To be bipolar, it was thought to be manic.

However, for most patients not manias, but depressions define bipolar

In fact,
more than 3 episodes of depression for every manic episode,
Also depressive episodes last much longer than manic episodes,

Spend a proportionally long time with depressive symptoms

 Yet research in treatment of BPAD depression lagged behind
that of manic phase and
similarly symptomed unipolar depression
In 1995, only one treatment lithium or lithium + antidepressant
In last 20 years, great strides made in understanding and Rx of BPAD
Although 15 medications approved by the FDA for Rx of some part of
BPAD
Only 3 (OLZ; OLZ+FLX combination; quetiapine IR/XR; lurasidone) for
BPAD depression
 clinically distinct, & difficult to differentiate between
bipolar depression, specifically, the depressive phase of BPAD II,
Unipolar depression

Both defined by presence of depressive symptoms (DSM V) and

Most BPAD II patients present for treatment when depressed
rather than hypomanic
Difficult to differentiate cross-sectionally
 If presentations so similar, why to differentiate?
2 key reasons.
1. Predictive validity: conveys probable treatment response
Interventions for 2 disorders almost totally different

2. Facilitate biological investigation

 BPAD II is MC misdiagnosed as recurrent MDD
wait up to 10 yrs for proper diagnosis of BPAD
RR >40% of being mistaken as MDD, when BPAD assessed in depressive phase.
Up to of patients with RDD - in fact suffer from BPAD II
Caveat: initial episodes may simply be depressive in nature;
manic or hypomanic episodes have simply not yet occurred

These results may be erroneous or profoundly inflated

STAR-D: among 4000 patients in depressive episode screened to exclude
obvious prior manic episodes a very small minority subsequently
exhibited mania
finding persisted even with prospectively established treatment resistance
 Patient side:
not complaining milder mood elevation or
not reporting periods of time with better functioning than usual

Clinician side:
do not adequately ask prior h/o of hypomania
 Borderline PD (BPD), anxiety disorder or adjustment disorder
In case of anxiety disorders:
Diagnosis more complex as very high comorbidity of anxiety in BPAD
ie both diagnosis may be correct
BPAD and BPD differences:
h/o of sexual or physical trauma
BPD more likely
self-mutilation or dissociative symptoms
f/h/o mood illness
marked episodic PMA activation, BPD less likely
absence of sexual trauma/self-mutilation
 Focus on longitudinal, rather cross-sectional approach
diagnosis is prognosis (Kraepelin)

1st Assessment of bipolar depression

2nd - Examine patients ever had a background of manic or hypomanic
episodes
 Indicators particularly prudent to assess for past history of
hypomanic or manic episodes:
A f/h/o bipolar
Atypical features, such as presence of hypersomnia or leaden paralysis
Psychosis
Melancholic features
Psychomotor disturbance
Early age of onset, particularly before 21 years of age
High frequency of episodes
Comorbid anxiety disorders, such as OCD or panic disorder
Presence of severe suicidal behavior
Major depressive episode refractory to at least 2 lines of ADs
Unipolar depression more likely if 4 Bipolar depression more likely if 4

Symptomatology
Insomnia Hypersomnia
Decreased appetite Hyperphagia
Psychomotor agitation Psychomotor retardation
Other atypical symptoms
Somatic complaints Psychosis and/ or pathological guilt
Mood lability or manic symptoms
Course of illness
Later onset > 25 yrs Earlier onset < 25 yrs
Long current depression > 6 months Multiple depressions 5 episodes
Family history
No bipolar disorder Bipolar disorder
Proposed by Task Force on Diagnostic Guidelines of the
 strategies for improving diagnosis:
the development of risk predictors
Greater use of standardized assessments
Integrating self-report measures with careful characterization of
longitudinal course may provide the best cross-sectional strategy for
diagnosis.
Thus, Clinicians and patients should recognize that
any initial diagnosis is provisional,
subject to later re-examination,
 Depression - MC as well as most difficult-to-treat phase of BPAD
3 times more depressed more than are manic (naturalistic treatment)
Many decades-long deficit in clinical treatment research
Conventional treatment toward the end of 20th century -
AD augmentation of mood stabilizers

Past decade has seen increasing evidence

not only ineffective treatment approach, but counterproductive.
Efficacy of APs in monotherapy or adjunctive therapy of BPAD depression

Recommended treatment paradigms use of mood stabilizers with

atypical APs
Absence of Antidepressant Efficacy
solid if not entirely consistent evidence suggesting
Lack of efficacy or
At least, an acute modest effect of ADs when added to mood stabilizers or
atypical antipsychotics,
but greater risk for manic episodes over a year of follow-up.

On the other hand, robust evidence suggesting

AD efficacy for MDD
In fact efficacious in moderate and severe depressive episodes, albeit less
so in mild ones.
Risk for AD-associated Mania
Meta-analysis treatments used for MDD may actually worsen the
long-term course of illness in BPAD, resulting in
increasing risk for manic episodes or
simply more frequent mood episodes or
cycle alteration

STAR-D study
20-50% AD-induced mania
 Another concern: AD use in BPAD depression may
precipitate or exacerbate mixed (manic) symptoms
may be assoc with increases in suicidality
Thus, AD-induced suicidality in children and adults
may actually represent the induction of mixed states by ADs in individuals
with undetected BPAD.
Incorrect assignment of BPAD among individuals who truly have
MDD (similar to opposite) may have undesired consequences
Ineffective or modestly effective drugs (for ex, lithium therapy,
lamotrigine) or
Substantial toxic and poorer tolerable drugs(2nd generation APs) given
 Treatment options poorly delineated, in absence of mood stabilizer
Li, CBZ, LTG and VAL
none have acute AD effects and none approved by FDA for this indication
Typically involved in the long-term prophylaxis of BPAD
BPAD depression breakthrough these agents alone and in combination is
quite common
Prevented by addition of an atypical AP a primary recommendation

Despite the emerging evidence of the inadequacy of AD

augmentation of mood stabilizers for BPAD depression,
the unimodal ADs are still one of the most widely used treatment
strategies.
 In BPAD depression, AD monotherapy never appropriate
Even ADs as augmentation of MSs ineffective and improvement
doesnt exceed that of placebo
ADs increase cycle alteration and could be assoc with an ultimately poor Rx
outcome
Some specific ADs,
particularly those with NE potency
assoc with a greater likelihood of switching into mania than other agents such
as SSRI or bupropion.
 Characteristics of BPAD depression associated with increased
risk of switching into mania on ADs even when used as
augmentation of MS
Younger age
BPAD I > BPAD II subtype
Rapid cycling (>4 episodes) in past year
Mixed depression (ie, activated, speeded up, racing thoughts)
TCAs > 2nd generation ADs
NE active > 5HT or DA
Substance abuse history
 Int Society for Bipolar Disorders, doesnt recommend,
nonetheless, AD use continues to be widespread
Because
1. Long tradition of use of ADs in bipolar depression, which not yet been
overruled by new evidence
2. A small subgroup of approx. 15% of depressed patients who respond to
AD augmentation of a mood stabilizer for several months appear to
continue to do well with continuation as opposed to discontinuation of ADs
over the next year
These subgroup also have more relapses into depression with AD discontinuation
Little evidence for AD-induced increases in switches into mania
(Meta-analysis by Sidor & MacQueen)
 At the same time, RCT by Ghaemi and colleagues showed:
If a patient has a rapid cycling course (4 or more episodes per year), then
AD continuation even after 8 weeks of apparent good responsivity is assoc
with a poor outcome
Surprisingly, this is revealed as increased number of depressive relapses
occurring over the subsequent year, suggestive of an increased rapidity of
cycling of depressions but not manias.
 Breakthrough depression in a patient with BPAD diagnosis on a
mood stabilizer
Augmentation with an AA (atypical antipsychotic) agent preferred choice
3 AA are currently FDA approved for BPAD depression
OLZ-FLZ combination, Quetiapine and Lurasidone, Cariprazine (soon join this
list)
OLZ-FLX combination:
Became 2nd line option (as potential s/e of wt gain and metabolic syn)
 FDA - both as monotherapy and as adjunct to Li or Valproate for long-term
prophylaxis
Recent data: monotherapy with quetiapine is more effective than placebo in
long-term prophylaxis
Thus, quetiapine unique profile of being effective in both manic and depressive phases of
acute and prophylactic treatment
In addition, Quetiapine FDA approved for augmentation of ADs in unipolar
depression.
Note: Aripiprazole shares this indication of augmentation of ADs in unipolar
depression, but not FDA approved for acute treatment of BPAD depression.
Quetiapine shows a rapid onset of AD effects, within 1st week of treatment.
 MOA:
not clearly delineated, its metabolite, norquetiapine, a 5-HT
antagonist and 5HT 1A partial agonist
A moderately potent inhibitor of the reuptake of NE
Also moderately potent as an inhibitor of mACh receptors
recently demonstrated iv scopolamine induces rapid onset of
AD effects in as little as 1 day.
Also increases BDNF in the hippocampus AD effects
 Both quetiapine and nor-quetiapine weak inhibitors of D2
receptors
So low incidence of EPS s/e
Accounts for the fact: higher doses of quetiapine (400-800mg/day)
required for its effects in mania and schizophrenia
S/e: related to potency of receptor binding
Most potent in inhibiting histamine receptors and sedation, accordingly,
most prevalent s/e
Sedation is adapted to, but approx. 10% drop out
Blockade mACh dry mouth and constipation
1 rec inhibition orthostatic hypotension and dizziness
 FDA-approved treatment in acute treatment of BPAD depression
both in monotherapy and as adjunct to treatment with Li and
valproate
In contrast to quetiapine, it is relatively weight neutral, less
sedating, and not assoc with metabolic syndrome
Different receptor potency profile:
Most potent blockade of 5HT7 rec AD effect
Blocker of 5HT2 and D2 rec AP effect
Increases BDNF and prevents stress-induced increases
Lack of H1 and ACh rec low potential for sedation, anticholinergic s/e

Absorbed much better (2-3 fold) on a full stomach after dinner or

after a 350-cal snack
 Lurasidone, Quetiapine and Aripiprazole metabolized by hepatic CYP-450
3A4 enzymes drug interactions lower blood levels by inducers like CBZ
 Not yet been FDA approved
Dosage of 1.5mg/day (but not lower or higher doses)
significant AD effects over placebo in acute BPAD depression
D2 and D3 partial agonist like aripiprazole, but cariprazine
shower greater potency for D3 than D2 rec.
Also antimanic efficacy and augmentation of ADs in unipolar
depression
Soon may become 1st line treatment algorithm for BPAD
depression along with quetiapine and lurasidone
 All Atypical APs (AAPs) show antimanic efficacy
When added to a mood stabilizer, show greater antimanic efficacy

However, the converse is not the case

No class effect of AAPs for acute treatment or prevention of BPAD depression

Quetiapine clearly is effective in decreasing the recurrence of both

manias and depressions in patients maintained on Li or VAL
However, OLZ, ARIP, ZIPRA, RSPN FDA approved for BPAD prophylaxis
dont show an independent effect on depression prophylaxis, although
decrease overall episode recurrence
Lurasidone approved for the acute treatment of depression either
in monotherapy or as an adjunct to Li or VAL
Not yet studied in long-term prophylaxis of depression
 LITHIUM
Treatment of choice for patients with classic presentations of
BPAD I illness
Includes
euphoric mania,
clear-cut episodes with well intervals in b/w,
no anxiety or substance abuse disorder comorbidity,
+ve f/h/o mood disorders in 1st-degree relatives
Less effective in long-term prophylaxis in those with
greater numbers of prior episodes or
rapid cycling,
sequence of episode pattern of Depression followed by Mania and then a well Interval
(DMI) as opposed to MDI pattern
 For acute treatment and long-term prophylaxis of BPAD depression
Best evidence for antisuicide effects in patients with recurrent affective disorders
Concentrations of natural Li in water supply assoc with a lower rate of suicide in general population

MOA:
increases hippocampal level and cortical gray matter volume;
increases Bcl-2 at blood levels decrease the size of lesions in neurodegenerative disorders

Long-term Li maintenance
decrease medical comorbidity. increase in longevity in patients compared to other agents
Result less likely diagnosis in old age

In nonpsychiatric patients with mild cognitive impairment

maintenance with Li 150mg/day resulted in less cognitive decline over 1-year study
 Many predictors of relative good response to CBZ are converse of Li
BPAD-II
Continuous cycling
Substance abuse
Anxiety comorbidity
Mood incongruent delusions
A negative family history of mood-disorders in 1st degree relatives

Some evidence of acute antidepressant effects

In rapid cyclers, a year on the combination of Li + CBZ was more
effective than a year on either agent alone
Moreover, the s/e of CBZ are prevented by Li in realm of
benign suppression of WBC (opposite effects of colony stimulating factor)
Induction of hyponatremia (differing effects on vasopressin like effects)
 Effective in noneuphoric mania
Anxious, irritable, pressured or dysphoric mania
Comorbid anxiety disorder
Comorbid migraine (FDA approved for prevention of migraine)

In patients maintained on valproate and experiencing

breakthrough episodes, addition of lamotrigine may be effective
than placebo
Careful about drug-drug interactions valproate doubles lamotrigine
levels increases risk of serious rash
 FDA approved only for the prevention of BPAD episodes,
particularly depressions
Can be used with Li, valproate, quetiapine treatment and
prevention of BPAD depression
Predictors of response to lamotrigine
Fewer no of prior depressive episodes
history of anxiety disorders
Family history of anxiety disorders and substance abuse
 Still common for depression to break through when combination
used in long-term prophylaxis of BPAD
However, less chance of relapse compared to monotherapy.
IN ACUTE TREATMENT OF BPAD DEPRESSION
NAC (N-acetylcysteine) A grade in evidence, tolerability and potential
utility in BPAD
More effective than placebo in reducing depression and anxiety (after 8 wks of Rx)
Also has advantage of being effective in many psychiatric or medical comorbidities of
BPAD illness, including OCD, trichotillomania, autism (stereotypy and irritability) and
substance abuse
500mg capsules, 1 BD for 1 wk and then 2 capsules BD therafter

Vitamin D3 A for safety and utility

1500 IU more effective than placebo in augmentation of ADs in unipolar disorder
High % of patients with BPAD, including children with serious psychiatric illnesses show
D3 levels below borderline or deficient
 Folic Acid (L-methyl folate)
Similar as Vitamin D3
Efficacy of ADs in unipolar depression
May potentiate long-term prophylactic effects of Li
L-methyl folate 15mgday in some 15 to 25% of patients who show 1 of 2
common genetic variants with deficient enzyme methyl-tetra-hydro-folate-
reductase (MTHFR)
 Thyroid augmentation (T3)
25-50mcg
Sparse data as adjunct in BPAD depression or ultrarapid cycling
Is effective in those with normal thyroid function at baseline

Levothyroxine (T4)
100mcg per week to final dosage of 300mcg per day
Only in women with treatment-refractory depression in BPAD compared to
placebo
 Augmentation with Li
Rational strategy to use in virtually any patient with BPAD depression who
is not already on Li
Minocycline
Anti-inflammatory, neuroprotective, anitbiotic
100mg twice a day
Some AD efficacy in BPAD depression
As approx. 1/3rd with BPAD depression have inflammation as marked by
increased CRP, IL-1, IL-6 or TNF alpha
 Ketamine
Acute onset (within 2hrs) of AD effects in depressed patients (including
BPAD)
IV 0.5mg/kg over 40 minutes
Effects typically lasts only 3 to 5 days
Associated antisuicidal effects so frequently used in emergency rooms

Scoplamanine
IV - Rapid-onset AD effect
Oral Augmentation greater benefit than patients with unipolar
depression
 Sleep Deprivation
One night sleep deprivation dramatic, overnight AD effects
Can be sustained by Li, phase advance and bright light therapy

rTMS and ECT

For incomplete or nonresponsive patient to pharmacotherapy
Lack of systematic literature guiding continuation Rx after a good acute
response
One study Rt UL brief-pulse ECT more effective than pharmacotherapy
in continuation
 tDCS and rapid fluxing low-level magnetic fields promising but
inadequately studied
VNS recent 5-year follow-up registry superior effects
Others
Modafinil or Armodafinil
Pramipexole
Agomelatine
Omega-3 FAs
Methylene blue
Pioglitazone
 TMAP
Lithium, Valproate or OLZ monotherapy OR in combination with SSRI or LAM for acute
bipolar depression
APA
OLZ + FLX, QTP and LA for acute depression
also recommend LA for maintenance
WFSBP
MS + AD with caution
CANMAT
MS + SSRI, OLZ+SSRI, MS+QTP/BUP
NICE
SSRI + AM, SSRI+MS
FDA: OLZ + FLX, QUT, LUR for acute depression
 Depending on which presenting problems are most severe,
providers can recommend a psychotherapy protocol that meets
patients needs
Effective psychotherapies
CBT
FFT
IPSRT
Mindful-based therapies
DBT
MBCT
 rapid or faster cycling frequencies
most difficult to treat and
less responsive to most drugs and naturalistic treatment

A research approach is use of Ca channel blockers Nimodipine

Gene encoding for 1 subunit of dihydropyridine L-type Ca channel
(CACNA1C) vulnerability factor for BPAD in genome-wide association
studies
Nimodipine has some evidence of antimanic and AD properties
Blood elements of patients with BPAD consistently show increased levels
of intracellular calcium
 Combination of Li and Nimodipine
Significantly increased response rate of 73% compared to Li-alone of 50%
Nimodipine combined with valproate or CBZ, the response rate remained
in the range of 50% -
So superiority of Li and Nimodipine combination
In patients who are unable to tolerate effective doses of Li,
augmentation with Nimodipine might be considered as it has an
absence of common s/e of Li, such as tremor, diarrhea or wt gain.
 30-50% incidence of an anxiety disorder comorbidity in BPAD
Assoc with a relatively poor prognosis
Unimodal ADs, which one think would be effective for anxiety
comorbidity,
do not appear to be very effective in patients with BPAD and
may even in some circumstances be counterproductive

Thus, Anticonvulsant MSs and SGAs with efficacy in BPAD

depression for anxiety comorbidity
Gabapentin though not effective of acute mania
Lamotrigine, CBZ, valproate
N-acetyl cysteine
 30-50% of abuse or addiction to alcohol or other substances
Complicates treatment
Provides a second difficult-to-treat chronic relapsing illness on top of
BPAD itself
Particularly high risk of marital, employment and legal difficulties
as well as incarceration, homelessness and suicide
So attempts at prevention and treatment even with off-label approaches
are imperative
 BPAD carries the highest burden of medical comorbidities
among the psychiatric illness
Cardiovascular illness (MI and stroke) is the major contributor to
1-2 decades of premature loss of life expectancy
Addressing the host of risk factors for cardiovascular disease would have
particular merit
Statins for hyperlipidemia not only reduce lipids, but suggestive data on
depression preventive effects in women followed prospectively
Combination of bupropion XR 150 to 300 mg and naltrexone 50mg often
with average loss of 10% body fat;
Anticonvulsants topiramte and zonisamide
Nicotine addiction than the general population, but have a
similar quit rate
 Present even during periods of euthymia, which occurs as a function
of the number of previous episodes of depression and/or mania
Treatment of cognitive deficits:
Lithium
Dose reduction or elimination of sedating and impairing treatments
Augmentaion with bupropion or modafinil for attention promoting effects
Cholinesterase inhibitors and/or memantine
Pramipexole and neutraceuticals
 Treatment of BPAD depression in children is more poorly defined
than that of mania
Although use of ADs has revealed a high incidence of activation, if not
outright switching into hypomania/mania
Lamotrigine in adolescents with BPAD depression
rTMS has been successfully used
Omega-3 FAs 1-2gm of combination of DHA and EPA,
Vitamin D3 augmentation
Quetiapine XR failed to separate from placebo in adolescents with BPAD
depression
 As UD is more common than BPAD depression, many would
endorse the use of ADs for childhood-depression, even in the
presence of +ve f/h/o
Caution: approx. 35% risk of subsequent BPAD diagnosis

One definitive recommendation FFT in those (with prodromal

illness such as anxiety disorder, depression or cyclothymia) with
a +ve f/h/o BPAD
Offspring of a parent with BPAD are at higher risk of a depression or
anxiety disorder than even BPAD and 74% of the offspring will have a
major psychiatric disorder on 6-year follow-up.
 Optimize the dose of MS, particularly lithium

For acute episodes

- Quetiapine
- Olanzapine + Fluoxetine
- SSRIs with MS
- ECT
Potential options for maintenance

- MS + LA
- MS + Quetiapine
- MS + Olanzepine + Fluoxetine
- MS + Olanzepine
Use antidepressants always in combination with MS or anti manic drugs
Pregnancy, Postpartum and Lactation
 Pregnancy and postpartum period most vulnerable time in a womens life for mental
health problems, especially true with BPAD
Pharmacological treatment becomes additionally complex during the continuum of
pregnancy and postpartum period
Misdiagnosis of BPAD depressive episodes as unipolar depression common
Risks triggering manic and psychotic symptoms severe outcomes including
Baby harm thoughts, suicide and (more rarely) infanticide
Diagnosis becomes more difficult due to inherent disruptions to sleep, energy and appetite, both
before and after delivery
Accurate diagnosis needed differentiating
Not only b/w UD and BPAD depression, but also
b/w subtypes of BPAD (I, II and mixed)
Some, common meds used in BPAD adverse effects to developing fetus
Risks of fetal & maternal exposure to untreated illness weighed against the risks of exposure to
medications (teratogenicity, obstetric complications, birth, neonatal and neurodevelopmental
outcomes
 BIPOLAR RATES IN WOMEN
NCS lifetime prevalence 3.9% among adult population
BPAD I:
Similar b/w men and women
Women with BPAD experience more depressive episodes during the active phases of illness
compared to men
BPAD II
Higher in women
Depressive symptoms 30times more prevalent than hypomanic symptoms
 BIPOLAR RATES DURING PREGNANCY AND POSTPARTUM PERIOD
70% of women with BPAD have acute mood episode (depression most frequent)during
pregnancy,
Although the postpartum phase may be most vulnerable
The risk of depression was consistently higher in BPAD patients compared with UD
Women with previous diagnoses of PMS and PMDD sensitive to hormonal changes
Higher risk for MDD or BPAD episodes during pregnancy and postpartum

RATES OF RELAPSE WITH SUDDEN STOPPING OF MEDICATIONS

After discontinuing Li, pregnant and nonpregnant women had similar recurrence rates
within 40wks (52%)
However, 41-50wks women in postpartum period were 2.9times more likely to have episodes
compared with other women
RISKS OF FETUS AND NEONATE WITH UNTREATED MATERNAL DIAGNOSIS OF BPAD
Placental abruption/abnormalities; preeclampsia; preterm delivery; IUGR; LBW; fetal
distress; low APGAR scores; congenital defects; still births and neurodevelopmental abN
 FDA teratogenic risk classification system as A, B, C, D and X
Lactation risk category L1, L2, L3, and L4
 PHARMACOKINETIC CHANGES IN PREGNANCY
Blood volume gradually increases to a peak increase of 40% to 50% by 32 weeks
increase in vol of distribution of hydrophilic medications, requiring larger doses

Serum albumin concentration decreases affects medications that are highly protein bound
increase amounts of unbound drug dosage reduction

Afferent and efferent arterioles dilate during pregnancy 50% increase in RBF and
clearance
increased elimination rate of drugs that are cleared by kidneys subtherapeutic concentrations

Sodium and water retention increased

Dilutional effects decrease in peak hydrophilic drug serum concentrations

Progesterone increase during pregnancy delayed gastric emptying

Lower peak conc and longer time to peak concentration of oral medications
 Metabolism altered in pregnancy
Phase I metabolism by CYP 450 enzymes:
CYP3A4 activity increased requiring dose adjustments in metabolized by the enzyme
CYP 1A2 activity reduced by 60% to 75%
CYP2C19 reduced by approx. 50%
CYP2D6 often induced
Phase II metabolism
Urine diphosphate-glucoronyltransferase (UGT) induction

At DELIVERY
Plasma volume drops dramatically
Predisposing women to toxicity if dosages increased throughout pregnancy

Renal clearance and hepatic metabolism return to preconception levels over the course of
1-2weeks
 LAMOTRIGINE
FDA pregnancy category C
During lactation is generally acceptable; however, infants monitored for toxicity
Lamotrigine clearance is dramatically increased through the course of pregnancy.
Clearance returns to normal rapidly after delivery
Drug concentrations should be monitored closely during pregnancy to ensure continued clinical
benefit and dosage adjusted accordingly
Dosage should be reduced after delivery to prevent toxicity
Extensive evidence support use and safety during pregnancy, with most data suggesting no
increased risk of congenital malformations
Seems among the safest choices for BPAD management during pregnancy
 VALPROATE
Should not be used during pregnancy due to well-documented dose-dependent teratogenic risks
associated with use
MC associated with NTDs and spina bifida
Foalte supplementation recommended before conception and throughout pregnancy
Generally considered compatible with lactation

CARBAMAZEPINE
MC associated with NTDs and spina bifida, although at rates lower than seen with valproate
Folate supplementation recommended
Generally considered compatible with lactation

OXCARBAZEPINE
Risks in pregnancy and lactation are largely unknown at this time
 LITHIUM
Exposure during 1st trimester increases the risk of fetal cardiac abnormalities
A fetal ECHO and level-2 USG recommended during 2nd trimester
To reduce the risk of toxicity in both mother and infant, Li doses should be held or reduced around the time
of delivery
Not considered compatible with breastfeeding
 ATYPICAL ANTIPSYCHOTICS
Use has increased in pregnancy, however, data remain limited
No increased risk of congenital malformations
FDA category C with exception of clozapine and lurasidone (category B)

Most consistent adverse effect during pregnancy wt gain

Increases the risk of obesity, gestational DM, HTN and metabolic syndrome in the mother
May increase the likelihood of infant being large for gestational age
Compared to FGAs or placebo
 FDA released a Drug Safety Communication in Feb 2011
Potential risk of withdrawal symptoms and EPS after delivery in infants whose mothers are treated
with SGAs during 3rd trimester
Withdrawal symptoms infants: abnormal muscle tone, tremor, agitation, difficulty breathing and
difficulty feeding
Decreased neuromotor performance at 6 months of age on use of APs compared to ADs/no meds
Developmental delay at 2months of age but resolved by 12months
FDA also reinforces that patients not to stop meds if become pregnant without talking to their
physician and they should not be stopped abruptly
Evaluate benefits vs risks of continuing SGAs during breast feeding
Smallest effective dose should be used and infants should be monitored
 OLANZAPINE
1st line therapy during pregnancy
Risk for weight that is large for gestational age
Excreted in breast milk

QUETIAPINE
Has the lowest placental transfer of SGAs
If a woman is clinically stable on quetiapine prior to conceiving, continuing on therapy is a reasonable
treatment strategy.
Greater incidence of sedation issue for women trying to be alert to care child after delivery
Excreted in breast milk

LURASIDONE
Limited data
 Summary of SGAs use in pregnancy and lactation
SGAs not shown an increased risk of congenital malformations.
MC effect on infants is a higher likelihood of large wt for GA
Infants exposed to an SGA could have withdrawal symptoms or EPS after delivery
Breastfeeding is typically not recommended with use of SGA
If a woman is clinically stable on an SGA, becomes pregnant
the benefits of mood control and
risks of relapse and fetal effects must be evaluated

ECT
Should remain an option of last resort for pregnant women
Due to risks of switching to mania when using SSRIs for depressive symptoms, which can be even more
difficult to manage during pregnancy
 To conclude
Keep mothers stable the best prevention of postpartum mood change is to maintain psychiatric
stability during pregnancy and through delivery and the postpartum year
Be familiar with fetal development and windows of risk during pregnancy
Treatment decisions during pregnancy must be made in conjunction with a treatment plan for the
postpartum period and lactation
Teratogenic classifications and lactation classifications should be considered but with the
understanding that they provide incomplete information
Patients and families do best when they can make informed decisions based on comprehensive
discussions with a clinician about risks and benefits
When using Li, discontinue medication when contractions start to prevent maternal and
fetal toxicity after delivery
If a patient is on an antiepileptic drug before conception, consider use of a atypical AP for
the 1st trimester, if possible, return to the antiepileptic drug in 2nd and 3rd trimesters
If Li or paroxetine has been the most effective medication for a patient, consider changing to
a lamotrigine or SGA for 1st trimester
 For (1) the strength of the existing evidence, the grades are as follows:
A = substantial evidence from at least one controlled clinical trial
B = large amount of data from partially controlled and opened clinical case series
C = a modicum of clinical and case series data including case reports
D = theoretic approaches with as yet relatively little data support

For (2) tolerability/safety, the grading is as follows:

A = excellent acute and long-term safety and tolerability
B = good tolerability with relatively minor safety issues
C = some acute or long-term safety concerns with relatively common s/e or rare serious A/E
D = substantial reasons for concern
 For (3) the utility in BPAD, ratings are as follows:
A: good direct or indirect evidence of efficacy and good tolerability (use endorsed)
B: some minor concerns about likely efficacy or tolerability
C: may be appropriate choice, but the risk-benefit ratio requires consideration and/or close
observation
D: likely inappropriate option because serious doubts about efficacy or safety