An appropriate treatment approach to depression begins with a consideration of the differential diagnostic possibilities outlined earlier in this chapter. Obviously, since there are no available biological tests (except for the medical/organic conditions), or even psychological tests, that are known to be informative in drawing these diagnostic distinctions, these diagnoses must be made on a purely clinical basis.

Since an acute transient disappointment reaction and a prodrome of a new psychotic episode are both possibilities when a new episode of depression appears in the course of schizophrenia, the prudent course is to react to such a new episode with increased frequency of surveillance. If the episode is a transient disappointment reaction, it will soon resolve spontaneously, and no other intervention beyond nonspecific support is indicated.

However, if the new onset of depression is the first harbinger of a new episode of psychosis, increased surveillance will allow this new episode to be caught quickly and “nipped in the bud” as much as possible through appropriate antipsychotic interventions. For a neuroleptic-treated schizophrenia patient with a continuing episode of depression, the next consideration is whether the neuroleptic medication is contributing to the manifestations of depression.

This could occur on the basis of either the hypothesized neuroleptic-induced dysphoria state or the extrapyramidal side effects of akinesia or akathisia. A reduction of neuroleptic dosage would be the first choice of how to treat any of these conditions, if there is leeway to accomplish that safely. A trial of a so-called atypical antipsychotic agent also may be quite helpful in this situation. Otherwise, a full dose of an antiparkinsonian medication, built up in suitable gradations, is the treatment of choice for the possibility of neuroleptic-induced akinesia.

If the depressive syndrome is thought to be the product of akathisia and an antiparkinsonian medication trial proves not to be helpful, a benzodiazepine or beta-blocker trial can be attempted. After a transient disappointment reaction, prodrome of psychosis, and neuroleptic side effect have been eliminated, as best as possible, as the cause of a continuing state of postpsychotic depression in schizophrenia, a trial of treatment with an antidepressant medication should be considered as an adjunct to the patient’s antipsychotic (and perhaps antiparkinsonian drug) regimen.

Table 2­1 shows the detailed results of the doubleblind, controlled studies that have examined this approach. Although the results are mixed, the studies that are methodologically the strongest are the ones that most support the efficacy and safety of an adjunctive antidepressant trial in this situation (Plasky 1991; Siris 1991, 1995, 2000). More favorable results were found among outpatients than among inpatients (Fisher exact test, P = 0.048 for the studies in Table 2­1), and less favorable results seemed to be obtained among patients who were prominently psychotic at the time of the adjunctive antidepressant trial (Kramer et al. 1989) than among those who were not psychotic at the time of the trial.

Table 2­1. Double-blind studies of antidepressants in “depressed” schizophrenia patients

Only one study has been reported concerning the efficacy of maintenance adjunctive antidepressant medication for patients who appeared to respond favorably initially (Siris et al. 1994). That study indicated that indefinite maintenance medication appeared to be warranted among patients who initially had responded favorably. Interestingly, patients receiving maintenance adjunctive antidepressant medication experienced fewer relapses into depression (P = 0.0007) and fewer exacerbations of psychosis (P = 0.018) than did those receiving maintenance adjunctive placebo. Half of the relapses into depression in the control group were accompanied by increases in psychosis ratings; none of the patients maintained on adjunctive antidepressant medication experienced such increases.

This raises the possibility that preventing a relapse into depression may be associated with patients’ not entering a concurrent exacerbation of psychosis. It also suggests that maintenance of adjunctive antidepressant medication may have been protective in this regard. As shown in Table 2­1, the studies of antidepressants in treating postpsychotic depression in patients with schizophrenia generally have involved cyclic antidepressants.

Selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) have not been adequately tested for this condition, although anecdotal information suggests that they may be useful. However, there have been encouraging doubleblind trials of SSRIs (Goff et al. 1995; Silver and Nassar 1992; Spina et al. 1994) and MAOIs (Bodkin et al. 1996; Bucci 1987; Perenyi et al. 1992) for “negative symptoms” in schizophrenia. It is also possible that there may be a role for the use of lithium in at least some cases of depression in patients with schizophrenia, although, again, proper studies of this issue have not been reported.

Most reports involving lithium in the treatment of patients with schizophrenia have examined its acute use in psychotic exacerbations rather than during the maintenance phase of treatment (Christison et al. 1991; Plasky 1991), with the most frequently cited indicators of favorable response being excitement, overactivity, and euphoria rather than depression. Nevertheless, depressive symptoms have occasionally been identified as a favorable prognosticator of adjunctive lithium response in patients with schizophrenia (Lerner et al. 1988), in addition to previous affective episodes, a family history of affective illness, and an overall episodic course (Atre-Vaidya and Taylor 1989).

A discussion of treatment strategies for depression in patients with schizophrenia is not complete without consideration of psychosocial interventions, even though controlled studies of these modalities have not been carried out in a specifically depressed schizophrenia patient population. Appropriate psychosocial modalities certainly can be valuable in the longterm management of schizophrenia (Hogarty et al. 1986). These approaches include stress reduction strategies, psychoeducation, skill building, instruction in problem-solving techniques, and family interventions targeted to minimizing expressed emotion. Interventions aimed at enhancing hope and self-esteem also may be useful.

Samuel G. Siris, M.D.

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