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Evidence-Based Reviews

Psychotic depression: State-of-the-art algorithm improves odds for remission

Consider an antipsychotic, even when paranoia or cognitive changes are more obvious than delusions or hallucinations.

Vol. 3, No. 1 / January 2004

Psychotic depression requires a unique antidepressant approach, but how can you be sure that a patient’s major depression has psychotic features? Delusions or hallucinations—psychotic depression’s hallmarks—may not be obvious.

This article describes how to detect the distinctive diagnostic signs of psychosis in a patient with a major depressive episode. We offer a treatment algorithm for:

  • choosing between electroconvulsive therapy (ECT) and medication
  • safely combining antidepressant and antipsychotic agents
  • addressing partial or nonresponse to ECT or medications.

Psychotic or nonpsychotic?

Similar clinical presentations make it difficult to distinguish psychotic depression from nonpsychotic depression, schizophrenia spectrum disorders, bipolar disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and body dysmorphic disorders. Comorbid substance abuse/dependency disorders can also complicate psychotic depression’s clinical manifestations and outcomes.

Because delusions and hallucinations are often subtle, researchers have sought other symptoms to differentiate psychotic from nonpsychotic depression. For example, patients with psychotic depression are more likely to exhibit paranoia1 (Table 1), which may explain their underreporting of symptoms.

Table 1

Diagnostic characteristics of psychotic depression

DSM-IV hallmark symptoms

Delusions or hallucinations in the context of a depressive episode

More subtle symptoms may include:

  • No diurnal variation in mood
  • Guilt
  • Psychomotor disturbance
  • Cognitive impairment
  • Paranoia
  • Hopelessness
  • Hypochondriasis
  • Anxiety
  • Early and middle insomnia
  • Constipation

Using the Hamilton Rating Scale for Depression (HRSD), Frances and colleagues 2 compared 64 depressed patients (34 with psychotic features and 30 without). On the scale’s paranoia item, the psychotic group’s mean score was 1.10, compared with 0.15 for those without psychosis (p = 0.01).

Family history and clinical course. Some studies suggest that first-degree relatives of patients with psychotic depression may have elevated rates of depression and the psychotic subtype. 3 Patients with psychotic depression typically suffer morefrequent relapses or recurrences and therefore:

  • use more psychiatric services
  • are more disabled
  • have a poorer clinical course. 4

Suicide risk. Psychotic depression is associated with increased risk of self-harm and hospitalization compared with nonpsychotic depression. Patients hospitalized for a major depressive episode are five times more likely to commit suicide if they show evidence of delusions. 5

Social impairment. Patients with psychotic depression often have “troubled” lives, with difficult marital and parental relationships, residential instability, inadequate support networks, and low economic status. These problems may be related to subtle cognitive deficits caused by hypothalamic-pituitary-adrenal (HPA) axis disturbance and elevated cortisol levels. 6

Confronting similar presentations

Using the BPRS. The Brief Psychiatric Rating Scale (BPRS) is a useful tool to differentiate psychotic depression from nonpsychotic depression. It can flag symptoms such as suspiciousness, grandiosity, and somatization that even a seasoned psychiatrist might miss. The BPRS also points out:

  • Any sign of psychosis is sufficient to designate major depression as “psychotic.”
  • One well-developed diagnostic sign is sufficient to warrant treatment for psychotic depression.

Schizophrenia spectrum disorders. When psychosis is prominent (particularly in young adults), differentiating schizophrenic spectrum disorders from psychotic depression can be extremely challenging. Although few biological differences have been documented, patients with psychotic depression and schizophrenia differ in HPA axis activity and all-night sleep electroencephalogram readings. 7

When the diagnosis is unclear, maintain a high index of suspicion for psychotic depression and its subtleties, and schedule frequent follow-up appointments.

Conversion to bipolar disorder. Adolescents diagnosed with unipolar major depression are at risk for converting to bipolar disorder, particularly if their depression includes psychotic features. In 60 hospitalized adolescents diagnosed with unipolar depression, a 20% conversion rate to bipolar disorder was predicted in part by a cluster of depressive symptoms:

  • mood-congruent psychotic features (75% of converters vs. 6% of nonconverters, p< 0.001)
  • psychomotor retardation
  • rapid symptom onset. 8

A similar study reported a 20% conversion rate to bipolar disorder in 206 adolescent outpatients diagnosed with unipolar depression. 9 Psychotic depression was more common in converters (42%) than in nonconverters (15%).

Anxiety disorders—such as PTSD or OCD—can be difficult to distinguish from psychotic depression when they present with sensory disturbance.

When in doubt, explore:

  • obsessions
  • intrusive thoughts
  • psychomotor behaviors
  • fear of certain external events or people without consistent cues from reality.

PTSD and psychotic depression are not mutually exclusive; a patient may have both. 10

Body dysmorphic disorder. Body image concerns correlate with poor self-esteem and depression. 11 According to DSM-IV criteria, an individual with body dysmorphic disorder displays excessive concern over an imagined or slight defect, and this concern causes substantial distress or functional impairment. The concern also is not better accounted for by another mental disorder, such as psychotic depression or an eating disorder.

The body is often a focus of psychotic depression’s delusions. During depressive episodes, a patient may have a frank belief about a body part that is not consistent with reality. The history may include negative medical workups or preoccupation with having a serious illness.

Hypochondriasis is a characteristic of psychotic depression, and distinguishing body dysmorphic disorder and other somatoform-spectrum disorders from psychotic depression’s delusions may be difficult:

  • Delusions in body dysmorphic disorder tend to be fixed over time.
  • Delusions in psychotic depression tend to fluctuate in severity and may subside when the acute psychotic-depressive episode resolves.


When ECT is preferred for psychotic depression

ECT may be slightly more effective than medications for treating psychotic depression. 13 ECT is not readily available in some regions, however, and the public has negative perceptions of “shock treatment.” Unfortunately, this stigma is often more influential than the evidence. According to some studies, less than 8% of U.S. psychiatrists offer ECT. 14

Because medications are usually needed for maintenance treatment in psychotic depression, many clinicians choose medications over ECT as a first-line treatment. ECT should be considered as a first-line treatment for psychotic depression:

  • in patients with a history of good response to ECT
  • in patients with suicidal intent or severe inanition
  • in older patients
  • as second-line therapy for patients who fail to respond to or experience complications with medications.

Treatment recommendations

When a patient meets diagnostic criteria for psychotic depression, American Psychiatric Association practice guidelines 12 recommend ECT or an antidepressant plus an antipsychotic. Although ECT may be slightly more effective than medications for treating psychotic depression, it is not readily available in many areas (Box). 13,14

Medication has been shown to be effective in early studies that combined tricyclic antidepressants (TCAs) with conventional antipsychotics and in trials using selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics.

Table 2

Medications reported effective for treating psychotic major depression

Study, year of publication



Double-blind studies

Spiker et al, 1985

Perphenazine, 54 to 64 mg/d

Amitriptyline, 200 mg/d

Anton et al, 1990


Amoxapine, 400 mg/d

Dube et al, 2002

Olanzapine, 5 to 20 mg/d

Fluoxetine, 20 to 80 mg/d

Case reports and open-label studies

Quitkin et al, 1978

Imipramine, 300 mg/d


Manberg et al, 1984

Haloperidol, 20 mg/d

Bupropion, 300 mg/d

Nelson et al, 1986

Perphenazine, 45 mg/d

Desipramine, 150 mg/d

Aronson et al, 1987

Chlorpromazine, 1,000 mg/d


Howarth et al, 1989

Imipramine, 248 mg/d


Rothschild et al, 1993

Perphenazine, 32 mg/d

Fluoxetine, 40 mg/d

Banov et al, 1994

Clozapine, 325 mg/d


Jacobsen, 1995

Risperidone, 2.5 mg/d


Wolfersdorf et al, 1995

Haloperidol, 2.5 to 10 mg/d

Paroxetine, 20 mg/d

Zarate et al, 2000

Quetiapine (various)

? (naturalistic chart review)

Spiker and colleagues 15 treated 58 patients with psychotic depression for 35 days, using amitriptyline, 200 mg/d; perphenazine, 64 mg/d; or the same dosages of amitriptyline plus perphenazine. 15 Fourteen of 18 patients (78%) taking combination therapy achieved a >50% reduction in HRSD score, compared with 7 of 17 (41%) taking amitriptyline alone and 3 of 16 (19%) taking perphenazine alone.

In a more recent study, 16 249 patients with psychotic depression were randomly assigned to:

  • olanzapine, 5 to 20 mg/d, plus fluoxetine, 20 to 80 mg/d
  • olanzapine, 5 to 20 mg/d, plus placebo
  • or placebo.

Patients receiving olanzapine plus fluoxetine showed greater improvement in HRSD scores, compared with olanzapine monotherapy or placebo. Anecdotal reports indicate that quetiapine, risperidone, or olanzapine may be effective for patients with psychotic depression. 17,18

We usually start with an SSRI plus an atypical antipsychotic (Algorithm). The atypicals have fewer side effects than conventional antipsychotics and may offer intrinsic antidepressant qualities through their effects on serotonin type-2 receptors. Table 2 lists recommended dosages.

When initial treatment fails

Consider second- and third-line options when patients fail to achieve remission with ECT or an SSRI plus an atypical antipsychotic. Document that first-line trials were of sufficient duration (8 to 12 weeks) and dosage.

We define remission as:

  • HRSD score of <10 for at least 2 weeks
  • score of 1 (no delusions or hallucinations) on the Schedule for Affective Disorders and Schizophrenia (SADS)
  • and no longer meeting full criteria for a major depressive episode on the Structured Clinical Interview for DSM-IV.

We define partial remission as:

  • HRSD score between 11 and 17
  • HRSD improvement of >30% from baseline
  • score of 1 on the SADS
  • and no longer meeting full DSM-IV criteria for a major depressive episode.

Algorithm State-of-the-art treatment of psychotic major depression

Lithium. We suggest adding lithium when patients respond partially to an SSRI/atypical antipsychotic combination. Although limited evidence supports lithium augmentation of antidepressants for psychotic depression, this strategy is often used.

Adding lithium to an antidepressant/antipsychotic combination was examined in a retrospective chart review of patients treated for bipolar and unipolar psychotic depression. 19 Lithium, 600 to 1,200 mg/d, was added when patients did not respond to desipramine, 150 mg/d, plus either perphenazine, 12 to 64 mg/d, or haloperidol, 4 to 20 mg/d. Eight of nine patients with bipolar psychotic depression achieved remission with the added lithium, compared with 3 of 12 patients with unipolar psychotic depression (p = 0.003).

To our knowledge, no data indicate how long to continue lithium augmentation. We start older adults on 300 mg/d and younger adults on 600 mg/d and increase by 300 mg per week. Target serum levels are 0.5 to 0.8 mEq/L, and maximum dosage is 1,200 mg/d for young adults and 900 mg/d for frail or elderly patients. We follow thyroid, renal, and hydration status and monitor for weight gain, tremors, cognitive slowing, and GI disturbances.

Other second-line options. Sufficient data support using the second-line drugs in our algorithm as first-line agents. However, the second-line agents pose a greater risk of adverse effects and decreased tolerability than SSRIs plus atypical antipsychotics. Second-line options include:

  • SSRIs plus conventional antipsychotics
  • amoxapine, a derivative of the conventional antipsychotic loxapine
  • venlafaxine or TCAs plus atypical antipsychotics.

As with first-line therapy, 8 to 12 weeks is an adequate trial for second-line medications. ECT may be considered for patients who fail to respond to medications or experience complications.

SSRI/conventional antipsychotic. Our group used fluoxetine, 20 to 40 mg/d, plus perphenazine, 32 mg/d, in the first study of combined SSRI/conventional antipsychotic therapy for patients with psychotic depression. 20 After 5 weeks, 22 of 30 patients’ HRSD and BPRS scores were reduced by >50%.

Amoxapine monotherapy. Anton and Burch 21 compared amoxapine, 400 mg/d, with amitriptyline, 200 mg/d, plus perphenazine, 32 mg/d. Response rates (>50% reduction on the HRSD) were 71% and 81% for the two groups, respectively. Extrapyramidal symptoms (EPS) were more frequent with the combination therapy.

Venlafaxine’s mechanism of action is thought to be similar to that of TCAs, and we know from the Spiker study 15 that TCAs are effective in treating psychotic depression. To our knowledge, venlafaxine dosages for psychotic depression have not been studied; 75 to 375 mg/d is recommended for nonpsychotic depression. Potential side effects include insomnia, nervousness, nausea, headache, dry mouth, fatigue, and elevations of supine diastolic blood pressure.

Third-line therapy. Clozapine may be considered when second-line options do not achieve adequate results. 22 When making this choice, consider the need for biweekly blood monitoring and the risk of serious side effects such as agranulocytosis and seizures.

Maintenance therapy

Psychotic depression has a higher relapse rate than nonpsychotic depression. Relapse rates are 50 to 92% in patients with psychotic depression, and recurrence often develops within 2 to 14 months after recovery from the index episode. 23 With little data on which to base a maintenance regimen, we recommend that you continue antipsychotics for 4 months after the acute episode resolves.

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