Psychotic depression combined treatment

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

The efficacy of psychotherapy and antidepressants is considered to be additive. Psychotherapy alone is not recommended for the acute treatment of patients with severe and/or psychotic major depressive disorders. For uncomplicated nonchronic major depressive disorder, combined treatment may provide no unique advantage. Cognitive therapy, behavioral therapy, and interpersonal psychotherapy appear to be equal in efficacy. 

To date, only one antidepressant, amoxapine, has proven effective in the treatment of PMD as the sole therapy. Amoxapine is a chemical congener of the antipsychotic drug loxapine, so it possesses both dopamine-blocking and monoamine-enhancing properties. One double-blind study has confirmed that amoxapine appears to be as effective as the combination of a TCA and an antipsychotic. R. F. Anton and Burch [1990] randomly selected 46 inpatients with psychotic depression to either amoxapine [to 400 mg/day] or ami-... 

Given the available data, it is extremely important that clinicians evaluate patients with major depression for features of psychosis, because the failure to do so may result in inadequate treatment for the patient. A practical problem encountered by clinicians, however, is the subtlety of delusions. For example, it is not unusual in geriatric depression for patients to present with a somatic preoccupation that borders on delusional. These so-called near delusions may put the patient into the arena of psychotic depression. Some evidence exists that patients with depression with near delusions may respond more favorably to combinations of antidepressants and antipsychotics or ECT. Once the presence of both major depression and psychosis is determined, other psychotic disorders including bipolar disorder and schizophrenic spectrum illness must also be ruled out because this may influence long-term treatment decisions. 

TCAs in more serious forms of depression such as melancholic or psychotic depression. Some studies have suggested that the SSRls do not work as well as the TCAs in melancholic depression (Roose et al. 1994]. Likewise, one study has suggested that venlafaxine, a drug with a mechanism of action similar to that of the TCAs, was superior to fluoxetine in the treatment of inpatients with melancholic depression (Clerc et al. 1994]. Still, other metaanalyses have failed to find a difference in the efficacy of SSRls versus TCAs in serious forms of depression [Nierenberg 1994]. Nonetheless, given that most studies have employed TCAs, and some debate exists about the utility of SSRls in severe subtypes, it may be prudent to start with a TCA in most patients until the debate is further resolved. For patients who present a significant suicide risk or who have not been able to tolerate TCAs, the SSRls in combination with a standard antipsychotic appears an effective option. 

The available data indicate that patients with PMD will often respond to combination drug therapy or amoxapine at adequate doses (>200 mg/day for amoxapine or TCAs] for at least 4 weeks. However, the course of psychotic depression is often prolonged, and it may take several months of treatment before a remission is secured. 

Nelson JC, Mazure CM Lithium augmentation in psychotic depression refractory to combined drug treatment. Am J Psychiatry 143 363-366, 1986... 

Rothschild AJ Delusional depression a review of the literature and current perspectives. McLean Hospital Journal 2 68-83, 1985 Rothschild AJ, Samson JA, Bessette MP, et al Efficacy of the combination of fluoxetine and perphenazine in the treatment of psychotic depression. J Clin Psychiatry 54 338-342, 1993... 

Psychotic depression has been reported to respond to combined treatment with antidepressants and antipsychotics patients with psychotic depression also show a dramatic response to ECT, which is often the treatment of choice for this disorder. Long-term treatment with antipsychotic medications is generally not warranted, but prophylactic antidepressant medication must be continued as in nonpsychotic depression. 

Treatment Implications. A review of response rates found that only 35% of patients with psychotic depression responded to treatment with a tricyclic antidepressant alone versus 67% of patients with nonpsychotic depression (Table 6-6) (13). Yet these patients have a better response to electroconvulsive therapy (ECT) (14). These patients have also been found to respond to combined treatment with an antidepresssant and an antipsychotic in comparison with either an antidepressant or antipsychotic alone (15). Despite these data, one study found that less than 50% of patients with psychotic depression referred to an ECT service had been treated with an antipsychotic and only 15% had received a daily dose equivalent to 200 mg or more or chlorpromazine ( 16). 

For these reasons, we recommend that such patients receive either combination treatment with an antidepressant and an antipsychotic or ECT. Even when treated appropriately, however, patients with psychotic major depression may have a substantially higher frequency of relapse or recurrence and a shorter time to these events when compared with nonpsychotic patients (17). 

Anton RF, Burch EA. Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression. Am J Psychiatry 1990 147 1203-1208. 

To this list, we would add delusional (or psychotic) depression (see also Chapter 6 and Chapter 7). Whereas some have suggested that pre-ECT nonresponse to adequate pharmacotherapy is a powerful factor for predicting nonresponse to ECT ( 39, 40), others have argued for its superiority over antidepressants (alone or in combination with antipsychotics) for prior drug-nonrespon-sive nonpsychotic or psychotic depressions ( 41, 42 and 43). Support for this latter position comes from the discussion by Schatzberg and Rothschild ( 44), who separate this condition from other depressive disorders, in part because of its differential responsivity to various treatments. 

One consistent finding has been that patients with psychotic depression treated with antidepressant monotherapy or even the combination of an antidepressant plus antipsychotic have a lower response rate than those depressed patients without psychotic symptoms (45). Although evidence supports an improved response when these patients undergo treatment with ECT, this apparent superiority may be related to a selection bias ( 46). Thus, it may be that patients with psychotic depression are more likely to receive ECT earlier in their course of illness and therefore the extent of their true drug resistance is unknown ( 1). 

When symptoms of major depression and psychosis coexist, medication treatment is always warranted. (Often hospitalization, ECT, or both may also be necessary.) Psychotically depressed patients do not respond to psychotherapy alone, and they represent a very high suicide risk when actively psychotic. It has been firmly documented that treatment with antidepressants alone is not very effective (only 25 percent). Likewise, treatment with antipsychotics alone produce disappointing results (35 percent effective). However, combined antidepressant-antipsychotic treatment is significantly more effective (60 to 70 percent). Electroconvulsive treatment is really the gold standard in the treatment of psychotic mood disorders (90 percent effective). (See chapters 14 and 17, on treatment with antidepressants and antipsychotics, respectively.)... 

Fluoxetine. The combination of perphenazine and fluoxetine was found to be effective in the treatment of psychotic depression in 30 patients, and the adverse effects (which included dry mouth, blurred vision, constipation, tremor or rigidity, orthostasis and hypotension) were thought to be easier to tolerate than an antipsychotic with a tricyclic antidepressant. However, one woman developed marked extrapyramidal symptoms within 2 weeks of starting perphenazine 4 mg twice daily and fluoxetine 20 mg daily. ... 

One of the more methodologically rigorous studies on the utility of TCA/antipsychotic combinations in treating PMD was completed by Spiker et al. [1985). In this study, 54 patients who met criteria for depression with psychotic features on the Schedule for Affective Disorders and Schizophrenia [Endicott and Spitzer 1978) and by Research Diagnostic Criteria [Spitzer et al. 1985) were randomly selected to treatment with amitriptyline alone, perphenazine alone, or the combination of two drugs. After a 7-day placebo washout, patients were treated for 35 days with doses averaging approximately 50 mg/day of perphenazine and approximately 200 mg/day of ami-... 

To date, only one study has been completed with an antidepressant other than a TCA combined with an antipsychotic in the treatment of PMD. Rothschild and colleagues (1993) investigated the efficacy of fluoxetine and perphenazine in the treatment of PMD and found that approximately 73% of 30 patients who met DSM-III-R (American Psychiatric Association 1987) criteria for major depression with psychotic features had at least a 50% reduction on their Hamilton Rating Scale for Depression scores over 5 weeks. Furthermore, the combination of fluoxetine and perphenazine appeared to be better tolerated than the combination of TCAs with antipsychotics. Although there is no evidence that monotherapy with an antidepressant other than amoxapine is efficacious, the combination therapy with many antidepressants other than the TCAs may prove useful. 

Hillert A, Maier W, Wetzel H, et al. Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome—a functional approach. Pharmacopsychiatry 1992 25 213-217. 

Muller-Siecheneder F, Muller MJ, Hillert A, Szegedi A, Wetzel H, Benkert O. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. J Clin Psychopharmacol 1998 18(2) 111-20. 

A combination of olanzapine and fluoxetine was used in two randomized, double-blind simultaneous 8-week trials in 249 patients with major depression with psychotic features (trial 1 n = 124, mean age 41 years, 52% women trial 2 n = 125, mean age, 41 years, 50% women), which have been jointly published (69). This multicenter study was completed by 51 subjects in trial 1 (41%) and 59 subjects in trial 2 (47%). Altogether, there were no significant differences in the rates of discontinuation due to adverse events among the different treatment groups placebo (n = 100), monotherapy with olanzapine 5-20 mg/day (n = 101), and olanzapine 5-20 mg/day plus fluoxetine 20-80 mg/day (n = 48). Dropout percentages were 59% in trial 1 (similarly distributed in the three groups) and 53% in trial 2 (ranging from 40% of dropouts... 

Use in combination with lithium or valproate for the acute treatment of mania or mixed states (primarily with psychotic features) for bipolar I disorder. Only olanzapine is FDA approved at this time for maintenance treatment and only quetiapine for bipolar depression. 

It is indicated in the treatment of depressive episodes associated with bipolar disorder. A combination of an antipsychotic drug and an antidepressant may be useful in some cases, especially in depressed psychotic patients, or in cases of agitated major depression with psychotic features. The first combination antipsychotic/antidepressant (olanza-pine/fluoxetine Symbyax) was recently FDA approved in the United States for treatment of depressive episodes associated with bipolar disorder. However, antidepressants and stimulants are unlikely to reduce apathy and withdrawal in schizophrenia, and they may induce clinical worsening in some cases. Adjunctive addition of lithium or an antimanic anticonvulsant, such as carbamazepine, may add benefit in some psychotic patients with prominent affective, aggressive, or resistant symptoms. 

In non-psychotic patients, oxcarbazepine and valproate have been shown to exert similar efficacy in controlling mood symptoms in schizoaffective disorder. It is reasonable (although not tested) to use them in combination with SCAs in iller patients. Carbamazepine seems to be equipotent to lithium in controlling mood symptoms however, lithium is probably less effective than carbamazepine in improving depressive episodes as part of schizoaffective disorder. All in all, lithium and valproate are the first-line treatment of acute non-psychotic mania. Lithium is most effective in euphoric mania and valproate is probably more effective in mixed states. The time to onset of action of lithium may be somewhat slower than that of valproate, although data are not well established. 

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