Psychotic depression

State-of-the-art algorithm

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

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improves odds for remission

sychotic depression requires a unique

antidepressant approach, but how can
you be sure that a patients major depression has
psychotic features? Delusions or hallucinations
psychotic depressions hallmarksmay 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.

Michael A. Bell, MD

PSYCHOTIC OR NONPSYCHOTIC?

Chief resident in ambulatory psychiatry and

psychopharmacology research

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 depressions 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

Anthony J. Rothschild, MD
Irving S. and Betty Brudnick Professor of Psychiatry
Director of clinical research

Image : Lisa Kimmell

Department of psychiatry
University of Massachusetts Medical School
Worcester

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Psychotic depression

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

with psychotic depression are more likely to

exhibit paranoia1 (Table 1), which may explain
their underreporting of symptoms.
Using the Hamilton Rating Scale for Depression (HRSD), Frances and colleagues2 compared
64 depressed patients (34 with psychotic features
and 30 without). On the scales paranoia item, the
psychotic groups 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
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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 followup 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:

Current
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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 disorderssuch as PTSD or OCDcan
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 depressions 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 depressions delusions may be difficult:
Delusions in body dysmorphic disorder
tend to be fixed over time.

Box

When ECT is preferred

for psychotic depression
CT 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.

Delusions in psychotic depression tend to

fluctuate in severity and may subside when the
acute psychotic-depressive episode resolves.
TREATMENT RECOMMENDATIONS

When a patient meets diagnostic criteria for psychotic depression, American Psychiatric Association practice guidelines12 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.
continued
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Psychotic depression

Table 2

Medications reported effective for treating psychotic major depression

Study, year of publication

Antipsychotic

Antidepressant

Spiker et al, 1985

Perphenazine, 54 to 64 mg/d

Amitriptyline, 200 mg/d

Anton et al, 1990

None

Amoxapine, 400 mg/d

Dube et al, 2002

Olanzapine, 5 to 20 mg/d

Fluoxetine, 20 to 80 mg/d

Double-blind studies

Case reports and open-label studies

Quitkin et al, 1978

Imipramine, 300 mg/d

None

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

None

Howarth et al, 1989

Imipramine, 248 mg/d

None

Rothschild et al, 1993

Perphenazine, 32 mg/d

Fluoxetine, 40 mg/d

Banov et al, 1994

Clozapine, 325 mg/d

None

Jacobsen, 1995

Risperidone, 2.5 mg/d

None

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 colleagues15 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 quetiap-

ine, risperidone, or olanzapine may be effective

for patients with psychotic depression.17,18
We usually start with an SSRI plus an atypical
antipsychotic (Algorithm, page 61). 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)
continued on page 61

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continued from page 58

Algorithm

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

Symptoms meet diagnostic
criteria for psychotic depression

No

Treat primary disorder

Yes

Treat with ECT or medications

6 to 12 weeks unilateral
ECT treatments

Review past medication

trials and response

Response

No

Response

Yes

Partial

Consider
Consider

Response

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.

Yes

No

Maintenance
medication

and no longer meeting full criteria for a

major depressive episode on the Structured
Clinical Interview for DSM-IV.

No

ECT
ECT

Antidepressant
+ conventional
antipsychotic

Yes

Amoxapine
Amoxapine

Response

Venlafaxine or
TCA + atypical
antipsychotic

Lithium
augmentation

Maintenance medication

No

Yes

Maintenance: ECT
or medication

Start SSRI + atypical antipsychotic

Consider antidepressant
+ clozapine

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
VOL. 3, NO. 1 / JANUARY 2004

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Psychotic depression

and unipolar psychotic depression.19 Lithium, 600

Amoxapine monotherapy. Anton and Burch21
compared amoxapine, 400 mg/d, with amitriptyto 1,200 mg/d, was added when patients did not
line, 200 mg/d, plus perphenazine, 32 mg/d.
respond to desipramine, 150 mg/d, plus either
Response rates (>50% reduction on the HRSD)
perphenazine, 12 to 64 mg/d, or haloperidol, 4 to
were 71% and 81% for the two groups, respective20 mg/d. Eight of nine patients with bipolar psyly. Extrapyramidal symptoms (EPS) were more
chotic depression achieved remission with the
frequent with the combination therapy.
added lithium, compared with 3 of 12 patients
Venlafaxines mechanism
with unipolar psychotic depression (p = 0.003).
of action is thought to be simiTo our knowledge, no data
lar to that of TCAs, and we know
indicate how long to continue
We continue atypical
from the Spiker study15 that TCAs are
lithium augmentation. We start
effective in treating psychotic depresolder adults on 300 mg/d and antipsychotics
sion. To our knowledge, venlafaxine
younger adults on 600 mg/d and 4 months after the
dosages for psychotic depression have
increase by 300 mg per week. acute psychotic
Target serum levels are 0.5 to 0.8 depression resolves not been studied; 75 to 375 mg/d is recommended for nonpsychotic depresmEq/L, and maximum dosage is
sion. Potential side effects include
1,200 mg/d for young adults and
insomnia, nervousness, nausea,
900 mg/d for frail or elderly patients. We follow
headache, dry mouth, fatigue, and elevations of
thyroid, renal, and hydration status and monitor
supine diastolic blood pressure.
for weight gain, tremors, cognitive slowing, and
Third-line therapy. Clozapine may be considered
GI disturbances.
Other second-line options. Sufficient data support
when second-line options do not achieve adeusing the second-line drugs in our algorithm as
quate results.22 When making this choice, consider the need for biweekly blood monitoring
first-line agents. However, the second-line agents
and the risk of serious side effects such as agranpose a greater risk of adverse effects and decreased
ulocytosis and seizures.
tolerability than SSRIs plus atypical antipsychotics. Second-line options include:
MAINTENANCE THERAPY
SSRIs plus conventional antipsychotics
Psychotic depression has a higher relapse rate
amoxapine, a derivative of the conventional
than nonpsychotic depression. Relapse rates are
antipsychotic loxapine
50 to 92% in patients with psychotic depression,
venlafaxine or TCAs plus atypical
and recurrence often develops within 2 to 14
antipsychotics.
months after recovery from the index episode.23
As with first-line therapy, 8 to 12 weeks is an
With little data on which to base a maintenance
adequate trial for second-line medications. ECT
regimen, we recommend that you continue
may be considered for patients who fail to respond
antipsychotics for 4 months after the acute
to medications or experience complications.
SSRI/conventional antipsychotic. Our group used
episode resolves.
fluoxetine, 20 to 40 mg/d, plus perphenazine, 32
Recently our group reported that after a taper
mg/d, in the first study of combined SSRI/conof perphenazinefollowing 4 months of treatventional antipsychotic therapy for patients with
ment with fluoxetine and perphenazine22 of
psychotic depression.20 After 5 weeks, 22 of 30
30 patients (73%) showed no signs of relapse over
patients HRSD and BPRS scores were reduced
the next 11 months.24 We usually maintain
patients on antidepressants indefinitely.
by >50%.
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disorder and posttraumatic stress disorder. J Clin Psychiatry

1999;60(5):311-4.

Related resources

11. Buhne A, Keuthen N. Prevalence of symptoms of body dysmorphic

disorder and its correlates: a cross-cultural comparison.
Psychosomatics 2002:43;486-90.

DeBattista C, Rothschild AJ, Schatzberg AF. A dynamic algorithm

for the treatment of psychotic major depression. Psychiatric Ann
2002;32:681-91.

Rothschild AJ. Challenges in the treatment of depression with

psychotic features. Biol Psychiatry 2003;53:680-90.

12. American Psychiatric Association. Practice guidelines for the treatment of major depressive disorder (revision). Am J Psychiatry
200;157:(suppl 4).

National Institutes of Health. http://www.clinicaltrials.gov.

Enter Medication treatment for psychotic depression
in Search clinical trials field, then click on appropriate link.

13. Parker G, Roy K, Hadzi-Pavlovic D, Pedic F. Psychotic (delusional)

depression: A meta-analysis of physical treatments. J Affect Disord
1992;24:17-24.

DRUG BRAND NAMES

Amitriptyline Elavil
Amoxapine Asendin
Bupropion Wellbutrin
Chlorpromazine Thorazine
Clozapine Clozaril
Desipramine Norpramin
Fluoxetine Prozac
Imipramine Tofranil

Loxapine Loxitane
Olanzapine Zyprexa
Paroxetine Paxil
Perphenazine Trilafon
Risperidone Risperdal
Quetiapine Seroquel
Venlafaxine Effexor

DISCLOSURE
Dr. Bell reports no financial relationship with any company whose products
are mentioned in this article or with manufacturers of competing products.
Dr. Rothschild receives research support from Bristol-Myers Squibb, Eli Lilly
and Co., Merck & Co., Wyeth Pharmaceuticals, and the National Institute
of Mental Health. He is a consultant to and/or speaker for Forest
Pharmaceuticals, Eli Lilly and Co., Abbott Laboratories, Bristol-Myers Squibb,
and Pfizer Inc. In the past, he has been a consultant to and received research
grants from Corcept Therapeutics.

14. Thompson JW, Weiner RD, Myers CP. Use of ECT in the United
States in 1975, 1980 and 1986. Am J Psychiatry 1994;151:1657-61.
15. Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treatment of delusional depression. Am J Psychiatry 1985;142:430-6.
16. Dube S, Rothschild A, Andersen SE, et al. Olanzapine-fluoxetine
combination for psychotic depression (presentation). Barcelona,
Spain: European College of Neuropsychopharmacology, 2002.
17. Hillert A, Maier W, Wetzel H, Benkert O. Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome: a functional approach. Pharmacopsychiatry 1992;25:213-17.
18. Zarate CA Jr, Rothschild AJ, Fletcher KE, et al. Clinical predictors
of acute response with quetiapine in psychotic mood disorder. J
Clin Psychiatry 2000;61:185-9.
19. Nelson JC, Mazure CM. Lithium augmentation in psychotic
depression refractory to combined drug treatment. Am J Psychiatry
1986;143:363-6.
20. Rothschild AJ, Samson JA, Bessette MP, Carter-Campbell JT.
Efficacy of combination fluoxetine and perphenazine in the treatment of psychotic depression. J Clin Psychiatry 1993;54:338-42.
21. Anton RF Jr, Burch EA Jr. Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression.
Am J Psychiatry 1990;147:1203-8.

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1. Lykouras E, Malliaras D, Christodoulou GN, et al. Delusional
depression: phenomenology and response to treatment, a prospective study. Acta Psychiatry Scand 1986;73:324-9.

22. Banov MD, Zarate CA Jr, Tohen M, et al. Clozapine therapy in

refractory affective disorder: polarity predicts response in long-term
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2. Frances A, Brown RP, Kocsis JG, Mann JJ. Psychotic depression: a

separate entity? Am J Psychiatry 1981;138:831-3.

23. Aronson TA, Shukla S, Gujavarty K, et al. Relapse in delusional

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4. Coryell W, Leon A, Winokur G, et al. The importance of psychotic

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5. Roose SP, Glassman AH, Walsh BT, et al. Depression, delusions,
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8. Strober M, Carlson G. Bipolar illness in adolescents with major
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Subtle symptoms such as paranoia

are clues to psychotic depression.
Treat with ECT or an SSRI plus an
atypical antipsychotic, followed by
lithium, other antidepressants,
conventional antipsychotics, or
clozapine, as needed. After recovery,
continue antipsychotics 4 months and
antidepressants indefinitely.

Line

3. Leckman JF, Weissman MM, Prusoff BA, et al. Subtypes of depression: family study perspective. Arch Gen Psychiatry 1984;41:833-9.

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