Schizophrenia: Augmentation of Typical Neuroleptics

Augmentation of Typical Neuroleptics

When a patient has shown an inadequate response to traditional neuroleptic agents from different classes and there is a good rea-son for not switching to a novel antipsychotic drug, other strate-gies may be necessary to ameliorate residual symptoms. Adding a different type of psychotropic medication may augment the neu-roleptic response in some individuals. Several neuroleptic aug-mentation strategies have been studied, including the addition of beta-blockers, thyrotropin-releasing hormone, clonidine and val-proic acid, with mixed results. Lithium has been evaluated exten-sively for its efficacy as an additional treatment of schizophrenia. In one study, lithium seemed to improve psychotic symptoms of patients who had not adequately responded to neuroleptics alone (Small et al., 1975). Although lithium does not seem to affect positive or negative symptoms specifically, it may be beneficial for patients who present at the depressed end of the spectrum (Meltzer, 1992). Similarly, carbamazepine has had mixed results as an augmentation agent although there is evidence that it can improve anxiety, withdrawal and depression. The use of benzodi-azepines as augmenting agents in the treatment of schizophrenia has also been extensively studied. There may be some patients who show improvement in psychotic symptoms, and others who show improvement in negative symptoms. Interestingly, there has been a suggestion that the triazolobenzodiazepines may be more effective than other types of benzodiazepines in augment-ing the neuroleptic response.

Antidepressant medications have also been considered in the treatment of depression associated with schizophrenia. Al-though there is some evidence that typical neuroleptics them-selves cause depression there undoubtedly are schizophrenic patients who have primary depressive symptoms. Negative symp-toms are often difficult to distinguish from depression (both have features of amotivation, apathy and social withdrawal), but those that are secondary to depression may respond to the addition of an antidepressant to the patient’s medication regimen.

With electroconvulsive therapy as an adjuvant treatment, it appears the patient may improve initially, but relapse is likely. However, patients with comorbid affective symptoms may have some increased benefit. In general, however, this option should be considered only if the patient is not a candidate for a trial with an atypical antipsychotic agent and only if the patient has severe persistent symptoms.

When agonists of the glycine site of the NMDA receptor were added to typical antipsychotic agents in a placebo-controlled study, significant improvement were reported in negative symp-toms and aspects of cognitive functioning (Heresco-Levy et al., 1999). D-cycloserine, a partial agonist at the glycine site pro-duced a selective improvement of negative symptoms at 6 weeks (Goff et al., 1999). Augmentation with another endogenous full agonist, D-serine was associated with significant improvement in negative, positive, and cognitive symptoms when added to con-ventional agents in an 8-week trial (Tsai et al., 1998).