Because antipsychotic medications often fail to resolve the full range of schizophrenic psychopathology and other common symptoms (e.g., anxiety, depression, mood instability, motor unrest), adjunctive treatments are commonly tried. Adjunctive pharmacological treatments in patients with schizophrenia have been the subject of numerous reviews (). In addition, some psychotropic medications other than antipsychotics have been used alone to treat schizophrenia. Below we summarize information on the use of anxiolytics/hypnotics, antidepressants, mood stabilizers, and dopamine agonists to treat either symptoms of schizophrenia or common comorbid conditions.
Antianxiety or Hypnotic Drugs
Benzodiazepines have been prescribed for patients with schizophrenia since the early 1960s, but there has been little recent systematic research in this area. This lack of research may be due to the potential for dependency and reluctance to prescribe these agents to patients with comorbid substance abuse or substance use disorders. In addition, reports indicate that benzodiazepines may result in a “disinhibiting” () or worsening of psychopathology in some patients ().
Carpenter and colleagues (1999) studied whether diazepam could help to prevent a psychotic relapse when given for symptoms thought to be prodromal of an impending psychotic exacerbation. In their double-blind, randomized clinical trial of 53 patients with schizophrenia, they compared diazepam with placebo and with fluphenazine and found that diazepam was superior to placebo and comparable to fluphenazine in preventing a psychotic relapse.
Few studies in the literature have rigorously tested the use of benzodiazepines to treat nonpsychotic symptoms common in people with schizophrenia. Nevertheless, some evidence suggests that schizophrenia patients with anxiety, depression, hostility, irritability, and motor unrest may benefit from benzodiazepines (). A very small study that examined benzodiazepine response among six anxious schizophrenia patients under double-blind conditions over 12 weeks concluded that some patients from this subgroup may experience reduced anxiety with a benzodiazepine used adjunctively to antipsychotics (). Although benzodiazepines are frequently used as hypnotic agents in clinical practice, no controlled studies have established their efficacy in patients with schizophrenia. At a minimum, the benzodiazepines appear to be a useful adjunct to antipsychotics in the treatment of agitation or anxiety in patients with schizophrenia.
Antidepressants do not appear to be effective as an adjunctive treatment for positive psychotic symptoms () and may worsen symptoms in persons who are acutely psychotic (). The efficacy of antidepressants for negative symptoms of schizophrenia has been examined in several studies but the effect, if any, is modest ().
Because secondary or postpsychotic depression among patients with schizophrenia is common, antidepressants are widely used to treat depression among persons with schizophrenia, although the evidence for the effectiveness of this strategy is modest. In a review of six double-blind, placebo-controlled studies that used tricyclic antidepressants in addition to an antipsychotic, two reported a significant reduction in depression. These two studies involved patients whose acute psychosis was under control, suggesting that adjunctive antidepressant treatment may be most successful for the treatment of depression when an acute psychotic episode has stabilized. However, in two studies of acutely psychotic patients, the antidepressants appeared to have resulted in a worsening of the psychosis (). Subsequent research has supported the use of antidepressants for schizophrenic patients with depression whose psychotic symptoms have stabilized (). Definitive conclusions cannot be drawn about antidepressant use for schizophrenia patients with depression, however, because few methodologically rigorous studies are available. Nevertheless, adjunctive antidepressant treatment is warranted when a patient reports persistent symptoms of depression when he or she is not in an acute episode of illness.
Important practical issues must be considered when antidepressants are used in combination with clozapine. Selective serotonin reuptake inhibitors — in particular, fluvoxamine, fluoxetine, and sertraline — inhibit the metabolism of clozapine and can cause large increases in clozapine levels that are potentially toxic. Serum clozapine levels and side effects, particularly anticholinergic side effects, should be monitored when using the combination of selective serotonin reuptake inhibitors and clozapine. Because bupropion and clozapine both increase the risk of seizures, this combination is not recommended.
Lithium has been used as monotherapy and as an adjunct to antipsychotics in the treatment of schizophrenia (). Antipsychotics are superior to lithium as a treatment for acute psychosis in schizophrenic patients, although some patients may improve while taking lithium alone (). There is no convincing evidence of the efficacy of lithium as an adjunctive agent to antipsychotics for schizophrenia. However, because of reports of benefit in some treatment-refractory patients, a trial of lithium should be considered if a patient has not adequately responded or was unable to tolerate a second-generation agent (e.g., clozapine). When concern about potentially toxic interactions between an antipsychotic and lithium was investigated (), little evidence supporting this association was found ().
Leucht and colleagues (2002) reviewed eight studies that compared carbamazepine plus antipsychotics with placebo plus antipsychotics in the treatment of schizophrenia. They concluded that carbamazepine should not be recommended for routine clinical use for treatment of schizophrenia or augmentation of antipsychotic treatment of schizophrenia. The review qualified that conclusion by indicating that a trial of carbamazepine may be warranted for those with a history of response to carbamazepine or for patients with associated electroencephalogram abnormalities.
For the subpopulation of aggressive, agitated patients, some evidence supports carbamazepine as an adjunctive agent to antipsychotics in the treatment of schizophrenia. Because of carbamazepine’s ability to upregulate hepatic enzymes, plasma antipsychotic levels may be lowered when carbamazepine is used. If antipsychotic efficacy is lost, antipsychotic levels can be checked, or the dosage can be increased (). Because of carbamazepine’s risk of bone marrow toxicity, including agranulocytosis, it should not be used in combination with clozapine.
Valproate (the active component of valproic acid and divalproex) is widely used as an adjunctive treatment for schizophrenia, but evidence supporting its use as a maintenance treatment is limited (). Linnoila and colleagues (1976) found that the combination of valproate with an antipsychotic was superior to an antipsychotic alone in reducing global psychopathology in a double-blind, crossover study of 32 patients with dyskinesias. In a small 21-day double-blind, randomized, placebo-controlled study of valproate as adjunctive treatment to haloperidol in 12 hospitalized patients with acute exacerbations of chronic schizophrenia, Wassef et al. (2000) found that the valproate group showed greater improvements than the placebo group on measures of psycho-pathology. Casey et al. (2003) conducted a 28-day double-blind, randomized controlled trial of 249 patients with schizophrenia that compared combination therapy of divalproex and risperidone or olanzapine with risperidone or olanzapine monotherapy and found faster improvement in psychopathology with combination therapy. Although the differences in psychopathology were not significant at the end of the 28 days, fewer combination therapy patients dropped out of the study compared with monotherapy patients (10% vs. 20%). Definitive conclusions on the efficacy of valproate for the long-term treatment of schizophrenia are premature, however. Although valproate is sometimes used as an adjunctive treatment for treatment-refractory patients, no strong evidence supports this use ().
Dopamine agonists have been associated with an exacerbation of psychotic symptoms in schizophrenic patients, but they also have been used as a treatment for negative symptoms. The strategy of using dopamine agonists for negative symptoms is consistent with the hypothesis that a hypodopaminergic state may be their cause (). L-Dopa, bromocriptine, and dextroamphetamine all have been studied in relatively small trials with only inconsistent and modest effects ().
Dopamine agonists have been insufficiently studied to draw definitive conclusions, but they may represent an underused class of medication for the treatment of negative symptoms. Clinicians are understandably hesitant to use these agents because of the risk of exacerbating symptoms, even though this risk may be small if patients are given maintenance antipsychotics ().
Because phencyclidine inhibits the neurotransmission of glutamate through N-methyl-D-aspartate (NMDA) receptors (i.e., is an NMDA antagonist) and has been shown to produce a syndrome similar to schizophrenic psychosis, it was hypothesized that reduced glutamate activity (possibly through NMDA receptor hypofunction) caused the symptoms of schizophrenia (). The potential therapeutic effects of three glutamatergic agents on schizophrenia have been studied to date: glycine (), D-cycloserine, and D-serine ().
Each of the three agents showed some benefit as an adjunctive treatment for psychotic symptoms when dosed appropriately, except when used with clozapine. Although dosing challenges with glycine and D-cycloserine may make them impractical for clinical use, studies of these compounds provide strong support for a role of glutamate in the pathophysiology of schizophrenia and further the understanding of the pharmacological mechanism of clozapine. D-Serine is the most promising agent in this group according to current findings. Investigators hope that this line of research will lead to improved symptom reduction for patients with schizophrenia and clues for the development of other novel therapeutic agents.
Although antipsychotic polypharmacy is a common treatment strategy, little evidence supports its use (). However, augmenting clozapine with other antipsychotics has some support in the literature. Part of the rationale for combined therapy is the use of agents with higher D2 receptor potency than that of clozapine, which has a relatively low affinity for and fast dissociation constant at this receptor type (). Shiloh and colleagues, in a double-blind, placebo-controlled study, evaluated the effectiveness of sulpiride, a selective D2 antagonist, as an add-on to clozapine. They found that clozapine-treated patients who received concomitant sulpiride (600 mg) had significant improvement in both positive and negative symptoms as compared with those who received placebo (). This finding has had further support from case reports of sulpiride combined with clozapine () and sulpiride combined with other atypical antipsychotics ().
Similarly, risperidone, an atypical antipsychotic with relatively high D2 receptor potency, has been found to improve symptoms in clozapine-treated patients. An investigation of the effect of risperidone as an add-on to clozapine in an open 4-week trial involving 12 patients found that 10 of the 12 patients had a 20% or greater reduction in the BPRS score (). A placebo-controlled trial involving 40 patients has added evidence to support the addition of risperidone to clozapine in patients who are nonresponsive or only partially responsive to clozapine alone (). This study found greater reduction in overall symptoms and in positive and negative symptoms in patients taking risperidone and clozapine compared with those taking placebo and clozapine.
Case reports and case series have used clozapine with loxapine (), pimozide (), and olanzapine (), but, again, controlled trials are lacking. Case series also have investigated the combination of clozapine with quetiapine () or with ziprasidone () and have shown a reduced need for clozapine (as reflected by lower clozapine dose following addition of the second antipsychotic) and a reduced clozapine side-effect burden, but these findings must be considered preliminary.
In summary, concomitant use of another antipsychotic, particularly one with relatively higher D2 receptor potency, with clozapine in patients with persistent symptoms may offer some benefit, but controlled trials are needed to verify the observations of open trials (). This verification is important given the potential adverse effects of antipsychotic polypharmacy, as has been reported for risperidone combined with clozapine ().
Aside from the clozapine literature, no controlled studies have examined the use of two or more antipsychotics in the treatment of refractory schizophrenia. Still, antipsychotic polypharmacy is common, and anecdotal evidence suggests that in some patients, combined use of antipsychotics may improve symptoms as compared with antipsychotic monotherapy. A small case series has been published suggesting that combined treatment with risperidone and olanzapine shows benefit in treatment-refractory patients (). Similarly, a case series found clinical improvement in olanzapine-treated patients after the addition of sulpiride (), an observation congruent with the clozapine literature. We recommend clozapine monotherapy prior to any adjunctive pharmacotherapy or antipsychotic polypharmacy for the treatment of schizophrenia. Unfortunately, in the event of clozapine refusal or intolerance, few data are available to guide the use of specific antipsychotic combinations.