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TREATMENT IN PSYCHIATRY

Treatment of Psychosis and Mania in the


Postpartum Period
Veerle Bergink, M.D., Ph.D., Karin M. Burgerhout, M.D., Kathelijne M. Koorengevel, M.D., Ph.D.,
Astrid M. Kamperman, M.Sc., Ph.D., Witte J. Hoogendijk, M.D., Ph.D., Mijke P. Lambregtse-van den Berg, M.D., Ph.D.,
Steven A. Kushner, M.D., Ph.D.

Postpartum psychosis is a severe disorder that warrants psychotic episode fullling DSM-IV-TR criteria. Using this
acute clinical intervention. Little is known, however, about treatment algorithm, the authors observed that nearly all
what interventions are most effective. The authors present patients (98.4%) achieved complete remission within the
treatment response and remission outcomes at 9 months rst three steps. None of the patients required ECT. At 9
postpartum using a four-step algorithm in patients with rst- months postpartum, sustained remission was observed in
onset psychosis or mania in the postpartum period. Treat- 79.7%. Patients treated with lithium had a signicantly
ment involved the structured sequential administration of lower rate of relapse compared with those treated with
benzodiazepines, antipsychotics, lithium, and ECT. The out- antipsychotic monotherapy. Multiparity and nonaffective
come of clinical remission was examined in 64 women psychosis were identied as risk factors for relapse. The
consecutively admitted for postpartum psychosis. Remission authors conclude that a structured treatment algorithm
was dened as the absence of psychotic, manic, and se- with the sequential addition of benzodiazepines, antipsy-
vere depressive symptoms for at least 1 week. Women chotics, and lithium may result in high rates of remission in
who remitted on antipsychotic monotherapy were advised patients with rst-onset postpartum psychosis and that
to continue this treatment as maintenance therapy, and lithium maintenance may be most benecial for relapse
women who required both antipsychotics and lithium to prevention.
achieve remission were maintained on lithium monotherapy.
Relapse was dened as the occurrence of any mood or Am J Psychiatry 2015; 172:115123; doi: 10.1176/appi.ajp.2014.13121652

Postpartum psychosis is a psychiatric emergency that re- thyroiditis (6), and, less frequently, autoimmune encephalitis
quires immediate medical attention and mental health care (7, 8), primary hypoparathyroidism (9), vitamin deciency,
referral. The prevalence in the general population is esti- stroke, and drug-induced psychosis (10). Case reports have
mated to be 12 cases per 1,000 childbirths (1, 2). In the ma- documented misdiagnosis of postpartum psychosis revealing
jority of cases, the onset is rapid and occurs within 2 weeks a late-onset urea cycle disorder (11) and type I citrullinemia
of delivery. Early symptoms often include insomnia, mood (12). Clinicians must ensure the adequate safety of the patient
uctuation, and obsessive concerns regarding the newborn, and her children, as postpartum psychosis is associated with
followed by more severe symptoms, such as delusions, hal- a highly elevated risk of suicide and infanticide.
lucinations, and disorganized behavior. Severe mood symp- Because of the severity of the symptoms and the un-
toms, such as mania, depression, or a mixed state are a hallmark predictable nature of the illness, pharmacological treatment
of the illness. Because clinical presentation, family history, and is typically initiated immediately. Unfortunately, however,
the longitudinal illness course overlap markedly with those few standardized treatment recommendations are currently
of bipolar disorder, postpartum psychosis is generally consid- available for postpartum psychosis, as research has been
ered a bipolar spectrum illness and not a primary psychotic limited and no randomized trials have been conducted. The
disorder (35). effects of lithium (13, 14), antipsychotics (15), ECT (13, 14),
The initial clinical evaluation for postpartum psychosis estrogen (1618), progesterone (19), and propranolol (20) have
requires a thorough medical and psychiatric history, physical been examined. A total of 21 treatment studies of postpartum
and neurological examinations, and comprehensive labora- psychosis can be found in the literature of the past few dec-
tory analysis to exclude organic causes for acute psychosis. ades, all of them based on small samples; the majority involve
The differential diagnosis should include infectious dis- case reports, and few studies have included more than 10 pa-
eases (e.g., mastitis, endometritis), eclampsia, postpartum tients (21, 22).

This article is featured in this months AJP Audio and provides Clinical Guidance (in the Table of Contents)

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A patient develops rst-onset postpartum psychosis after the birth of her rst child.
Ms. B, a 28-year-old primiparous primigravid woman investigations, including thyroid screening, were normal.
with no previous psychiatric history, delivered a healthy During periods of clinical stability, Ms. B was encouraged
daughter after an unremarkable pregnancy. She breast- to perform daytime bottle feedings under the supervision
fed her daughter every 23 hours without difculty. On of a nurse. Nighttime feedings were performed exclusively
the third day postpartum, Ms. B expressed concern that by nursing staff.
her husband wanted to kill their newborn. In response to On admission, Ms. B was treated with lorazepam
her mothers suggestion that she discontinue breast- monotherapy for 3 days without signicant clinical im-
feeding to enable better sleep, Ms. B became extremely provement, after which haloperidol was initiated. After 2
violent and kicked her mother in the abdomen. Over the weeks of treatment with haloperidol, Ms. B remained ac-
next 4 days (postpartum days 47), Ms. B became pro- tively manic with psychotic features, and lithium was
gressively more impulsive, irritable, and disorganized. added to her treatment regimen. With a combination of
On day 7 postpartum, Ms. B was admitted with her lorazepam, haloperidol, and lithium, her manic and psy-
daughter to the Mother-Baby Unit of the Erasmus chotic symptoms remitted over the next 3 weeks. Ms. B
Medical Center. During the admission interview, she and her daughter were discharged home from the hos-
exposed her breasts while shouting: Look at these! pital 7 weeks after delivery, with close outpatient follow-
My breasts are great! I want to breastfeed 24 hours up, lithium monotherapy, and mother-child interaction
nonstop! She was diagnosed as manic with psychotic therapy. Lithium was discontinued after 9 months. Over
features (Young Mania Rating Scale score, 34). Find- the past 4 years of outpatient follow-up since discharge,
ings from physical examination and routine laboratory Ms. B has remained in full remission.

In the absence of formal guidelines, treatment in clinical lithium is recommended (step 3). One small open-label study
practice is typically based on the most prominent symptom and a case report have suggested that the combination of lith-
dimensions. Benzodiazepines are used for insomnia and ium and antipsychotics is more effective than antipsychotic
agitation, antipsychotics and mood stabilizers for psychotic and monotherapy in patients with postpartum psychosis (13, 14).
manic symptoms, and antidepressants for depressive symp- Furthermore, studies have demonstrated efcacy of lithium in
toms. ECT has been described as an effective treatment option the prevention of postpartum psychosis (2831).
in patients with severe catatonic features. Recently, ECT has Finally, in patients whose symptoms have not responded
even been proposed as a rst-line treatment option (2325). after 12 weeks of combination treatment with a benzodiaz-
We have developed a four-step standardized treatment epine, an antipsychotic, and lithium, ECT is recommended
algorithm with guidance from the extensive literature on (step 4). Case reports and case series have described positive
bipolar patients, and here we examine prospectively how treatment outcomes with ECT in women with treatment-
this treatment approach might affect outcomes. The rst refractory postpartum psychosis (25, 32).
step in treatment involves benzodiazepines at bedtime for 3
days (step 1). The purpose of starting with an initial period of
METHOD
benzodiazepine monotherapy is to evaluate whether resto-
ration of sleep results in clinical remission of manic and Participants
psychotic symptoms, as sleep loss has been considered an The study was approved by the Institutional Review Board
important etiological factor in postpartum psychosis (26). of the Erasmus Medical Center (Rotterdam, the Nether-
For patients whose manic or psychotic symptoms persist lands). All patients provided written informed consent. The
after 3 days of benzodiazepine monotherapy, the next rec- study was performed at the Mother-Baby Unit of the De-
ommended step involves antipsychotic medication begin- partment of Psychiatry at the Erasmus Medical Center, a
ning on day 4 (step 2). Although the efcacy of antipsychotics ve-bed inpatient unit that specializes in the care of patients
in the absence of mood stabilizers has been described in only with severe psychopathology in the postpartum period.
three case reports, antipsychotics are frequently used world- Women are given the option for admission together with
wide as rst-line treatment for patients with postpartum psy- their baby in a fully staffed nursery adjoining the unit (33).
chosis and mania (15). Furthermore, antipsychotics are often Every patient admitted to the unit between August 2005 and
considered the preferred pharmacological treatment option June 2011 (N5200) was screened for study inclusion and
for acute mania outside the postpartum period (27). assessed with the Structured Clinical Interview for DSM-IV
The step 2 treatment with a combination of benzodiaze- Axis I Disorders, Patient Edition (SCID) (34).
pines and antipsychotics is recommended for 2 weeks. If at Patients 1845 years of age with a diagnosis of postpartum
2 weeks there is no signicant clinical response, then adjunctive psychosis were eligible for the study. As postpartum psychosis

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TREATMENT IN PSYCHIATRY

is not described as a distinct illness entity in DSM-IV-TR, we this treatment as maintenance therapy until 9 months post-
dened eligible subjects as those patients for whom the SCID partum. Women who achieved clinical remission using both
interview generated any of the following diagnoses and re- antipsychotics and lithium were advised to gradually ta-
quired the specier onset postpartum: depressive disorder per off antipsychotic treatment, with maintenance lithium
with psychotic features, psychotic disorder not otherwise speci- monotherapy until 9 months postpartum. Lithium dosing
ed, brief psychotic disorder, or mania. The specier onset for relapse prevention was achieved based on plasma level
postpartum requires that the onset of symptoms occur within (target, 0.60.8 mmol/L).
4 weeks after delivery. All women were encouraged to continue maintenance
Overall, 83 patients fullled the criteria for postpartum monotherapy throughout the rst 9 months postpartum.
psychosis or mania. Of these, 15 patients had a history of psy- Women who remained clinically stable after 9 months
chosis or mania outside the postpartum period and therefore were assisted in gradually tapering their medication to
were excluded from our analyses. One patient was excluded discontinuation.
because of substance abuse, and two patients declined par-
ticipation. One patient was lost to follow-up after remission; Assessments
we describe her illness course separately. In total, 64 patients In addition to the SCID, all participants and their relatives
with psychosis or mania limited to the postpartum period were interviewed by a psychiatrist (V.B. or K.M.K.). Dura-
were evaluated weekly during admission and at 9 months tion of episode was dened as the number of days from the
postpartum. initial onset of psychiatric symptoms until remission. Phe-
nomenology was quantied using the Bipolar Affective Disor-
Nonpharmacological Treatment der Dimension Scale (36), a dimensional rating scale intended
All women received nonpharmacological interventions to for use in clinical cohorts with a high incidence of bipolar spec-
optimize mother-baby interaction (35). These interventions trum illness. There are four identied dimensions: mania,
included feedback from nursing staff, video-interaction guid- depression, psychosis, and
ance, and baby massage. mood incongruence. Dur- The rate of sustained
ing hospitalization, clinical remission was higher for
Pharmacological Treatment evaluation was performed patients using maintenance
Step 1. All patients were initially treated with lorazepam at weekly using the Young monotherapy with lithium
bedtime for 3 days. Mania Rating Scale (37), than for those using
the Edinburgh Postna- maintenance monotherapy
Step 2. For patients receiving lorazepam monotherapy who tal Depression Scale (38), with antipsychotics.
had persistent manic or psychotic symptoms, antipsychotic and the Clinical Global
medication was recommended beginning on day 4. Our pri- ImpressionsBipolar Disorder scale (CGI-BP), a modied
mary recommendation for antipsychotic treatment was hal- version of the CGI scale that allows the clinician to rate the
operidol at 26 mg/day. For patients in whom side effects global illness severity and time course in patients with bi-
occurred, we switched to an atypical antipsychotic. For a polar spectrum disorders (39).
subset of patients (N511) who had already been treated with Clinical remission was dened as the absence of psy-
an antipsychotic for more than 2 days before admission (e.g., chotic, manic, and depressive symptoms for at least 1 week,
by acute services), we skipped step 1 and continued treat- with a CGI-BP score #3, a Young Mania Rating Scale score
ment with the same antipsychotic. #8, and an Edinburgh Postnatal Depression Scale score
#10 (40). We dened relapse as the occurrence of any mood
Step 3. After 2 weeks of combination treatment with a ben- or psychotic episode fullling DSM-IV-TR criteria or a
zodiazepine and an antipsychotic, adjunctive lithium was CGI-BP score .3. Accordingly, sustained remission was
recommended for those patients who did not have a signi- dened as absence of any DSM-IV-TR mood or psychotic
cant clinical response. Lithium dosing was achieved based episodes throughout the follow-up period, as well as main-
on plasma level (target, 0.81.2 mmol/L). taining a CGI-BP score #3. Longitudinal assessment of
mood episodes was performed using the National Institute
Step 4. For patients who did not have a response after 12 of Mental Health Life-Chart Method at 8 months post-
weeks on combination treatment with a benzodiazepine, an partum (41).
antipsychotic, and lithium, ECT was recommended. All psy- In our data analysis, categorical demographic variables were
chotropic medications would be tapered to discontinuation compared with Fishers exact test, and continuous demographic
before initiation of ECT. variables were compared with the Mann-Whitney U test. Cat-
egorical outcomes of relapse risks were examined using Fishers
Maintenance Treatment exact test, logistic regression analysis, and Kaplan-Meier esti-
After complete remission of symptoms, all women were ad- mation of the log-rank test. Analyses were performed using
vised to taper benzodiazepines to discontinuation. Women re- SPSS, version 20.0 (IBM, Armonk, N.Y.). A two-tailed p value
ceiving antipsychotic monotherapy were advised to continue ,0.05 was considered statistically signicant.

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TABLE 1. Demographic and Clinical Characteristics of Women With Sustained Remission or Relapse After Postpartum Psychosis
Women With Women Without
All Women Sustained Remission Sustained Remission
Characteristic (N564) (N551) (N513) pa
Mean SD Mean SD Mean SD
Mean age (years) 31.9 4.7 31.6 4.7 32.8 4.4 0.40
N % N % N %
Dutch ethnicity 56 87.5 45 88.2 11 84.6 0.66
Education beyond high school 36 56.3 28 54.9 8 61.5 0.76
Married or living with partner 62 96.9 50 98.0 12 92.3 0.37
Multiparity 14 21.9 8 15.7 6 46.2 0.03
Psychiatric history
No psychiatric history 46 71.9 37 72.6 9 69.2 1.00
Previous postpartum psychosis 10 15.6 6 11.8 4 30.8 0.19
Previous depression or anxiety 8 12.5 8 15.7 0 0.0 0.19
Affective psychosis
With manic psychotic features 42 65.6 35 68.6 7 53.8 0.34
Depressed or mixed 17 26.6 14 27.5 3 23.1 1.00
Nonaffective psychosis 5 7.8 2 3.9 3 23.1 0.05
Psychotic symptoms
Mood incongruence 40 62.5 32 62.7 8 61.5 1.00
First-rank symptomsb 6 9.4 4 7.8 2 15.4 0.59
Median IQRc Median IQRc Median IQRc
Onset (days postpartum) 8 514 7 514 10 516 0.54
Duration of episode (days) 40 2665 42 2369 38 2948 0.90

N % N % N %
Treatment
Step 1 4 6.3 4 7.8 0 0.0 0.57
Step 2 12 18.8 6 11.8 6 46.2 0.01
Step 3 48 75.0 41 80.4 7 53.8 0.07
a
Women with sustained remission were compared with women without sustained remission. Categorical variables were tested using Fishers exact test, and
continuous variables were tested using the Mann-Whitney U test.
b
First-rank symptoms include thought echo, insertion, withdrawal, or broadcasting; passivity experiences; hallucinatory voices giving running commentary,
discussing subject in third person, or originating in some part of the body; bizarre delusions; or catatonia.
c
IQR5interquartile range.

RESULTS the 3-day step 1 period. As expected, they had a substantially


longer duration of illness, although they both ultimately
We assessed treatment outcomes for 64 enrolled patients.
achieved full remission (median time to remission, 161 days).
Participants demographic and clinical characteristics are
Twelve patients (18.8%) remitted during treatment with
summarized in Table 1. The phenomenological classication
a combination of benzodiazepines and antipsychotics (step 2).
included manic-psychotic features (65.6%), mixed episode
Of these, seven were treated with haloperidol, four with
(17.2%), and depression with psychotic features (9.4%). Only
olanzapine, and one with quetiapine. Ten of these patients
ve patients had a postpartum psychosis without prominent
experienced full resolution of manic and psychotic symptoms
affective symptomatology (7.8%). The median onset of initial
within 2 weeks of treatment initiation, despite a more per-
psychiatric symptoms occurred at 8 days postpartum (inter-
sistent affective instability (median time to remission, 30 days;
quartile range [IQR]5514). The median time to clinical re-
IQR52141). The remaining two patients were limited to step
mission was 40 days (IQR52665).
2 despite persistent symptoms: one declined adjunctive lith-
A owchart of treatment outcomes is presented in Figure 1.
ium, and in the other patient lithium was contraindicated be-
cause of psoriasis (median time to remission, 39 days).
Complete Remission Forty-eight patients were treated with a combination of
Four of the 64 patients (6.3%) remitted at step 1 of the treatment benzodiazepines, antipsychotics, and lithium. Of these,
algorithm. Two of these patients experienced remission of 47 patients (73.4%) remitted under step 3 of the treatment
manic and psychotic symptoms after only 3 days of benzodi- algorithm (Figure 1). Antipsychotic treatment was as fol-
azepine treatment (median time to complete remission, 21 days). lows: 37 patients were treated with haloperidol, nine with
Two patients declined to advance further in the treatment olanzapine, and one with quetiapine. Of the 37 patients
algorithm, despite having persistent symptoms at the end of treated with haloperidol, eight were switched to an atypical

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FIGURE 1. Flowchart of Treatment Outcomes in 64 Women With Postpartum Psychosis

Women followed
through 9 months
postpartum (N=64)

STEP 1 STEP 2 STEP 3


Acute treatment with Acute treatment Acute treatment
benzodiazepines only, with benzodiazepines with benzodiazepines, Admission
or no medication and antipsychotics antipsychotics, and
(N=4) (N=12) lithiuma (N=48)
Never
achieved
remission
(N=1)
Fully remitted, Fully remitted, Fully remitted,
tapered off tapered off tapered off
benzodiazepines benzodiazepines benzodiazepines
(N=4) (N=12) and antipsychotics
(N=47)

Discontinued Maintained Discontinued Maintained Discontinued 9 months


benzodiazepines on antipsychotics antipsychotics on lithiumb lithium (N=7) postpartum
(N=4) (N=8) (N=4) (N=40)

Sustained Sustained Relapse Sustained Relapse Sustained Relapse Sustained Relapse


remission remission (N=4) remission (N=2) remission (N=4) remission (N=2)
(N=4) (N=4) (N=2) (N=36) (N=5)

a
One patient declined antipsychotic medication.
b
Three patients were maintained on both lithium and an antipsychotic.

antipsychotic because of side effects (ve were switched to of the 64 enrolled patients were treated with ECT (step 4).
olanzapine, two to quetiapine, and one to risperidone). The However, the one patient who was lost to follow-up did not
remaining patient advanced from step 1 directly to step 3 respond to the sequential addition of benzodiazepines, anti-
after declining antipsychotic treatment and was therefore psychotics, and lithium and remitted only after ECT treat-
treated with only benzodiazepines and lithium. The median ment. This patient suffered from depression with psychotic
time to remission for patients treated under step 3 was 44 features and was without manic symptoms. Her psychiatric
days (IQR52669). symptoms began at postpartum day 4; the duration of illness
Of the 48 patients treated with lithium, four were di- was 186 days, after which the patient was discharged home
agnosed as having clinical thyroid dysfunction at 9 months and subsequently lost to follow-up.
postpartum, compared with two patients found to have clin- We compared the demographic and clinical character-
ical thyroid dysfunction among the 16 who were not treated istics of patients who achieved clinical remission at step 1, 2,
with lithium. All patients with clinical thyroid dysfunction or 3. Women who received a combination of benzodiaze-
were specically diagnosed with autoimmune thyroid disease, pines and antipsychotics (step 2) were signicantly older on
as evidenced by thyroperoxidase antibody positivity. Five of average than those who received adjunctive lithium treatment
the lithium-treated patients had transient subclinical thyroid in step 3 (Fishers exact test, p,0.01). No other differences
dysfunction, for which no treatment was needed. Of these, were identied in demographic characteristics, psychiatric
three patients were thyroperoxidase antibody positive. Nota- history, phenomenological characteristics, or postpartum la-
bly, none of the lithium-treated patients without autoimmune tency to onset of symptoms.
thyroid disease developed clinical thyroid dysfunction. There
were no other adverse consequences of lithium treatment. Sustained Remission and Relapse Rates After 9 Months
In total, 63 of the 64 enrolled patients (98.4%) achieved Sustained remission at 9 months postpartum was observed
a full clinical remission within the rst three steps of the in 51 of the 64 patients (79.7%) (Figure 1). Of the remaining
clinical algorithm (Figure 1). The remaining patient was 13 patients, 12 relapsed (18.8%) and one had not remitted by
discharged against medical advice during step 3 and did not 9 months postpartum (1.6%). Among the 12 patients who
achieve remission during the 9-month follow-up period. None experienced relapse, 10 had a depressive episode (83.3%),

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FIGURE 2. Kaplan-Meier Curve of Relapse After Full Remission of (N56/12, 50.0%) compared with those receiving adjunctive
Symptoms in Women With Postpartum Psychosis Using Either lithium in step 3 (N56/47, 12.8%) (Fishers exact test, p50.01;
Antipsychotic or Lithium Maintenance Monotherapya
odds ratio56.8, 95% CI51.728.3).
We also evaluated whether noncompliance or medication
100
discontinuation might have inuenced the signicantly higher
rate of sustained remission in patients treated with adjunctive
lithium. Among the 12 patients who remitted with benzodia-
Percent in Remission

zepines and antipsychotics under step 2, eight were continu-


ously maintained on antipsychotics throughout the follow-up
50 period, and four of these patients relapsed (N54/8, 50.0%).
Similarly, of the four patients who discontinued antipsychotic
treatment, two relapsed (N52/4, 50.0%). Therefore, relapse
was not associated with antipsychotic discontinuation during
the follow-up period.
Among patients who received adjunctive lithium (step 3),
0
0 50 100 150 the majority (N540/48, 83.3%) were continuously main-
Days of Remission Until Relapse tained on lithium throughout the follow-up period. Of these
40 patients, four relapsed (10.0%); their mean lithium level
Step 3: Initial treatment with benzodiazepines, antipsychotics, during follow-up (0.57 mmol/L, SD50.41) was similar to
and lithium; maintenance treatment with lithium (N=47)
that of patients who had sustained remission (0.58 mmol/L,
Step 2: Initial treatment with benzodiazepines and antipsychot-
ics; maintenance treatment with antipsychotics (N=12) SD50.27). Eight patients discontinued lithium treatment
a
during the follow-up period; of these, one never achieved
Log-rank test, p50.002. The N listed for step 3 is 47 because one of
the 48 patients never achieved remission.
remission and two relapsed (37.5%) (Fishers exact test, p5
0.08; odds ratio55.4, 95% CI50.931.6).

one had manic symptoms without psychosis (8.3%), and one


DISCUSSION
had a nonaffective psychotic episode (8.3%). Relapse occurred
a median of 54 days after full remission (IQR=23101). The Given that postpartum psychosis is a severe, potentially life-
median duration of the relapse episode was 61 days (IQR530 threatening disorder during the acute phase, the prognosis is
73). remarkably good. Using a four-step clinical treatment algo-
There were no differences in age, ethnicity, education, rithm, we observed high remission rates in the acute phase
psychiatric history, or onset or duration of episode between (98.4%), and a considerable proportion of patients achieved
patients who had a sustained remission (N551) and those sustained remission (79.7%). The majority of patients re-
who did not (N513) (Table 1). Sustained remission was, how- quired combination treatment with a benzodiazepine, an
ever, associated with parity; primiparous women were more antipsychotic, and lithium to achieve clinical remission.
likely to achieve sustained remission (N543/50, 86.0%) com- Moreover, the rate of sustained remission was higher for
pared with multiparous patients (N58/14, 57.1%) (Fishers patients using maintenance monotherapy with lithium
exact test, p50.03; odds ratio54.6, 95% CI51.217.4). Among than for those using maintenance monotherapy with an
the six multiparous patients who experienced relapse, two antipsychotic.
had a single previous episode of postpartum psychosis, and four All but one patient achieved full clinical remission. The
had two previous episodes of postpartum psychosis. median duration of illness (from onset of postpartum psychosis
With regard to phenomenology, patients with affective until remission) was 40 days. This nding might suggest that
psychosis were more likely to achieve sustained remission the four-step treatment algorithm was highly effective. On the
(N549/59, 83.1%) compared with those with nonaffective other hand, it might also be attributed to a spontaneously re-
psychosis (N52/5, 40.0%) (Fishers exact test, p50.05; odds mitting illness course of relatively short duration. We and
ratio57.4, 95% CI51.149.8). Among patients with affective others have described a higher biological vulnerability during
postpartum psychosis, sustained remission was not associ- the postpartum period, including transient immunological and
ated with manic, mixed, or depressed symptomatology, nor endocrine alterations (42, 43). Therefore, even in the absence
with the mood congruence of psychotic symptoms. of treatment, substantial recovery might occur as a result of the
spontaneous resolution of these transient changes in post-
Effect of Medication on Relapse Rates partum physiology. However, previous studies of medication-
Treatment received was highly predictive of sustained re- free patients do not support this alternative hypothesis. In the
mission (log-rank test, p50.002) (Figure 2). None of the pa- absence of pharmacological treatment, patients experience
tients treated with benzodiazepine monotherapy relapsed (N54). a substantially longer duration of illness until clinical remission
Patients treated with the combination of benzodiazepines and (8 months on average) (44). Moreover, in the present study,
antipsychotics (step 2) were signicantly more likely to relapse the two patients who declined antipsychotic and lithium

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treatment experienced a much longer duration of illness (.5 An overwhelming majority of our patients with post-
months), compared with the median duration of illness in the partum psychosis were primiparous, which is consistent
full cohort (40 days). with previous studies describing primiparity as a signi-
Overall, the naturalistic design of our study warrants a cant covariate of postpartum psychosis (33, 4648). Unex-
cautious interpretation of the effectiveness of each treatment pectedly, we identied multiparity as a signicant risk factor
step. Allowing a 3-day period of benzodiazepine treatment for relapse, as six of 14 multiparous women relapsed. Of
(step 1) before the initiation of antipsychotics (step 2) en- note, this multiparous group included patients with a pre-
abled us to carefully evaluate the inuence of sleep hygiene vious history of postpartum psychosis (N510/14, of whom
on the severity of symptoms, given that restoration of sleep four relapsed). Accordingly, the threshold for manifesting
might lead to recovery in a subgroup of patients. Indeed, clinical mood symptoms might be lower in these patients as
two patients responded promptly to benzodiazepine mono- a consequence of past episodes of postpartum psychosis,
therapy. If antipsychotic treatment had been initiated a phenomenon known as the kindling hypothesis of mood
sooner, the recovery of these two patients may well have disorders (49). However, the relapse rate of 50% among
been falsely attributed to the use of antipsychotics, and those multiparous patients who had no previous postpartum
maintenance antipsychotic treatment would likely have been episodes is not explained by this hypothesis, although the
recommended. numbers are too small (two of four patients) to establish rm
The majority of patients responded to adjunctive lithium conclusions.
treatment and achieved clinical remission. Our results pro- Psychotic symptoms in the absence of affective symptoms
vide strong evidence that lithium is highly benecial for were also identied as a signicant risk factor for relapse.
acute treatment when given together with antipsychotics. Notably, affective symptoms were present in .90% of our
However, it remains an open question whether this bene- participants. There was no difference in relapse risk for
t would be fully realized with lithium monotherapy, or patients with manic-psychotic symptoms (N542) compared
whether combination treatment with an antipsychotic is re- with patients with depressed-psychotic or mixed-psychotic
quired. Future studies should also consider the potential symptoms (N517). However, patients with nonaffective
benets of initiating lithium earlier in the algorithm, in par- psychosis (N55) had a signicantly poorer prognosis, with
ticular for women with postpartum psychosis and either a a 60% relapse rate, compared with only 15% for patients with
depressive or a mixed episode without severe manic or psychotic affective psychosis. Remarkably, affective symptoms were
features. In contrast, it appears likely that the combination of present in 12 of the 13 patients who relapsed (92.3%). To-
lithium and an antipsychotic is the optimal strategy for the acute gether, these ndings contribute novel and compelling evi-
treatment of women with postpartum psychosis who have pro- dence to a broadening consensus that postpartum psychosis
minent manic or psychotic symptoms, given the proven benets should be classied as an affective disorder and not a pri-
of antipsychotics over lithium monotherarpy for the treatment of mary psychotic disorder (31, 47).
acute mania or psychosis. As for antipsychotic options, our The illustrative case vignette we present serves to make
study was not designed to compare conventional and atypical additional points about the diagnostic classication for pa-
antipsychotics, but this is undoubtedly another important tients with postpartum psychosis. Ms. B was primiparous,
question that should be addressed in future studies. had no psychiatric history, and had prominent affective
Lithium monotherapy was highly protective against re- symptoms (mania). After remission, she has remained stable
lapse compared with antipsychotic monotherapy. Although throughout 4 years of follow-up. According to both DSM-IV-
lithium has not been described previously as a rst-line op- TR and DSM-5 criteria, Ms. B should be diagnosed as having
tion for maintenance therapy after postpartum psychosis, bipolar I disorder. However, this diagnosis suggests a lifelong
there is extensive evidence of the benets of lithium for vulnerability to manic and depressive episodes, whereas in fact
maintenance treatment in bipolar patients (45). We previously some patients may have a biological vulnerability to severe af-
reported evidence that rebound activation of the immune fective psychosis that is limited to the postpartum period.
system during the postpartum period may be central to the The postpartum period is well established as having a
pathogenesis of postpartum psychosis (43). Accordingly, it is dramatically elevated risk for affective instability and psy-
tempting to speculate that the immune suppressive action chosis; the risk during the postpartum period is estimated to
of lithium may have contributed to our positive treatment be 2025 times higher than during other periods (1). More-
outcomes. over, several studies have demonstrated that over long follow-
ECT has been reported to accomplish a swift reduction of up periods, a sizable proportion of women show no evidence
symptoms in postpartum psychosis (2325). In our study, of mania or psychosis outside the postpartum period (4).
severe symptoms such as agitation, mania, and psychosis Therefore, we suggest that Ms. B would be better served by
responded well to pharmacotherapy, and a prolonged ill- a distinct diagnostic category of postpartum mania, for
ness course was mostly due to affective instability. Re- which the need for lifelong mood stabilization treatment is
markably, only one patient with depression with psychotic currently unknown. Naturally, however, Ms. Bs diagnosis
features was refractory to pharmacotherapy and required should be converted to bipolar disorder should she ever meet
ECT treatment. the diagnostic criteria outside the postpartum period.

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TREATMENT IN PSYCHIATRY

SUMMARY AND CONCLUSIONS Antipsychotics are recommended for the acute treatment
of manic and psychotic symptoms.
In this study, we found that patients with postpartum psychosis
or mania achieved favorable treatment outcomes using a We recommend maintenance treatment using lithium
structured treatment algorithm during the acute phase of the monotherapy during the rst 9 months postpartum (target
illness. After remission, maintenance with lithium mono- plasma level, 0.60.8 mmol/L). After 9 months, a gradual
therapy appears to be highly protective against relapse. tapering off of lithium should be considered in patients
Based on observations from our case series and the ex- who remain in full clinical remission.
isting literature, we propose the recommendations below for
the treatment of patients with postpartum psychosis. ECT
The choice between pharmacotherapy and ECT should be
General Strategies
made in consultation with the patient, particularly with
Inpatient psychiatric treatment is essential to ensure the regard to their preference for breastfeeding.
safety of mother and baby. Admission to a mother-baby ECT has been described as a highly effective treat-
unit is associated with improved patient satisfaction and ment option in patients with severe catatonic features
may help reduce time to recovery (50). (2325).
ECT should be considered for treatment of postpartum
The clinician must inquire about any thoughts the patient
depression with psychotic features, given the relatively
might have of harming herself or her children.
longer median duration of illness compared with post-
The initial clinical evaluation for postpartum psychosis partum mania (33).
requires a thorough medical and psychiatric history, in-
cluding physical and neurological examinations. Labora-
tory testing should include a complete blood count, liver AUTHOR AND ARTICLE INFORMATION
function tests, and levels of electrolytes, blood urea nitro- From the Department of Psychiatry and the Department of Child and
gen, creatinine, calcium, and glucose. A urine drug screen Adolescent Psychiatry/Psychology, Erasmus Medical Center, Rotterdam,
should also be performed. We also suggest measuring the Netherlands.
thyroid-stimulating hormone, free T4, and thyroid peroxi- Address correspondence to Dr. Bergink (v.bergink@erasmusmc.nl).
dase antibodies, at the time of diagnosis as well as 6 months Drs. Bergink and Burgerhout contributed equally to this study.
postpartum. With proper clinical indication, brain CT or The authors are grateful to Annemarie van Hulst and Monique Raats for
MRI, CSF analysis, limbic encephalitis antibody screening, guidance in developing a standardized treatment algorithm and Mirjam
measurement of serum vitamin B1, B12, and folate levels, Timmermans, Jeroen Vervoort, and Siska Verploegh for their manage-
ment and database assistance.
and urinalysis should also be performed.
The authors report no nancial relationships with commercial interests.
Focus on sleep hygiene and a structured rhythm of feedings.
Received Dec. 16, 2013; revisions received March 22 and July 3, 2014;
In clinical practice, this often means cessation of breast- accepted July 14, 2014.
feeding. Use of lactation inhibitors should be avoided.
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