New approaches to managing psychotic depression

New Approaches to Managing Psychotic Depression New Approaches to
Managing Psychotic Depression
Alan F. Schatzberg, M.D.
Major depression with psychotic features, while fairly common, is frequently misdiagnosed.
Symptoms seen in these patients are those of an overall severe depressive disorder with psychomotorimpairment (retardation or agitation), guilt, suicidal preoccupation, and neuropsychological impair-ment. A number of biological characteristics and behavioral symptoms are specific to patients suffer-ing from psychotic depression and differ significantly from those of nonpsychotic depression. Psy-chotic depression is seen in patients of all ages, and it has a high short-term morbidity and risk ofsuicide. Data support the use of antipsychotics in combination with antidepressants for major depres-sion with psychotic features, but other treatments may have as great or greater efficacy for the dis-order. This article focuses on recognizing the features of psychotic depression, the success of currenttreatment options, and new treatments under investigation.
(J Clin Psychiatry 2003;64[suppl 1]:19–23) lthough major depression with psychotic features distinct clinical entity due to a number of biological and represents about 25% of consecutively admitted behavioral symptoms that are specific to the disorder.5,6 depressed patients,1 it is frequently overlooked.2 Patientsare often careful about revealing cognitive deficits and delusions and will sometimes deny thoughts of suicide,3which makes this disorder difficult to diagnose. Similari- While symptoms of psychotic depression can be pro- ties in the symptoms of psychotic depression, schizo- found, differentiation from other disorders and detection phrenia, and schizoaffective disorder also make diagnosis of undisclosed symptoms often require extensive exami- more difficult.2 Data have shown that psychotic depres- nation of the patient. Responding to data that patients with sion is more similar to schizophrenia than to nonpsychotic delusional depression were less responsive to tricyclic antidepressants than were patients with nondelusional In the Diagnostic and Statistical Manual of Mental depression, Glassman and Roose7 conducted a study to Disorders, Fourth Edition, psychotic depression is classi- differentiate symptoms of psychotic and nonpsychotic fied as a major depressive disorder, severe, with psychotic depression. They found that patients with psychotic symptoms. This classification requires the usual criteria depression are more likely to show clinically significant for a major depressive episode with the additional symp- psychomotor agitation than their nonpsychotic counter- toms of hallucinations or delusions, which can be either parts. These findings have been confirmed in subsequent mood-congruent or -incongruent. Some researchers have argued that psychotic depression should be classified as a The delusions experienced by psychotically depressed patients are typically guilty,5,7,10 paranoid,3,5 and somatic5;and their hallucinations are auditory, visual, or somatic.5Studies conducted to test the neurovegetative symptomsof psychotic depression have shown symptoms of severe From the Department of Psychiatry and Behavioral depression5,9 and fixed depressive thought content5,10 and Sciences, Stanford University School of Medicine, Stanford,Calif. both higher levels of retardation5 and higher levels of cog- This article is derived from the teleconference “New nitive disturbance5 according to Hamilton Rating Scale Approaches to Managing Difficult-to-Treat Depressions,” whichwas held May 13, 2002, and sponsored by an unrestricted for Depression (HAM-D) scores and compared with non- educational grant from Eli Lilly and Company. Also supported psychotic patients. In studies,4,11 Stroop Color and Word by National Institute of Mental Health grant MH50604. Test scores indicated that psychotically depressed pa- Erin Hanski assisted in the preparation of this manuscript.
Corresponding author and reprints: Alan F. Schatzberg,
tients’ attention and response inhibition were impaired.
M.D., Department of Psychiatry and Behavioral Sciences, Patients also had impaired immediate and delayed recall Stanford University School of Medicine, 410 Quarry Rd.,Admin. 3rd Floor, Stanford, CA 94305-5717 memory for semantically organized information but were able to retain verbal material normally. These data suggest OPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
an attentional component to the problems with recall.
depression. Amoxapine is a dibenzoxazepine TCA with Patients with psychotic depression have shown a higher antidepressant and antipsychotic effects that has shown rate of errors of commission on verbal memory tests.11,12 effectiveness in patients with delusional depression.22 The Serretti et al.13 found that these patients had a higher rate of serotonin-2 antagonist and mild dopamine-2 antagonist cluster A personality disorder and a lower level of educa- properties of amoxapine have led some to argue that tion compared with patients with nonpsychotic depression.
amoxapine should be considered an atypical antipsy- Other features characteristic of psychotic depression chotic.23 Anton and Burch22 compared the combination compared with nonpsychotic depression include a history of amitriptyline and perphenazine with amoxapine in 38 of past delusions10 but fewer previous episodes,7 a positive patients with psychotic depression in a 4-week double- family history of mental disorder,14 previous suicide at- blind study. Patients in each group showed similar im- tempt,14 greater suicidal ideation and intent,10 and reduced provement in depression and psychosis.
or absent diurnal variation of depressive symptoms.5 Psy- There are some positive data on selective serotonin chotic depression is often considered a disorder of the reuptake inhibitors (SSRIs) as monotherapy for the treat- elderly, but at least one study has reported that younger ment of psychotic depression. In a double-blind European age was found to be a more common characteristic of psy- trial comparing sertraline with paroxetine for delusional chotic rather than nonpsychotic depression.9,10 In compari- depression, 75% of patients treated with sertraline and son with patients with schizophrenic disorders, patients 46% of patients treated with paroxetine were considered with psychotic depression have shown greater emotional responders.24 A trial of fluvoxamine monotherapy for de- impact features and greater volitional dyscontrol.15 If a lusional depression showed a response rate similar to that patient’s psychotic depression is further complicated by of antidepressants plus antipsychotics and of ECT.25 Of agitation, determining whether the patient is suffering the 57 patients who completed the 6-week trial, 48 pa- from agitated psychosis, severe anxiety, or a dysphoric tients recovered. American investigators have been skep- manic state may be difficult. A number of questions can tical of the efficacy of SSRI monotherapy.
help in the differential diagnosis. Does the patient sufferfrom insomnia? If so, does the patient believe that he or she needs less sleep than usual? If delusions are present, Atypical antipsychotics alone may be effective for psy- are they guilt-ridden as in a depressive state or pleasure- chotic depression. The earliest observation of atypical seeking as in a hypomanic or manic state? Has the psycho- antipsychotic monotherapy treatment reported that ris- sis been present in the absence of affective symptoms? Is peridone seemed to be effective in 10 patients with there a family history of psychotic or affective illness? schizodepressive disorders or a psychotic major depres- Biological symptoms that have been found to be indi- sive episode.26 In a more recent, multicenter, double-blind, cators of psychotic depression are related to excessive parallel group trial,27 the efficacy of risperidone was com- hypothalamic/pituitary/adrenal (HPA) axis activity.4 This pared with a combination of haloperidol and amitriptyline is reflected in high levels of 24-hour urinary free cortisol,16 in 123 patients over 6 weeks. Although overall, the com- high rates of dexamethasone nonsuppression,11,17–20 and bination treatment showed greater efficacy, risperidone high post-dexamethasone cortisol levels.11,18 produced a 37% reduction in patients’ Positive and Nega-tive Syndrome Scale–derived Brief Psychiatric Rating Scale (BPRS) scores and a 51% reduction in patients’Bech-Rafaelsen Melancholia Scale total scores. A case Psychotic depression is also a difficult-to-treat disorder, report28 of a female patient with psychotic depression sug- and in general, patients with psychotic depression are gests that risperidone monotherapy can be efficacious in inadequately treated. In a survey of 187 patients referred some patients who have not responded to other treatments.
for electroconvulsive therapy (ECT), Mulsant and col- The patient was first treated with a combination of fluoxe- leagues21 reported high rates of inadequate treatment.
tine and flupenthixol, and then a regimen of fluoxetine, They found that only 2 (4%) of 53 patients with psychotic trifluoperazine, and bilateral ECT 3 times a week, both of depression received at least one adequate medication trial.
which were unsuccessful. Risperidone monotherapy was In contrast, 70 (52%) of 134 patients with nonpsychotic initiated, which resulted in an improvement in psychotic depression received at least one adequate trial. Of patients as well as mood disturbances without emergence of side with psychotic depression, 25 (47%) received either no antipsychotic medication or treatment for less than 3 Olanzapine has also been found successful as mono- therapy in psychotic depression. DeBattista et al.29reported a substantial improvement in symptoms of psy- chotic depression in a patient taking olanzapine mono- Tricyclic antidepressant (TCA) monotherapy, other therapy, and a case report in Germany also found olanza- than amoxapine, is generally ineffective for psychotic pine effective for psychotic depression.30 OPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
New Approaches to Managing Psychotic Depression Antidepressant-Antipsychotic Combinations Figure 1. Percentage of Patients Considered Responders
The drug treatments that have typically been most (50% Improvement) to Olanzapine-Fluoxetine Combination
effective for psychotic depression include combinations Treatment According to HAM-D Scoresa
of antidepressants with antipsychotics. Traditionally these treatments have included TCAs combined with conven-tional antipsychotics. In a double-blind study by Spiker et al.,31 the combination of amitriptyline and perphenazine was significantly more effective for psychotic depression than either drug alone. A meta-analysis32 of 597 patients showed a 77% response rate to TCAs combined with anti- psychotics, and 3 retrospective chart reviews33–35 revealed good responses to TCA and antipsychotic combinations.
The SSRI fluoxetine combined with perphenazine showed efficacy similar to that reported for amoxapine, ECT, andTCA-antipsychotic combination therapy in a 5-week aReprinted with permission from Dubé et al.38 trial.36 Of 30 patients, 22 had a 50% or greater reduction in Abbreviation: HAM-D = Hamilton Rating Scale for Depression.
Recent data suggest that the combination of SSRIs and atypical antipsychotics might be particularly effective for ports of the induction and exacerbation of psychotic symp- the treatment of psychotic depression. Olanzapine was toms by fluoxetine40 and sertraline41 in patients with psy- reported to be effective in combination with citalopram in chotic depression who are taking antipsychotics.
a case report of a patient who was resistant to other treat-ments.30 Another case report37 found the combination of olanzapine and sertraline effective for severe depression While ECT is a remarkably effective treatment for psy- with psychotic features in a suicidal patient who had failed chotic depression,33,34,42,43 requirements for its use are treatment with the combination of mirtazapine and halo- stringent, and public perception about the overall appro- peridol as well as venlafaxine and haloperidol. The priateness of shock treatment is negative.
patient’s condition deteriorated when olanzapine was Lithium has shown some effectiveness as an augmenta- withdrawn but quickly improved when olanzapine therapy tion strategy in patients with psychotic depression who do not respond to the combination of tricyclic antidepressants Beyond case reports, more substantial data for the com- and neuroleptics.44 In an open comparison of lithium plus bination of olanzapine and fluoxetine in the treatment of amitriptyline and haloperidol plus amitriptyline, Ebert45 psychotic depression have recently been presented. Dubé described fewer side effects and better improvement of et al.38 conducted 2 parallel, 8-week, double-blind trials some depressive symptoms in patients taking the lithium that compared treatment with olanzapine plus fluoxetine to olanzapine or placebo in 249 patients with psychoticdepression. While 110 patients completed the acute phase, rates of study discontinuation due to adverse events were An emerging area of study for treating patients with higher for the olanzapine-fluoxetine combination com- psychotic depression is based on the markedly abnormal pared with placebo (6.0%, p = .016) but not different from HPA axis and high cortisol levels in those patients.4,5,12 Cli- the rate with olanzapine alone (8.9%, p = .085). Mean nicians have hypothesized for a number of years that psy- changes in HAM-D scores were significantly greater for chosis and the cognitive disturbance seen in these patients the olanzapine-fluoxetine combination than for either pla- may be due to excessive glucocorticoids and that inhibi- cebo or olanzapine alone. The response rates were 56% for tion of the HPA axis might be an effective treatment. There the combination, 36% for olanzapine alone, and 30% for are 2 types of receptors for cortisol. One is the mineralo- placebo (Figure 1), and 20% of patients in the combination corticoid receptor, which is a high-affinity receptor that is group remitted (Table 1). Rothschild et al.39 retrospec- responsible for much of the diurnal variation of cortisol tively compared olanzapine against typical antipsychotics metabolism and secretion. The other receptor is the low- in 15 inpatients with psychotic depression, most of whom affinity glucocorticoid receptor (GR) that tends to be acti- were also taking antidepressants. Response to treatment vated only under high levels of stress.46 was evaluated by reviewing and scoring patient records Mifepristone is a potent GR antagonist that has shown using a 7-point Likert rating scale. Ten of the 15 patients potential for rapidly reversing psychotic symptoms in taking olanzapine compared with 4 of 15 patients taking delusional depression. Belanoff et al.47 conducted a small, other antipsychotics were considered much or very much double-blind, placebo-controlled, crossover study of mife- improved upon discharge. However, there have been re- pristone in 5 patients with psychotic major depression.
Table 1. Percentage of Patients Achieving Response or Remission While
Taking Placebo, Olanzapine Alone, or Olanzapine Plus Fluoxetinea

tant when progesterone is blocked for pro- longed periods (months) because unopposed estrogen could lead to menstrual problems.
detect and to treat, but there are specific psy- aReprinted with permission from Dubé et al.38 Abbreviation: HAM-D = Hamilton Rating Scale for Depression.
bMedian days to response/remission based on Kaplan-Meier survival analysis.
clinicians can become familiar with in order cp = .041 vs. olanzapine-fluoxetine combination.
d to identify this disorder. Symptoms of a se- p = .005 vs. olanzapine-fluoxetine combination.
vere, debilitating depressive disorder shouldprompt a clinician to examine the patient Patients were given 600 mg/day of mifepristone for 4 more closely for delusions or other symptoms of psycho- days. All patients completed the protocol and no adverse sis. Hospitalization and stabilization may be necessary for effects were observed or reported. All patients showed severely psychotic and suicidal depressed patients. Often, substantial improvements in their HAM-D scores while re- patients with paranoid delusions will be more willing to ceiving mifepristone, and 4 of the 5 patients showed sub- accept treatment with a single medication rather than a stantial improvement in their BPRS scores.
combination. For this reason, it may be optimal to sta- In a more recent study, Belanoff et al.48 conducted an bilize the patient with an antipsychotic agent and add an open-label trial of mifepristone in 30 inpatients with psy- antidepressant to the treatment after the patient is more chotic major depression. Patients were randomly assigned willing to accept additional medication. Olanzapine and to receive 50 mg, 600 mg, or 1200 mg of mifepristone fluoxetine may be a useful combination. While there are once daily for 7 days. Patients taking both the 600-mg/day sufficient data to recommend ECT for the treatment of and 1200-mg/day doses showed significant reductions in psychotic depression, there are both real and perceived their psychosis in 1 week or less. More than 40% of pa- drawbacks to ECT; therefore, it may be best considered tients taking the 2 higher doses had a greater than 50% after other options have failed. Limited data confirm the reduction in their HAM-D scores, and over 60% demon- efficacy of options such as HPA axis inhibition for the strated at least a 30% reduction in BPRS scores. This strat- treatment of psychotic depression. These options may also egy may open up some alternative methods for treating be best considered after standard therapies have failed.
delusional depression that are more acceptable than ECT.
A GR antagonist may have more rapid effects than atypical Drug names: amitriptyline (Endep, Elavil, and others), amitriptylineand perphenazine (Etrafon and others), citalopram (Celexa), fluoxetine antipsychotic–antidepressant combination therapy, which (Prozac and others), fluvoxamine (Luvox and others), haloperidol (Hal- may not separate from placebo for several weeks.
dol and others), mifepristone (Mifeprex), mirtazapine (Remeron), My colleagues and I have used mifepristone for olanzapine (Zyprexa), paroxetine (Paxil), perphenazine (Trilafon andothers), risperidone (Risperdal), sertraline (Zoloft), trifluoperazine psychotic depression acutely then switched patients over (Stelazine and others), venlafaxine (Effexor).
to antidepressant monotherapy or an antidepressant-antipsychotic combination.46 The clinical improvement Disclosure of off-label usage: The author of this article has determined achieved with the GR antagonist seems to be maintained that, to the best of his knowledge, amitriptyline, amoxapine, citalopram,fluoxetine, fluvoxamine, haloperidol, lithium, mifepristone, mirtaz- after patients are switched; however, in an attempt to dem- apine, olanzapine, paroxetine, perphenazine, risperidone, sertraline, onstrate that sustained effect in a controlled study, we are trifluoperazine, and venlafaxine are not approved by the U.S. Food and now conducting longer-term, placebo-controlled trials Drug Administration for the treatment of psychotic major depression.
of mifepristone. In these studies, patients are assessed forresponse after 1 week of treatment with mifepristone.
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