Bipolar Disorder And Medications

What is Biploar Disorder?
Bipolar or manic depressive illness is a brain disorder that causes a typical changes in mood, energy and activity levels. Bipolar 1 disorder is diagnosed as having manic or mixed episodes, which are not normal of the person's behaviour. The episodes last for at least a week and require medical attention. The person also experiences depressive episodes, which last approximately two weeks. In between the cycling of manic and depression, many can live normal lives. Symptoms first appear in teens or early 20s, with many developing the disorder before the age of 50.

Bipolar Disorder Medications
Many different medications are needed for the best course of treatment as patients respond to the drugs differently. The medication should be taken continuously for the prevention of a relapse. Manic episodes in bipolar I disorder require treatment with drugs, such as antidepressants, mood stabilizers, benzodiazepines, and newer antipyschotics.

To track and treat the illness, the patient carries out a daily life chart of their mood symptoms, treatments, sleeping patterns and life events. Usually, the first choice of treatment is the long term use of mood stabilisers. With the exception of lithium, they are anticonvulsants to treat seizures as well as controlling mood. There are many types of mood stabilisers on the market. Lithium was the first to be approved by the U.S. Food and Drug Administration (FDA). It is frequently effective in controlling the symptoms of mania, and preventing the recurrence of manic and depressive episodes.

Valproic acid is as effective as lithium for treating mania. Lamotrigine is the more recent for maintaining the treatment. Less prescribed anticonvulsants include gabapentin, topiramate and oxcarbazepine as they are not more effective than the mood stabilisers. It is thought that by taking valproic acid, lamotrigine and other anticonvulsants, it increases the risk of suicidal thoughts and behaviours and therefore patients are closely monitored.

In addition to the disorder, patients often have problems with their thyroid gland. The overproduction or underproduction of the thyroid hormone can lead to mood and energy changes. It has been seen that hypothyroidism is associated with the rapid cycling of the bipolar disorder, occurring especially in women.

Atypical antipsychotic drugs are often used for treatment. They are usually taken with other drugs. These include: olanzapine, which is given with an antidepressant to help relieve symptoms of severe mania or psychosis. It can also be given intravenously to treat agitation of manic or mixed episodes. Aripiprazole has the same effect as olanzapine as well maintaining treatment after a severe or sudden episode. Quetiapine relieves the symptoms of severe and sudden manic episodes. Risperidone and ziprasidone are also prescribed for controlling manic or mixed episodes.

Other treatments include:
Psychotherapy to educate, support and provide guidance to people with the disorder and their families. A study carried out by NIMH had found that patients that were treated with medication and extensive psychotherapy, underwent fewer relapses, fewer admissions to hospitals, and were able to stick to treatment plans.

Electroconvulsive therapy is used to treat severely depressive, manic or mixed episodes. It is not usually given as a first line of treatment.

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We Are Not Manic We Have Bipolar Disorder

The stigma for a mental illness is enormous and even in this era of modern technology it still haunts the mentally ill. Bipolar carries a nasty stigma with it because of its former name, manic depression. Mania definitely sounds crazy even too me, and I don't know if bipolar depression will ever be just bipolar illness as long as mania stays in its definition.

I have yet to figure out why they don't define bipolar 1 sufferers as experiencing periods of extreme highs which is often seen as doing things on impulse without thinking of consequences, like overspending, unsafe and excessive sex, chemicals, gambling, quitting a job suddenly, and saying unkind things with no regret. A bipolar 1 has extreme highs which are usually brief but very intense and depressive lows which can last for weeks and months or they cycle very rapidly as in days or hours. Bipolar 2 sufferers experience a very deep depression which is often misidentified as major depression but bipolar 2 depression is extremely low when compared to when their mood is elevated.

The elevated mood is often seen as their functioning level instead of a slightly elevated from normal. Someone with bipolar 2 may not even realize their mood is elevated slightly more than normal The depression can be so devastating you can't even get out of bed, and the hopelessness and helplessness make you wonder if life is really worth all of this mental pain.. Bipolar disorder also affects, memory, concentration, appetite, sleep patterns, and self-esteem. Additionally, bipolar disorder has been linked to anxiety and health problems such as diabetes, heart disease, migraines, and high blood pressure. It really is not known for sure if any of these affects are caused by the medications we are prescribed or if it is coincidental.

Some bipolar sufferers figure out how to live very normal lives. Others like myself have learned to live makeshift normal lives in that we live as normal of a life as we are able to but still need disability. Then there are those who are desperately searching for a way to manage their illness. This is very positive believe it or not if they're able to hang in their long enough to find medications, skills or both to manage their illness. They'll have a great chance at a normal life. Lastly you have those who like the highs so much they don't want to do anything about their illness and for those my thoughts are with you especially when you hit the lows and start coming back up.

Bipolar sufferers knows that it isn't the extreme depression that will kill you because you don't have enough energy to take your life. But, it is when you start coming back out of the depths that you are able to find the energy to kill yourself. Regardless of how you choose to treat your bipolar the word mania or manic doesn't need to be in the definition or descriptions of what bipolar sufferers experience. Let's get them removed.

Nowhere in my definition do you find mania or manic it isn't necessary. It's time to rally together and get manic and mania eliminated from the definition of bipolar 1 and 2. We really are not crazy, just people who have a mental illness which can be managed whether by medication, therapy or self awareness.

Patty Hauer
http://iambipolar2.net/
Diagnosed with bipolar 1993

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Can feeling too good be bad? Positive emotion in bipolar disorder

ScienceDaily (July 22, 2011) — Positive emotions like joy and compassion are good for your mental and physical health, and help foster creativity and friendship. But people with bipolar disorder seem to have too much of a good thing. In a new article to be published in the August issue of Current Directions in Psychological Science, a journal of the Association for Psychological Science, psychologist June Gruber of Yale University considers how positive emotion may become negative in bipolar disorder.

One of the characteristics of bipolar disorder is the extreme periods of positive mood, or mania. People in the grip of mania also have increased energy, sleep less, and experience extreme self-confidence. At first glance, this may sound good and even desirable. However, during these times of mania, people with bipolar disorder often take dangerous risks, run up their credit card debt, and wreak havoc in marriages. "The fact that positive emotion has gone awry is something unique about bipolar disorder, as almost all other emotional disorders are characterized by difficulties in negative emotions" Gruber says.

Gruber points out that positive emotions are problematic for people with bipolar disorder even when they're not experiencing mania. Gruber has studied people whose bipolar disorder is in remission and found that they still experience more positive emotions than people who have never had bipolar disorder. More positive emotions may not sound like a bad thing, but there are times when these positive emotions aren't appropriate. "In our work, those with bipolar disorder continue to report greater positive emotions whether it's a positive film, very sad film clip of a child crying over his father's death, and even disgusting films involving someone digging through feces" she says. In more recent work Gruber and her colleagues have found they still feel good even if a close romantic partner tells them something sad face to face, they still feel good. "It's rose-colored glasses gone too far."

Clinical psychologists may also be able to use this research to figure out who with bipolar disorder is likely to relapse; people who have a lot of positive emotions, even at inappropriate times, may provide a window into possible early warning signs, Gruber says. In a study of healthy college students who had never been diagnosed with bipolar disorder, Gruber found that those who showed these same high levels of positive emotions that persisted across positive, negative and neutral situations were at higher risk for bipolar disorder.

But not all emotions are alike in bipolar disorder; in fact, they seem to have particular kinds of positive emotions. They report feeling more achievement and self-focused emotions like pride and rewarding feelings like joy. They don't differ social emotions that connect us with others, like love and compassion. "This mirrors early clinical observations and more recent scientific work," Gruber says -- that people with bipolar disorder set very high, ambitious goals, are sensitive to rewards, and in periods of mania, some believe they have special powers.

Psychologists should also consider that there are downsides of positive emotions even for people who don't have bipolar disorder, Gruber says. "Although positive emotions are generally good for us, when they take extreme forms or when they're experienced in the wrong context, the benefits of positive emotion begin to unravel," she says. The goal: "experience it in moderation, in the right place and time."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Association for Psychological Science.

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Limitations of evidence base for prescribing aripiprazole in maintenance therapy of bipolar disorder

ScienceDaily (May 3, 2011) — The evidence base for the prescribing of aripiprazole in maintenance treatment of bipolar disorder is limited to a single trial, sponsored by the manufacturer of aripiprazole, according to a rigorous appraisal of the evidence for its use led jointly by Alexander Tsai of Harvard University, Boston USA, and Nicholas Rosenlicht of the University of California San Francisco, USA. In the paper, published in PLoS Medicine, the authors describe key limitations of the trial, which were not identified in most subsequent review articles and guidelines for the treatment of bipolar disorder in which the trial was cited.

Bipolar disorder (also known as manic depression) is a common and serious psychiatric illness. Individuals with bipolar disorder experience mood swings with manic episodes (where they may feel euphoric, restless, and behave impulsively), along with depressive episodes where they may feel low, worthless, and suicidal. Aripiprazole is a second-generation antipsychotic medication and the newest of such drugs to have received approval by the US Food and Drug Administration (FDA) for use both in treatment of acute episodes and, more recently, for maintenance therapy.

Drs. Tsai and Rosenlicht and their colleagues conducted a systematic search to find all published and unpublished studies relating to use of aripiprazole for maintenance therapy of bipolar disorder, including a request to the FDA under Freedom of Information Act legislation. They critically appraised this evidence and then used citation searches to examine how the primary evidence was subsequently referenced in the medical literature. The authors found only a single trial describing the use of aripiprazole during the maintenance phase of bipolar disorder. Further, they found significant limitations of this trial that constrain its interpretation as supporting the use of aripiprazole for this indication. First, the trial duration was too short to show that the drug was truly helpful in maintaining initial benefit or preventing mood swings over the long term. Second, very few participants in the trial completed the entire study. Third, the trial was based on a select minority of subjects who had shown an initial response to the drug, making it difficult to extrapolate these findings to patients with bipolar disorder more widely. Fourth, the trial had a design whereby patients assigned to placebo were abruptly taken off aripiprazole treatment given to them during a previous "run-in" phase and reassigned to placebo; differences in risk of relapse seen between trial arms may thus also reflect the potentially harmful effects of rapid drug withdrawal in patients given placebo.

Despite these shortcomings, the authors found that this single trial was subsequently cited by 104 review articles and treatment guidelines, with very few mentioning the study's limitations.

The authors comment that "…alternative modifications or study designs may improve the probability of generating more useful data from studies in this vulnerable patient population to inform the treatment of similar patients in the future."

Patients (or their family members) who may learn of this study's findings are urged to contact their physician if concerned about what these findings may mean for their treatment. Specifically, the findings do not mean patients should cease their medication; despite the limitations of the evidence described here, this drug may be helpful to them. In addition, the study did not assess the evidence for the use of aripiprazole in acute treatment of bipolar disorder.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Public Library of Science, via EurekAlert!, a service of AAAS.

Journal Reference:

Alexander C. Tsai, Nicholas Z. Rosenlicht, Jon N. Jureidini, Peter I. Parry, Glen I. Spielmans, David Healy. Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature. PLoS Medicine, 2011; 8 (5): e1000434 DOI: 10.1371/journal.pmed.1000434

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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"Normal" Serum Lithium Levels Might be Neurotoxic in Geriatric Bipolar Disorder

March 20, 2008 (Orlando, Florida) — In a study of bipolar patients treated with lithium, serum lithium levels did not correlate with brain lithium levels in older patients. In addition, higher brain lithium levels but not higher serum lithium levels predicted greater executive dysfunction and somatic symptoms of depression in older subjects.

These findings by Brent P. Forester, MD, from the McLean Hospital in Belmont, Massachusetts, and Harvard Medical School in Boston, Massachusetts, and colleagues were presented in a poster here at the American Association for Geriatric Psychiatry (AAGP) 2008 Annual Meeting.
"When you are treating an older patient with bipolar disorder who has been on lithium and they're having subtle signs of attentional problems (that look like mild delirium or confusion), even if their serum level is 0.6 or 0.8 [mEq/L], which would be 'normal' in a younger person, it might actually be quite toxic in an older person," Dr. Forester told Medscape Psychiatry.

There is no reason to take older bipolar disorder patients who are mildly lithium neurotoxic off this medicine completely, forever if their kidneys are functioning well, he added. Clinicians need to take a step back and say, "maybe the patient just needs a lower dose and they'll be fine," and not just rely on serum levels to make these decisions, he said.
Lithium remains one of the first-line treatments for mania in older adults, despite the lack of randomized controlled trials of this drug in this patient population, the group writes. Concerns about neurotoxicity have led to questions about the most effective way to use lithium safely in older adults with bipolar disorder.

The clinical practice of monitoring serum lithium levels is based on the assumption that serum levels linearly correlate with the amount of lithium in the brain. However, in the elderly, this relation might be more variable.
The group aimed to examine the relation between brain and serum lithium levels in adult patients with bipolar disorder and to look at the effects of lithium on neuropsychological functioning and mood in a group of older patients.

The study enrolled 26 subjects, aged 20 to 85 years, who had bipolar disorder and were currently being treated with lithium. The subjects included 16 younger patients (<50 years; mean age, 29.3 years) and 10 older patients (≥50 years; mean age, 65.3 years).
The mood of each subject was assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Frontal lobe executive functioning was determined in the older subjects using the Stroop interference test, the Trail Making Test (part A), and the Wisconsin Card Sorting Test.

Serum and brain lithium levels were obtained for all subjects. Brain lithium levels were measured using 7-lithium magnetic resonance spectroscopy, a test that is used in research but is not available in clinical practice, said Dr. Forester.

Breakdown in Serum to Brain Lithium Relation in Older Adults

Brain lithium levels correlated with serum lithium levels in young subjects, but this correlation was not present in the older subjects.

In the older subjects, higher brain but not serum lithium levels correlated with higher Hamilton Depression Rating Scale scores and with an increase in somatic symptoms (fatigue and gastric distress). Higher brain lithium levels in these older patients also had a significant adverse effect on the Stroop interference test and on perseverative errors on the Wisconsin Card Sorting Test.

Age-associated changes in the blood–brain barrier might alter lithium uptake into the brain, the group suggests.

In older adults with bipolar disorder, clinical monitoring of serum lithium alone, without an assessment of cognitive functioning, might not be an adequate predictor of neurotoxicity, and clinicians should consider lithium toxicity when confronted with a depressive syndrome in such patients, they write.

This study provides further insight into lithium dosing in older patients with bipolar disorder, said Dr. Forester. "We're trying to learn how better to use this medicine because it's highly underutilized these days. It still has a lot of benefits."

The researchers have disclosed no relevant financial relationships.

American Association for Geriatric Psychiatry 2008 Annual Meeting: Poster 6. March 14-17, 2007.

The Management of Bipolar Disorder During Pregnancy

Zachary N. Stowe, MD; D. Jeffrey Newport, MD, MS, MDiv
Medscape Psychiatry & Mental Health. 2007; ©2007 Medscape

Posted 12/14/2007

Introduction

The management of mental illness during pregnancy and the postpartum period, specifically the use of psychiatric medications during pregnancy and lactation, remains the center of vigorous debate. Despite the burgeoning attention, there has been limited focus on the management of bipolar disorder (BPD) over the course of pregnancy.

BPD is a significant and often chronic psychiatric condition that affects 0.5% to 1.5% of individuals in the United States. The emerging literature regarding "bipolar spectrum disorders" suggests that the incidence may be much higher than early estimates. In contrast to major depression, the prevalence of BPD is similar in men and women. Women with BPD typically are more likely to have rapid-cycling (more than 4 episodes per year) and depressive episodes with illness onset in their teens or early twenties.^[1] The age of onset usually precedes family planning and necessitates developing management guidelines that address the myths associated with BPD during pregnancy.

General guidelines for the treatment of BPD are available from the American Psychiatric Association (APA),^[2] and treatment algorithms from the Canadian Health Network^[3] and Texas Algorithm project^[4] have outlined incremental levels of intervention for BPD. A recent review of management of women with BPD during pregnancy and the postpartum period provided an overview of the extant data on course of illness and treatment options.^[5] The treatment of women with BPD during pregnancy, specifically the use of medications, has also been incorporated into a Practice Bulletin for the American College of Obstetrics and Gynecology (ACOG) published in November 2007.^[6]

Navigation of the complexity of the clinical decisions in the management of women with BPD during pregnancy requires a working knowledge of:

Course of illness; Impact of maternal illness; Available treatment options; Reproductive safety data on treatment options; Pharmacologic strategies to reduce risks; and Incorporation of this information into a general approach to minimize risks.

Course of Bipolar Disorder During Pregnancy and the Postpartum Period

The natural course of illness for women with BPD over the course of pregnancy is obscure. Kraepelin observed that attacks of mania and melancholia were more common after childbirth than during pregnancy.^[7] Similarly, several early case reports suggested that some women with BPD maintain euthymia during pregnancy even after discontinuation of medication.^[8-11] Lier and colleagues^[10] found that pregnancy was not associated with significantly altered risk for BPD recurrence. Furthermore, a retrospective study by Grof and colleagues^[11] suggested an apparent protective effect of pregnancy on the course of lithium-responsive type I BPD.

In contrast, 3 retrospective studies and some case reports suggest that pregnancy is not protective and may instead represent a time of substantial risk for relapse.^[12-14] In one large, well-characterized clinical sample, Blehar^[12] found that 45% of women with BPD experienced an exacerbation of their illness during pregnancy. More recently, Freeman and colleagues^[13] found that at least 50% of a sample of women with BPD became symptomatic during pregnancy. A retrospective study of women with BPD who discontinued lithium proximate to conception found nearly identical high rates of recurrence within 40 weeks in 42 pregnant (52%) and 59 nonpregnant (58%) women.^[14] Recurrence rates were similar for BPD I and II subtypes, higher in those with more than 4 prior episodes or who discontinued lithium therapy, especially rapidly or abruptly. Prospective investigations supported by the National Institute of Health (NIH) have demonstrated significant risk for relapse (greater than 70%) in women discontinuing mood-stabilizing medications compared with those who continued medications (approximately 25% relapsed).^[15,16]

The postpartum period is a particularly high-risk period for women with BPD. Recurrence rates in women with BPD during the first 3-6 months postpartum are at least 20% to 50%, and recent observations suggest that the postpartum relapse risk without mood-stabilizer therapy may be as high as 70%.^[17-28] Symptom emergence is often rapid and may occur in late pregnancy or within the first few days to weeks after delivery. Women with BPD are at very high risk for postpartum psychosis (10% to 20%), at least 200-fold higher than the background rate of 0.05%.^[25-27]

In summary, women with BPD have a variable course during pregnancy that is significantly influenced by decisions regarding pharmacotherapy. In contrast, the postpartum period is a time of increased risk, and the prophylactic benefit of continued pharmacotherapy warrants further investigation.

Impact of Maternal Bipolar Disorder on Outcome

The data regarding the potential effects of maternal BPD on obstetrical and infant outcome are limited. Given that the majority of BPD relapses during pregnancy are "depressive,"^[14,16] it is feasible that symptomatic women with BPD may have the same risks as those with major depression. Studies have found an association between maternal depressive symptoms and poor neonatal outcome.^[29,30] The burgeoning clinical and preclinical data indicate that even modest maternal depression/stress can adversely affect infant well-being.^[31] These data underscore the value of maternal emotional well-being in optimizing outcome.

Ferreting out the impact of pharmacologic agents from the impact of active maternal illness remains a central focus of investigations of:

Maternal depression; Anxiety; BPD; and Epilepsy.

Treatment Options for Women With Bipolar Disorder During Pregnancy

The literature is replete with review articles on the treatment of women with mental illness during pregnancy and lactation. The pharmacologic armamentarium approved by the US Food and Drug Administration (FDA) for the treatment of BPD has expanded:

Lithium; Antiepileptic medications including carbamazepine, lamotrigine, and valproic acid; and Atypical antipsychotic medications: aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone.

In addition, there are a variety of medications and adjunctive therapies that have not undergone the scrutiny of FDA approval.

Formal prospective investigation of the efficacy of individual medications in maternal BPD over the course of pregnancy is limited to continuation of lithium^[14,32] and lamotrigine.^[15]

Risks Associated With Mood-Stabilizing Agents During Pregnancy

The potential risks of medications during pregnancy include:

Malformations; Obstetrical and neonatal complications; and Long-term neurobehavioral effects.

Neurobehavioral teratogenicity can result from medication exposure after the first trimester of pregnancy. Unfortunately, there is a dearth of long-term studies of children of women with BPD exposed to medications during pregnancy. Maximizing safety requires familiarity with the impact of individual medications across these domains and interventional strategies to reduce risks.

Malformations associated with maternal drug use depend on the properties of the drug and the point of exposure:

Up to 32 days post-conception can affect neural tube development and closure; Days 21-56 after conception may affect normal heart formation; and During days 42-63 may influence development of the lip and palate.

Craniofacial anomalies can also occur after the first trimester. Given that more than 50% of pregnancies are unplanned, by the time women and their clinicians are aware of pregnancy, the period of susceptibility to these risks will have already occurred. As such, clinicians should provide maintenance treatments in anticipation of potential pregnancy and be aware of which medications pose the fewest risks.

Lithium. Lithium remains one of the mainstays of acute and maintenance treatment of BPD. The International Registry of Lithium Babies, a voluntary physician-reporting database,^[33-37] noted a 400-fold increased rate for cardiovascular malformations, most notably Ebstein's anomaly, associated with lithium exposure in utero. Subsequent investigations identified a risk for Ebstein's anomaly among lithium users at between 1 per 1000 (0.1%) to 2 per 1000 (0.2%), or 20-40 times higher than rates in the general population.^[34-37] Thus, the relative risk for Ebstein's anomaly is somewhat increased, though the absolute risk remains small.

Lithium use is associated with higher-weight babies, and there are numerous reports of neonatal complications in association with lithium treatment in late pregnancy, including:

Cardiac dysfunction; Diabetes insipidus; Hypothyroidism; Low muscle tone; Lethargy; Hepatic abnormalities; and Respiratory difficulties.

Recognizing lithium's low therapeutic index, it seems plausible that such complications are directly related to the level of lithium exposure proximate to delivery. In a small prospective sample, Newport and colleagues^[38] demonstrated that discontinuation of lithium proximate to delivery and reinstitution immediately after delivery significantly reduced neonatal complications while maintaining maternal euthymia.

Long-term follow-up data are sparse. Sixty children older than 60 months, identified from the International Registry as being exposed to lithium during either the first trimester or throughout pregnancy, did not differ behaviorally from their nonexposed siblings.^[39] A second investigation found that attainment of major developmental milestones for 22 lithium-exposed subjects was comparable to that of controls.

Carbamazepine. Carbamazepine is a known human teratogen.^[40-44] The rate for neural tube defects in that report and others ranges between 0.5% and 1%.^[40,43,44] The teratogenic potential of carbamazepine is enhanced when it is given with other agents, valproate in particular, perhaps because the toxic epoxide metabolites are increased.^[43] In theory, oxcarbazepine, which does not produce the epoxide metabolite, may be less teratogenic. However, studies have not been performed to confirm this speculation.

Carbamazepine has been associated with lower birth weight and mean head circumference (standardized for gestational age and sex). Carbamazepine can cause fetal vitamin K deficiency. Because adequate levels of vitamin K are necessary for normal mid-facial growth and for the functioning of clotting factors, carbamazepine exposure in utero could increase the risk for neonatal bleeding and mid-facial abnormalities.:

Most experts recommend administering vitamin K 20 mg by mouth daily throughout pregnancy. Pediatricians should also administer vitamin K 1 mg intramuscularly to neonates after in utero carbamazepine exposure. Case reports of transient symptoms, such as hepatic toxicity hyperbilirubinemia, in neonates exposed during pregnancy underscore the need for observation.

Lamotrigine. Lamotrigine is a potential maintenance therapy option for pregnant women with BPD owing to its^[45]:

Protective effects against BP depression; General tolerability; and Growing reproductive safety information relative to alternative mood stabilizers.

Briefly, the pooled risk for reported major fetal anomalies following exposure to lamotrigine during pregnancy is 2.6% (78 of 2974 first-trimester exposures, including a rate of 0.34% [8 of 2372 exposures] for midline cleft formations); these rates are within the range of births not involving drug exposures.^[46-53] A relatively high risk for midline facial clefts (0.89% of 564 exposures) was reported by 1 pregnancy registry,^[49] and another reported greater risk for birth defects at higher maternal daily doses (greater than 200 mg/day).^[51]

To date, there are no reports of obstetrical or neonatal complications associated with lamotrigine monotherapy exposure. There is very limited long-term follow-up information.

Valproate. Sodium valproate is a known human teratogen (neural tube, cardiovascular, craniofacial) with acute and long-term adverse effects on infant development.^[54-60] Exposure during the first trimester is associated with neural tube defect rates of approximately 5% to 9%.^{[54,55,59,60]} The effect of drug on neural tube development is related to the use of valproate 17-30 days post-conception and the risk is increased with higher maternal daily doses/serum concentrations.^[60,61] The neural tube defect found in exposed infants is more likely to be lumbosacral rather than anencephalic, which suggests a drug effect on neural crest closure.^[62]

Similar to carbamazepine, transient neonatal symptoms have also been reported, including:

Liver toxicity; Hypoglycemia; and Withdrawal symptoms of irritability, jitteriness, feeding difficulties, and abnormal muscle tone.

One of the greatest concerns is the burgeoning clinical and preclinical data showing that valproate is a profound neurobehavioral teratogen. Investigations in the mid 1980s utilized in utero exposure to valproate as an animal model for autism. Several human investigations have demonstrated^[63]:

Increased risk for mental retardation; Higher rate of special educational needs; and

Decrease in both overall and verbal intelligence quotient (IQ).

Atypical antipsychotic medications. The use of atypical antipsychotics has dramatically increased over the past decade in pediatric populations, patients with BPD, and as adjunctive medications for a variety of symptoms, such as depression, sleep, and agitation. Those more commonly used include:

Aripiprazole; Olanzapine; Quetiapine; Risperidone; and Ziprasidone.

A recent investigation demonstrated that atypical antipsychotics cross the placenta^[64]; however, the obstetrical outcome data on these medications are extremely limited. The largest single investigation failed to identify any pattern of defects, though sample sizes were limited.^[65]

The obstetrical complication data are limited to case reports on olanzapine of maternal^[66]:

Weight gain; Insulin resistance; Gestational diabetes; and Pre-eclampsia.

There are no published infant/child follow-up studies.

Typical antipsychotic agents. Typical antipsychotic agents continue to have a role in the acute treatment of mania during pregnancy. Some experts consider the risk associated with typical antipsychotic agents, which have been available for decades, to be less than the risk associated with mood stabilizers. One of the largest databases available is for the older, "typical" antipsychotic agents, although even this information is limited. Phenothiazines and butyrophenones historically have been used to treat hyperemesis gravidarum, nausea, and (less commonly) psychotic disorders in pregnant women; they are the drug classes with the largest amount of reproductive information within this broad group of medications.

Adjunctive/alternative medications. There are a variety of additional medications that may be used in the management of BPD, including:

Antidepressants; Benzodiazepines; and Sedative hypnotics.

These classes of medication are seldom efficacious as monotherapy for BPD, and their use during pregnancy has been the center of considerable debate.

Electroconvulsive therapy (ECT). When used in pregnant patients, ECT has relatively few side effects and may pose fewer risks than untreated mood episodes or pharmacotherapy with a teratogenic agent. Although there have been occasional reports of congenital malformations in offspring exposed to ECT in utero, neither the number nor the pattern of these implicates ECT as a causal factor. Overall, reported complications of ECT during pregnancy are uncommon and transient.^[67,68] Barbiturates and atropine can reduce beat-to-beat variability in the fetal heart rate, and atropine can cause fetal tachycardia. The risk for fetal cardiac arrhythmias can be minimized by:

Avoiding atropine; Ensuring adequate oxygenation; Avoiding excessive hyperventilation; and Elevating the right hip.

Fetal cardiac monitoring during ECT will allow for detection of arrhythmias and correction of any contributory problems.

Treatment Planning for Women With Bipolar Disorder During Their Reproductive Years

Overall, the general approach to the treatment of women with BPD during pregnancy remains one of balancing the risk and benefits of illness vs treatment. Similarly, if pharmacologic treatment is deemed the best option, the clinician has several alternatives to reduce the risks. The following provides the clinician with a reasonable approach and rationale consistent with ACOG guidelines to minimize risks^[6]:

1. Treat all women of reproductive age: Document birth control method at every visit; Provide education about the risks of medications and potential pregnancy; Select maintenance medications with reduced teratogenic risk; Reduce other risk factors, including smoking, obesity, alcohol, and illicit drug use; and Supplement with folic acid: 1 mg for all, 3-5 mg for women treated with antiepileptic medications.

The rationale for instituting these measures throughout the reproductive years includes:

The high rate of inadvertent conception provides unanticipated exposure during organogenesis; and The primary potential benefits of folic acid occurs early in gestation often before knowledge of conception.

Although folic acid has not been definitively established in reducing the risks of antiepileptic drugs, the American Academy of Neurology has recommended 3-4 mg per day but states that the optimal dose has yet to be established.^[69]

2. Maintenance treatment that reduces risk in the context of inadvertent conception. All too often, clinicians are hesitant to consider optimal maintenance pharmacotherapy early in the treatment course for women with BPD. Of the available medication options, valproate is the most hazardous in pregnancy with respect to rates and severity of both malformations and adverse neurodevelopmental sequelae.

3. Monotherapy is preferable to multiple medications. There are very limited data about the impact of combined medications on pregnancy outcome. Extrapolation of the experience of our colleagues in neurology/epileptology clearly demonstrates an increased risk from multiple medications compared with monotherapy.

4. Develop an a priori treatment plan for pregnancy. BPD is a chronic medical illness and with onset typically prior to family planning. Therefore, it is likely that at some point over the course of treatment the clinician will encounter this situation.

5. Do not abruptly change or discontinue medications at knowledge of conception. Pregnancy is not a medical emergency. Abruptly changing or discontinuing medications in reaction to pregnancy simply increases the risks and seldom reduces fetal exposure. In fact:

Changing medications exposes the fetus to additional drugs, a situation with limited reproductive safety information; The change may increase the risk for maternal symptoms; Abruptly discontinuing medications appears to increase the risk for relapse; and The window of highest teratogenic risk for exposure may have already passed.

6. Over the course of pregnancy, maternal daily-dose adjustment may be required to maintain maternal well-being. Investigations of lithium, antiepileptic drugs, and antidepressants have all demonstrated decreased serum concentrations in later pregnancy. Failure to monitor and adjust the dose may result in exposure to both maternal symptoms and medications, hence the risk/benefit balance has failed.

7. Consider adjusting medications proximate to delivery. Preliminary studies with lithium suggest that reducing exposure proximate to delivery, ideally within 24 hours of a planned induction or planned cesarean section, reduces neonatal complications without compromising maternal well-being.

8. Postpartum treatment plan. There is good agreement that women with BPD are at risk for severe symptoms during the early postpartum period. A postpartum treatment plan and frequency of observation should be established prior to delivery.

9. Do not switch medications for breastfeeding. The central nervous system continues to have considerable growth and development during the postpartum years. Changing medications simply exposes the child to additional medications and, for a period of time, to multiple medications due to the delay of neonatal clearance of the original medication. Furthermore, abrupt medication switches in the immediate aftermath of delivery arguably increase the likelihood of maternal relapse.

In summary, the treatment of women with BPD during pregnancy remains a complex clinical situation that continues to generate angst for both the patient and clinician. Fortunately, the area of perinatal psychiatry has grown rapidly, and there are several academic programs that offer consultation and information in such situations.

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Zachary N. Stowe, MD, Women's Mental Health Program, Emory University School of Medicine, Atlanta, Georgia

D. Jeffrey Newport, MD, MS, MDiv, Women's Mental Health Program, Emory University School of Medicine, Atlanta, Georgia

Zachary N. Stowe, MD, has disclosed that he has received grants for clinical research from, grants for educational activities from, and has served as an advisor or consultant to GlaxoSmithKline, Wyeth, and Pfizer. Dr. Stowe has also disclosed that he has served as an advisor or consultant to Bristol-Myers Squibb and that he has served on the speaker's bureau for GlaxoSmithKline, Wyeth, Pfizer, and Eli Lilly.

D. Jeffrey Newport, MD, MS, MDiv, has disclosed that he has received grants for clinical research from Eli Lilly, GlaxoSmithKline, Janssen, and Wyeth. Dr. Newport has also disclosed that he has served on the speaker's bureau for AstraZeneca, Eli Lilly, GlaxoSmithKline, and Pfizer.

WFSBP Treatment Guidelines on Bipolar Disorders

• World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of bipolar disorders, part I: Treatment of bipolar depression.
  The World Journal of Biological Psychiatry 3: 115-124

• World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for
  biological treatment of bipolar disorders, part II: Treatment of mania.
  The World Journal of Biological Psychiatry 4: 5-13

• World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for
  the biological treatment of bipolar disorders, part III: Maintenance treatment.
  The World Journal of Biological Psychiatry 5: 120-135