uestion:
If this patient is severely ill (e.g. - unable to cooperate with oral
medication), has this patient had a course of ECT?uestion:
If this patient is severely ill (e.g. - unable to cooperate with oral
medication), has this patient had a course of ECT?
Help: From a variety of kinds of evidence, it seems that ECT may be the most effective, and sometimes the most rapidly effective (if it can be started within 5 days of admission) of the available treatments for depression with psychotic features (frequently referred to as delusional depression, although hallucinations are present in a significant minority of patients).¹ Hence it is proposed that ECT be thought of before proceeding to pharmacotherapy, especially for severe cases. Diagnosis should be made carefully: these are melancholic depressions, with high Hamilton scores (usually over 30), accompanied by paranoid, somatic, and (more rarely) nihilistic delusions. Self-deprecatory guilty delusions are not sufficient for the diagnosis according to the DSM criteria.
The average age of onset of this disorder is the late 30's with the typical patient being over 50 with a history of one or two previous episodes. Occasionally it is seen in young patients, and there seems a high incidence of such patients going on to manifest bipolar disorder.
Additional diagnostic issues of possible importance: 1. Most delusional depressions begin with depressive symptoms and the delusions begin when the depression becomes more severe. It seems rare to have initial onset of psychosis without mood disturbance; the latter are probably schizoaffective. Thus, it is useful to inquire about initial symptomatology and course of symptoms. 2. Past episodes of depression in patients with psychotic depression usually were psychotic. Thus any non-psychotic depressed patient with a previous history of delusional depression should be considered suspicious of having underlying psychotic depression, expecially if appearing refractory to treatments usually effective in non-psychotic depression.
¹Spiker DG, Perel JM, Ianin I, et al. The pharmacological treatment of delusional depression. Am J Psychiatry 1985;142:430-436.
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Consider a trial of ECT.¹ The best studied pharmacotherapy (neuroleptic plus antidepressant) takes about 6 weeks to work well (slower than in non-psychotic depression), and ECT may be significantly faster if it can be started quickly.
¹Khan A, Cohen S, Stowell M, et al. Treatment options in severe psychotic depression. Convulsive Therapy 1987;3(2):93-99.
Recommendation #05
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uestion: Has the patient had an adequate trial of a
tricyclic antidepressant with an antipsychotic?
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Help: The best established pharmacotherapy for psychotic depression appears to be a combination of a tricyclic and an antipsychotic. There are a number of other medication options, many of which were reviewed by Schatzberg and Rothschild.¹ Amoxapine has been found to be useful in one study. Amoxapine as a parent compound has weak antipsychotic effects, but it has active metabolites which are potent neuroleptics. Using this drug is like using a fixed combination of a tricyclic antidepressant and an antipsychotic, except that you do not know the exact amounts of antipsychotic effect you are getting because of variable metabolism. It seems better to give combination therapy as above, and be able to control how much of each you are giving in accordance with the patient's needs. That is why we have not included it as a specific suggestion in the algorithm, but it is certainly an acceptable alternative
Another alternative is a combination of an SSRI and an antipsychotic. Only one study has demonstrated this combination to be effective.² Considerable recent evidence suggests that psychotic depression is a subtype of severe, melancholic depression (rather than a subtype of major depression as the DSM-IV classifies it).(2a) Much evidence now suggests that tricyclics and other dual-action antidepressants such as mirtazapine and venlafaxine are superior to SSRIs in severe, melancholic non-psychotic depression.(2b) Hence, we favor use of a tricyclic (or, potentially, although there is not much evidence, mirtazapine or venlafaxine) rather than an SSRI as the antidepressant to use with an antipsychotic in psychotic depression.
Tricyclic monotherapy seems occasionally effective, but a meta analysis of 26 studies concluded that tricyclics are not better than placebo.³ Placebo has a very low response rate in psychotic depression, much lower than in non-psychotic depression.
Two studies from Italy found that certain SSRI's (fluvoxamine and sertraline [with paroxetine seemingly less so] are effective as monotherapy in delusional depression.(4,5) There has been no US experience that we know of to confirm these surprising reports as of yet. Questions have been raised about whether the depression of these patients was comparable in severity to that of the patients treated in the US studies which found a need for tricyclic-plus-neuroleptic combination therapy.
¹Schatzberg AF, Rothschild AJ. Psychotic (delusional) major depression: should it be included as a distinct syndrome in DSM-IV? Am J Psychiatry 1992;149:733-745.
²Rothschild AJ, Samson JA, Bessette MP, Carter-Campbell JT. Efficacy of the combination of fluoxetine and perphenazine in the treatment of psychotic depression. J Clin Psychiatry 1993;54:338-342.
2a. Parker G et al. Subtypine depression by clinical features: the Australasian database. Acta Psychiatrica Scandinavica 2000;101:21-28
2b Osser DN, Patterson RD. Algorithms for the Pharmacotherapy of depression, part one. Directions in Psychiatry 1998;18:303-317.
³Khan A, Noonan C, Healey W. Is a single tricyclic antidepressant trial an active treatment for psychotic depression? Prog Neuro-psychopharmacol & biol psychiat 1991;15:765-770.
(4)Gatti F, Bellini L, Gasperini M, et al. Fluvoxamine alone in the treatment of delusional depression. Am J Psychiatry 1996;153:414-416.
(5)Zanardi R, Franchini L, Gasperini M, et al. Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry 1996;153:1631-1633.
uestion: Is the recommendation of a tricyclic antidepressant plus
an antipsychotic acceptable to you for treating your patient?
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Help: Although we currently still prefer a combination of an antipsychotic and a tricyclic antidepressant as the first line treatment for the psychopharmacologic treatment of psychotic depression (ECT having been considered and rejected for first line treatment), you may consider other options, depending on which aspects of the proposed first-line treatment you find problematic for your patient.
Our first choice treatment is a tricyclic plus an antipsychotic. (See the general discussion of other options in the Help section of the previous question). Although the two major studies of this combination used amitriptyline and desipramine, respectively as the tricyclic, we suggest nortriptyline instead. There is no reason to think it is any less effective, and the side effect profile is slightly more favorable, with its relatively low incidence of postural hypotension and moderate sedation and anticholinergic effects. Available evidence suggests that the tricyclic needs to be titrated to full therapeutic levels, which in the case of nortriptyline would be 50-150 ng.ml.
The antipsychotic used in the Spikar et al. study was perphenazine, and the doses used when results were optimal were 32-64 mg per day. Haloperidol has also been used, and optimal results were with 10 mg per day.¹ These suggested doses go against the intuitive tendency of clinicians to want to use the lowest dose possible, given the risk of tardive dyskinesia with neuroleptics, a risk which is apparently greater with mood disordered patients compared with schizophrenic patients. The studies do show that results correlate with full dosaging.
The new antipsychotics are now in widespread clinical use for psychotic depression, although no studies have confirmed their comparability. Given that their safety seems clearly better, they may be considered first-line now. In theory, their 5-HT(2) blockade could add to antidepressant efficacy, and reports of antidepressant-like effects including stimulation of mania in bipolar patients support this theory. Olanzapine was found to be better than haloperidol in treating depressive symptoms in schizophrenic patients.² Similar claims, with less robust evidence, are made for risperidone. Little experience has accrued with quetiapine and ziprasidone so far in this regard.
It takes a full five to six weeks for this combined pharmacotherapy to work.
A comment about maintenance treatment after successful treatment with tricyclic + neuroleptic therapy: most patients relapse within a few months if you try to taper off the neuroleptic, unfortunately.³ Probably the same would occur with the newer antipsychotics.
¹Nelson JC, Price LH, Jatlow PI. Neuroleptic dose and desipramine concentration during combined treatment of unipolar delusional depression. Am J Psychiatry 1986;143:1151-1154.
²Tollefson GD, Beasley CM Jr., Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997;154:457-465.
³Aronson TA, Shukla S, Hoff A. Continuation therapy after ECT for delusional depression: a naturalistic study of prophylactic treatments and relapse. Convulsive Therapy 1987;3(4):251-259.
Recommendation #06
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uestion: Has the patient had a trial of
lithium augmentation of the tricyclic plus antipsychotic therapy of this
delusional depression?
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Help: If the patient fails on TCA + antipsychotic therapy, there is scant literature regarding what would be the next psychopharmacologic option. (There's even less if an SSRI was the antidepressant). Clearly ECT appears again as an option, as it was before the choice of trying pharmacotherapy, and it deserves reconsideration if not used before. In Spikar's series, all six of the patients who failed to respond to TCA + antipsychotic treatment responded to ECT. Clinical experience suggests that lithium augmentation appears to offer a frequently effective pharmacotherapy option that works fairly quickly. However, in the only small published case series, it actually worked only in bipolar refractory psychotic depressed patients.¹ It is possible that SSRI augmentation could be helpful but we are aware of no case reports of this.
¹Nelson JC, Mazure CM. Lithium augmentation in psychotic depression refractory to combined drug treatment. Am J Psychiatry 1996;143:363-366.
Again, our first choice is ECT but if you find that is inappropriate, rejected by the patient, not available, etc, perhaps you should go ahead and try adding lithium to the tricyclic + antipsychotic combination. It is assumed that you have first optimized the tricyclic blood level, and the antipsychotic dose.
Recommendation #07
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uestion: Has the patient had a trial of methylphenidate
augmentation of TCA plus antipsychotic?
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Help: There's really practically no literature to help at this juncture. One report from 1971 of seven patients claimed that a stimulant, methylphenidate, augmented tricyclic response in patients with psychotic depression.¹
¹Wharton RN, Perel JM, Dayton PG, et al. A potential clinical use for methylphenidate with tricyclic antidepressants. Am J Psychiatry 1971;127:1619-1625.
Add methylphenidate, starting with 5-10 mg bid and increasing to up to 60 mg per day, as tolerated.
Recommendation #08
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,
If you have not been able to persuade the patient to try ECT by now, maybe this time you will be able to. Or, you may have to go back and try other antidepressants or combinations with the antipsychotic. For example, tranylcypromine plus lithium (without a neuroleptic) was successful in a few patients with psychotic depression previously unresponsive to multiple other regimens in a published case series.¹ One could try an SSRI plus tricyclic plus antipsychotic combinations. If the newer antipsychotics have not been used, they may be substituted. Clozapine was reported as effective in two cases of refractory patients.²,³
Recommendation #09
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¹Price LH, Charney DS, Heninger GR. Efficacy of lithium-tranylcypromine treatment in refractory depression. Am J Psychiatry 1985;142:619-623.
²Parsa MA, ramirez LF, Loula EC, et al. Effect of clozapine on psychotic depression and parkinsonism. J Clin Psychopharmacol 1991;11:330-331
³Dassa D, Kaladijian A, Axorin JM, et al. Clozapine in the treatment of psychotic refractory depression. Br J Psyschiatry 1993;163:822-824.
uestion: Has the patient had a trial of an SSRI added to an
antipsychotic?
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Help: As SSRI's have replaced tricyclics for general use in uncomplicated depression, clinicians are turning to them when dealing with psychotic depression. Impressions vary as to how effective they are but certainly many patients are getting improvement from them.
SSRIs and have all been used in combination with antipsychotics, either in published reports or anecdotally. As indicated above, several have been used as the sole treatment, as well. When used in combination with an antipsychotic, all EPS side effects of the antipsychotic, whether it is a standard, typical neuroleptic or one of the second generation drugs, may be enhanced due to pharmacokinetic or pharmacodynamic interactions depending on the SSRI.
Recommendation #25
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uestion:Has the patient had a trial of lithium augmentation
of the SSRI plus antipsychotic therapy of this delusional depression?
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Help: If the patient fails on SSRI + antipsychotic therapy, there is scant literature regarding what would be the next psychopharmacologic option. ECT appears again as an option, as it was before the choice of trying pharmacotherapy, and it is well worth reconsidering now. In Spikar's series, all six of the patients who failed to respond to TCA + antipsychotic treatment responded to ECT. Clinical experience suggests that lithium augmentation appears to offer a frequently effective pharmacotherapy option that works fairly quickly. However, in the only small published case series (which included some SSRI's), it actually worked only in bipolar refractory psychotic depressed patients.¹
As you are about to select your combination therapy for this patient, it is worth noting that use of antipsychotics alone (without an antidepressant) may be effective. Although standard, typical neuroleptics were the least effective treatment in the Spikar et al study (19% improved, vs. 40% on the amitriptyline alone), a series of 7 patients treated with risperidone seemed to derive antidepressant effects from it.² Also, a recent case report noted that olanzapine monotherapy was very effective for one patient,³ and a few more responders were noted in a chart review study. (4) A prospective study of olanzapine in psychotic depression is currently underway. As noted earlier, the newer antipsychotics may have greater antidepressant effects than the older generation.
¹Nelson JC, Mazure CM. Lithium augmentation in psychotic depression refractory to combined drug treatment. Am J Psychiatry 1996;143:363-366.
²Hillert 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
³DeBattista C, Solvason HB, Belanoff J, et al. Treatment of psychotic depression with olanzapine. Am J Psychiatry 1997;154:1625-1626.
(4)Zarate CAJr., Narendran R, Tohen M, et al. Clinical pridictors of acute response with olanzapine in psychotic mood disorders. J Clin Psychiatry 1998;59:24-28.
Again, our first choice is ECT but if that is inappropriate, rejected by the patient, not available, etc, perhaps you should go ahead and try adding lithium to the SSRI + antipsychotic combination.
Recommendation #10
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If you have not been able to persuade the patient to try ECT by now, maybe this time you will be able to. Or, you may have to go back and try other antidepressants or combinations with the antipsychotic. For example, tranylcypromine plus lithium (without a neuroleptic) was successful in a few patients with psychotic depression previously unresponsive to multiple other regimens in a published case series.¹ One could try an SSRI plus tricyclic plus antipsychotic combinations. If the newer antipsychotics have not been used, they may be substituted. Clozapine was reported as effective in two cases of refractory patients.²,³
¹Price LH, Charney DS, Heninger GR. Efficacy of lithium-tranylcypromine treatment in refractory depression. Am J Psychiatry 1985;142:619-623.
²Parsa MA, ramirez LF, Loula EC, et al. Effect of clozapine on psychotic depression and parkinsonism. J Clin Psychopharmacol 1991;11:330-331
³Dassa D, Kaladijian A, Axorin JM, et al. Clozapine in the treatment of psychotic refractory depression. Br J Psyschiatry 1993;163:822-824
Recommendation #11
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uestion: Has the patient had a trial of an antidepressant
alone?
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Help: Although tricyclics alone were not apparently effective for psychotic depression in a meta-analysis of relevant studies, as indicated earlier, Spiker's study found that 40 % of amitriptyline patients responded under double-blind controlled conditions, while perphenazine alone only helped 19% (there was no placebo control). As this is one of the few prospective controlled studies, it deserves some credence. Some early work suggested that delusional depression will respond to tricyclics, but only at higher doses. Therefore, there are times when it may be reasonable to try a tricyclic alone. It may be that a tertiary amine tricyclic such as amitriptyline, with its serotoninergic and anticholinergic effects, is the tricyclic of choice when used as monotherapy. As indicated earlier, two studies with certain SSRI's as monotherapy (fluvoxamine and sertraline [which was better than paroxetine]) indicated effectiveness, and more U.S. experience is needed to confirm this counter-intuitive result.
Amitriptyline may be the tricyclic of choice in this situation, based on the better than average results with this tricyclic reported by Spiker's group (ie-40%). If this is due to amitriptyline's combined norepinephrine and serotonin reuptake blockade, then clomipramine and in theory venlafaxine might be worth trying. Whatever tricyclic is used, the blood level should be titrated to the upper end of the usual plasma level range, if tolerated and if it is reasonably safe to try this.
Recommendation #13
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If the tricyclic fails and you still want to avoid a neuroleptic, and also are still not able to turn to ECT, the tricyclic may be augmented with lithium. Price et al report a 40% conversion to responder rate in psychotic depressives whose tricyclic therapy was augmented by lithium.¹ There was another more recent report endorsing this combination.²Another option is trying an MAOI, tranylcypromine, augmented by lithium.³
¹Price LH, Charney DS, Heninger GR. Variability of response to lithium augmentation in refractory depression. Am J Psychiatry 1986;143:1387-1392.
²Ebert D. Lithium-TCA combination treatment of psychotic depression: comparison with TCA-neuroleptic treatment. J Clin Psychopharmacol 1997;17:129-130.
³Price LH, Charney DS, Heninger GR. Efficacy of lithium-tranylcypromine treatment in refractory depression. Am J Psychiatry 1985;142:619-623.
Recommendation #12
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