenia, a dementing illness, or a delirium. This problem is minimized when the henzodiazepine is administered in conjunction with a high-potency neuroleptic. For this reason, the neuroleptic should generally be given first. By taking these precautionary steps and being alert to this possible effect, the clinician can avoid it or manage it without substantial difficulties. If behavioral disinhibition does occur, the patient should be given another dose of either the neuroleptic or the benzodiazepine. With an increased dose, the sedative effects of the benzodiazepine will supersede the disinhibitory effect.
Although the abuse risk with the benzodiazepines is low in comparison with many other sedative-hypnotics, it is not absent. Patients with psychotic illnesses may misuse these agents. Such abuse can further complicate the treatment of their psychotic illness. When actively abusing sedatives, patients' compliance with their medication regimen is frequently compromised, increasing the risk of a psychotic relapse. Withdrawal effects, such as increased anxiety and insomnia, can also be confused with early symptoms of a psychotic relapse or may contribute as stressors to such a relapse.
Problems with Benzodiazepines as Treatment for Psychotic Disorders
For these reasons, care should be taken when prescribing benzodiazepines on a maintenance basis to patients with psychotic disorders. First, they should generally be avoided in a patient with past history of alcohol abuse or dependence. Second, the patient should be warned about the abuse potential and should be instructed not to increase the dose without doctor's orders. Third, care should be taken to ensure that the patient is not running out of medication early. Such a pattern may be a warning sign of dose escalation and/or abuse. Fourth, the physician may prefer to switch from a high-potency, short-lived benzodiazepine, such as lorazepam, used in the first stages of treatment to a high-potency but longlived benzodiazepine, such as clonazepam, for maintenance treatment. This strategy should reduce the risk of interposed withdrawal symptoms (e.g., anxiety). Also, the abuse potential appears to be less with long-lived versus short-lived compounds of equivalent potency.
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Use of Benzodiazepines in Psychotic Disorders
Use of Benzodiazepines as Primary Acute Drug Therapy
Problems with Benzodiazepines as Treatment for Psychotic Disorders