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Bipolar Spectrum Disorders: Diagnosis and Pharmacologic Treatment
by John Preston, Psy.D., ABPP and Li Liang, MD

2 CE Hours - $49

Last revised: 03/12/2024

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Learning Objectives

This is an intermediate-level course. After completing this course, mental health professionals will be able to:

The materials in this course are based on the most accurate information available to the author at the time of writing and this course has been updated by Li Liang, MD. New developments in the field of psychopharmacology occur each day and new research findings may emerge that supersede these course materials. This course is updated regularly as new practice guidelines are developed. However, it should be noted that “official” guidelines (e.g., those offered by the American Psychiatric Association, and other groups), as of the current update, are outdated since in recent years we have a few new medications approved by the FDA to treat bipolar spectrum disorders. The material in this course while partly derived from such guidelines, is augmented with a number of guidelines drawn from more recent clinical and research studies. This course will equip clinicians to evaluate the needs for medical treatment for their psychotherapy clients, to assess responses to treatment, and to more effectively collaborate with primary care physicians and psychiatrists.

Outline

Introduction

Bipolar disorder is a common type of mood disorder. Previously termed manic depression, it has 4.4% lifetime prevalence according to the Harvard Medical School, 2007, National Comorbidity Survey. Its typical age of onset is the early 20s. The patient can have recurrent episodes of mania/hypomania and depression. Without treatment the patient’s impaired functioning can be persistent. It is now appreciated that there are a number of different types of bipolar disorder and together these are often referred to as bipolar spectrum disorders. These disorders include bipolar I disorder, bipolar II disorder and cyclothymic disorder, substance/medication-induced bipolar disorder and related disorders, bipolar and related disorders due to another medical condition, other specified bipolar and related disorders, and unspecified bipolar and related disorders. These are lifelong disorders that require ongoing medical treatment. Mood-stabilizing medications can effectively reduce episode severity and frequency. Nevertheless, there is currently no cure for bipolar disorders. We need to understand that there are co-occurring mental disorders which usually occur at the same time as bipolar spectrum disorders. Bipolar disorders can be associated with anxiety disorders, ADHD, borderline personality disorder, and any of the substance use disorders. When an individual has multiple psychiatric illnesses, we have to set up a comprehensive treatment plan.

Diagnostic Issues

Bipolar disorders are recurrent and often chronic mental illnesses marked by episodes of mania, hypomania, and depression, and are always associated with a change or impairment in functioning. They are separated from a depressive disorder, usually called unipolar depression, in the DSM-5-TR. As clinicians, we need to be familiar with DSM-5-TR diagnostic criteria for bipolar spectrum disorders. This course focuses on understanding bipolar I disorder, bipolar II disorder, and other common bipolar spectrum disorders. Here we focus on recognizing symptoms of mania, symptoms of hypomania, and symptoms of depression.

Manic Episode (Table1)

Criteria

Symptoms

A. Lasts at least one week, or any length if hospitalized due to mania

Abnormal and persistent extreme expression of emotion or irritable mood, and abnormal and persistent increase in activity or energy

B. During criterion A symptoms, three or more of these symptoms (four if mood is only irritable)

1. Inflated self-esteem and grandiosity

2. Decrease in need for sleep (e.g., feels rested after only 3 hours of sleep)

3. More talkative than baseline or fast talking

4. Flight of ideas or subjective experience that thoughts are racing

5. Distractibility (reported or observed)

6. Increase in goal-directed activity (socially, at work, school, or sexually) or psychomotor agitation (i.e., purposeless non-goal-directed activity)

7. Excessive engagement in activities with high risk of painful results (e.g., unrestrained buying sprees, sexual indiscretions, or foolish business investments).

C. Mood disturbance severity

Causes marked impairment in social or occupational functioning or requires hospitalization to prevent harm or there are psychotic traits

D. Differential diagnosis

Substance use and medical causes are ruled out

Hypomanic Episode (Table 2)

Criteria

Symptoms

A. Distinct period that lasts at least four consecutive days and is present most of the day, nearly every day

Abnormally and persistently elevated expression of emotion or irritable mood and abnormal and persistent increase in activity or energy

B. In context of criterion A, three or more of these symptoms (four if mood is only irritable) have persisted and are markedly different from baseline and have been present to a significant degree

1. Inflated self-esteem and grandiosity

2. Decrease in need for sleep (e.g., feels rested after only 3 hours of sleep)

3. More talkative than baseline or fast talking

4. Flight of ideas or subjective experience that thoughts are racing

5. Distractibility (reported or observed)

6. Increase in goal-directed activity (socially, at work, school, or sexually) or psychomotor agitation

7. Excessive engagement in activities with high risk of painful results (unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C. Unambiguous change in functioning not characteristic of the person when not symptomatic

 

D. Mood disturbance and change in function are observable by others

 
E. Episode does not cause significant impairment and is not severe enough to require hospitalization If there are psychotic features, it is a manic (not hypomanic) episode.
F. Not attributable to a different diagnosis Substance use and medical causes are ruled out

Major Depressive Episode (Table 3)

Criteria

Symptoms

A. Symptoms and duration

Five or more symptoms during the same two-week period

Represents a change from functional baseline

At least one of the symptoms is either:

1. Depressed mood, or

2. Loss of interest or pleasure

1. Depressed mood most of the day, nearly every day by subjective report or observation

2. Marked decrease in interest or pleasure in all, or almost all, activities most of the day, nearly every day (subjective or objective)

3. Significant weight loss without dieting, or weight gain, or decrease or increase in appetite nearly every day

4. Insomnia or hypersomnia nearly every day

5. Psychomotor agitation or retardation nearly every day (observable by others, not just by self-report)

6. Fatigue or loss of energy nearly every day

7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day

8. Decreased ability to think or concentrate, or indecisiveness, nearly every day

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

B. Distress and impairment

Symptoms cause significant distress, or Impairment in social, occupational, or other important areas

C. Differential diagnosis

Substance use and medical causes are ruled out

Having a manic episode is required in order to make a diagnosis of bipolar I disorder, while having a major depressive episode is not required. The 12-month prevalence rate for bipolar I disorder in United Stated is 0.6%. The lifetime male-to-female prevalence ratio is approximately 1.1:1. Bipolar II disorder has at least one hypomanic episode and one or more major depressive episodes. In the United States, the 12-month prevalence rate for bipolar II disorder is 0.8% and it has affected females more than males (APA, 2022).

It is a common misconception about bipolar II disorder that we always think hypomania is a milder version of mania. We know that a manic episode can lead to hospitalization with a clearer clinical presentation. Compared to individuals with bipolar I disorder, however, those individuals with bipolar II disorder have greater chronicity of illness and spend, on average, more time in the depressive phase of their illness (APA, 2022) In general, the suicide rate for all those with bipolar I disorder and bipolar II disorder are about 3% to 14% (APA, 2022)

Other Types of Bipolar Spectrum Disorders:

Cyclothymic Disorder: We can think of it as the subthreshold of bipolar disorder with a longer duration. It usually has an insidious onset and a persistent course. There is a 15% to 50% risk that an individual with cyclothymic disorder will subsequently develop bipolar I disorder or Bipolar II disorder (APA, 2022). According to the DSM-5-TR, these individuals can have a major depressive or hypomanic-like episode, while never having met the criteria for any episodes. Duration is at least two years for adults and at least one year for children and adolescents. During these time frames, the hypomanic and depressive periods must have been present for at least half the time and the individual has not been without the symptoms for more than two months at time. We also need to rule out other psychological causes, such as a substance use disorder or a medical condition.

Substance/Medication-induced Bipolar and Related Disorders: By definition, throughout the psychiatric evaluation, there is a clear indication that the manic episode, hypomanic episode, and major depressive episode occur during or soon after substance intoxication or withdrawal, or after exposure to a medication. The common substances include alcohol, hallucinogens, and cocaine. The common medications are sedatives, hypnotics, anxiolytics, stimulants, or steroids.

Bipolar and Related Disorders

Due to Another Medical Condition: This is explored if the history, physical examination, or laboratory findings reveal that an individual’s mania or hypomania or depression cannot be explained by another mental disorder, family history of mental illness, or past psychiatric history. The patient presents with the sudden onset of a manic episode, hypomanic episode, or depressive episode which is determined to be directly related to the pathophysiological consequence of a medical condition. The well-established medical conditions that can cause mood changes include Cushing’s disease, thyroid diseases (hypothyroidism and hyperthyroidism), multiple sclerosis, stroke, and traumatic brain injury. Each of these underlying pathophysiological consequences can precede mood changes.

DSM-5/DSM-5-TR has used specifiers to provide an opportunity to define a more homogeneous subgrouping of individuals with the disorder who share certain characteristics (APA, 2013) Here are two of the most common specifiers for describing bipolar I disorder and bipolar II disorder:

1. Rapid cycling: A complication of bipolar disorder affecting about 20% of sufferers is called rapid cycling. It requires at least four mood episodes within 12 months and the mood episodes have met the criteria for manic, hypomanic, or major depressive episode. Most cases of rapid cycling last a few months to a year and a half, and then subside. The most common cause for rapid cycling is substance use and/or abuse. Rapid cycling has also been attributed to the use of antidepressants by bipolar patients. Antidepressants, as will be discussed shortly, can be problematic in treating bipolar disorder. If more frequent episodes are evident, it is referred to as ultra-rapid cycling or ultradian cycling bipolar.

2. Mixed features: It is very difficult to differentiate and it can apply to the current manic, hypomanic, or depressive episode in bipolar I disorder and bipolar II disorder. We cannot double-count symptoms such as distractibility, psychomotor agitation, insomnia, or irritability (APA, 2022). See table 4.

DSM-5-TR Mixed Features Course Specifier (Table 4)

Hypo(manic) With Mixed Features

Depressive With Mixed Features

Meets criteria for (hypo)mania + ≥ 3 of the following:

Meets criteria for depression + ≥ 3 of the following:

Dysphoric or depressed

Less interest/pleasure in activities

Observable psychomotor retardation

Fatigue

Feeling worthless, excessive/inappropriate guilt

Recurrent thoughts of death, suicidal ideation (with or without plan), suicide attempt

 Elevated, expansive mood

 Inflated self-esteem, grandiosity

 Pressured speech

 Racing thoughts

 Increase in energy/goal-directed activities

 Increased/excess involvement in risky activities

 Feeling rested with decreased need for sleep

Medication Treatments: General Considerations

General references for use as guidelines:

1. Texas Department of Mental Health (2007). Texas Medication Algorithm Project: Bipolar Disorder Algorithms. The Commonwealth Fund.

2. Ketter, T. A. (Ed.). (2005). Advances in the Treatment of Bipolar Disorder. American Psychiatric Association.

3. National Institute of Mental Health (2006). STEP-BD Program.

4. Goodwin, F. K. & Jamison, K. R. (2007). Manic-Depressive Illness (2nd ed.). Oxford University Press.

5. Hirschfeld, R. (2005). Guideline Watch: Practice Guideline for Patients with Bipolar Disorder (2nd ed.). American Psychiatric Association.

6. Connolly, K. & Thase, M. (2011). The clinical management of bipolar disorder: a review of evidence-based guidelines. Primary Care Companion CNS Disorders 2011:13(4).

7. Butler, M, & Urosevic, S. (2018). Treatment for bipolar disorder in adults: a systematic review. Comparative Effectiveness Review, No.208.

8. Levenberg, K., & Cordner, Z. (2022). Bipolar Depression: a review of treatment options. General psychiatry; Vol 35(4) doi: https://doi.org/10.1136/gpsych-2022-100760

Please note that the official treatment guidelines listed above can only be used as guidelines because the research on the treatment for bipolar spectrum disorders always evolves and progresses. In this course we will include information from these sources as well as adding information from more recent experts and research in this area. The choice of medications used to treat bipolar disorder depends on the mood state the patient is currently experiencing (i.e., mania or depression). In addition, for the medication choice one must always take into consideration the ultimate goal of treating the acute phase of mania, hypomania, mixed episodes and depression, as well as the maintenance treatment phase. In order to prevent recurrences, it requires mood stabilizers, as monotherapy, or in combination. Antidepressants alone are not indicated for bipolar spectrum disorder. A mood stabilizer is generally defined as a medication with efficacy in at least one phase of the illness (depression, mania, hypomania, and mixed features) or prophylaxis against depression or mania and one that does not exacerbate any phase of illness (Stern, et al., 2021)

Management of bipolar spectrum disorders also requires a long-term plan that includes medication, continual medical follow up, and adjunctive psychosocial therapies such as a healthy lifestyle including sleep, hygiene, exercise, and stress management.

Currently, there are many medications that are approved by the Food and Drug Administration (FDA) for the treatment of bipolar disorder: Lithium, Depakote, Equetro, Lamictal, Symbyax, Zyprexa, Risperdal, Seroquel, Geodon, Abilify, Latuda, Saphris, Vraylar, and Caplyta. However, a number of other effective drugs are in common use by patients as well. The use of medications not approved by FDA for the treatment of certain conditions is referred to as “off-label use.” It is important to note that off-label use of medications is a very common practice in every branch of medicine. Commonly used off-label medications for bipolar disorders are other antiseizure medications such as Tegretol, and antipsychotic medications such as Thorazine, and Haldol.

Recent surveys reveal that in the United States only 11% of people being treated for bipolar disorder are taking just a single drug (monotherapy); thus, this is the exception and not the rule. On average, most people being treated are taking three or four medications simultaneously. The reason for this is simple – medication combinations are often clearly superior to monotherapy for most people suffering from bipolar disorder.

All medications have side effects and, unfortunately, the drugs used to treat bipolar disorder are known to produce significant side effects for the majority of people being treated. Side effects can be mild and easy to tolerate. However, they are often more noticeable and, in rare instances, they can be dangerous. In every single case, once the current mood episode has subsided, people with bipolar disorder must continue to take medications (mood stabilizers) to help prevent or reduce the likelihood of recurrence. This is absolutely essential!

However, some estimates suggest that as many as 90% of people who start medical treatment for bipolar disorder will recover from their first episode, but within weeks or several months will stop taking their medications, against medical advice. The most common reasons for doing so are: the patient is experiencing unpleasant side effects; there is a negative stigma associated with having a serious psychiatric condition; and/or the person suffering from bipolar disorder concludes that the episode they experienced is not really bipolar disorder, but was just a single episode and that there will be no recurrence. This last conclusion is borne out of hopefulness that it is not really going to be a recurring illness (Pope & Scott, 2003). These reasons for discontinuing the medication are entirely understandable, but they almost invariably lead to the emergence of another episode. This next episode may occur within a few months following the initial episode, but more commonly occurs several years later.

For many patients, taking medications when you feel well is counterintuitive. However, the picture is clear that bipolar disorder is always recurring, and over a period of time, there is a tendency for episodes to become increasingly severe and harder to treat. There is also research that reveals that untreated or poorly treated bipolar illness can ultimately result in lasting damage to the nervous system and cause functional impairment which can then lead to a disability. During mood episodes, there are often toxic levels of certain neurotransmitters (e.g., glutamate) and stress hormones (e.g., cortisol) that are released which can damage nerve cells. Fortunately, studies also reveal that ongoing treatment with some bipolar medications may prevent this from happening (Bauer, 2003; Bottern, et al., 2002; Goodwin, 2002; Medina, 2003; Medina, 2003; Williams, et al., 2002). In a very real sense, some of these drugs such as Lithium, Seroquel, Lamictal, and Depakote, appear to be “neuro-protective.”

The good news is many side effects can be managed by dosage adjustments or by switching to other medications. This is one reason that most people will need to go through systematic trials on a variety of medications to determine which ones are the most effective, and which drugs are best tolerated by the individual. Every effort should be made to find the right medication or medication combinations in an attempt to minimize side effects. This is often something that can be accomplished. However, it is frequently the case that it can take a year of trials on various medications to finally discover the specific medication or medication combinations that will be effective and that will be best tolerated. This is the rule and not the exception.

It is very important for patients not to become too discouraged if the first medication is less than optimally effective or there are problematic side effects. A competent and compassionate psychiatrist will work with patients in carrying out systematic medication trials until the best treatment is finally identified. Sometimes, side effects can be minimized. Many people, however, end up having to find ways to tolerate some side effects. Obviously, this is not pleasant, but is ultimately necessary to reduce or eliminate severe mood swings. Unfortunately, a very small number of people are simply unable to tolerate any bipolar medications, so we always encourage patients to talk to their psychiatrist to adjust their medication treatment.

What are Realistic Outcomes?

Bipolar disorder is similar to a number of other chronic medical conditions, such as diabetes, asthma, and arthritis. It is not a condition that can be cured by currently available medications. The medications discussed below are simply effective in relieving many of the more serious symptoms of bipolar illness. They often can reduce the frequency of mood episodes for most people, if patients receive appropriate treatment and stick with it. The good news, but also the not-so-good news, is that with aggressive, appropriate, and ongoing medication treatment started during the first or second mood episode, about 30% of people will not experience recurrences. That is, in about one out of three to four people, the medications are successful in preventing relapses. However, if the first appropriate medical treatment begins after the second episode, treatment typically becomes somewhat more challenging and the outcomes are not quite as robust. For the majority of the rest of the people receiving treatment and taking medications as prescribed, the recurrence rates for severe episodes can be reduced by about 75% and hospitalizations can often be avoided. Subsequent episodes that do occur tend to be mild depressions and hypomanias (Gitlin, 2002; Bowden & Singh, 2005).

Medication treatments are far from perfect, but they have the kind of effectiveness that can substantially reduce suffering, keep families together, avoid catastrophes, and save lives.

The material below begins with a brief overview of bipolar medication classes and specific drugs. This is followed by a discussion of treatment guidelines. Finally, detailed information is presented regarding specific medications (e.g., doses, side effects).

Bipolar Medications: Overview

Note: To the best of my knowledge recommended doses and side effects listed herein are accurate. However, this is meant as a general reference only and should not serve as a guideline for prescribing. Please check package inserts and the PDR for specific information on prescribing and taking them.

There are three major classes of psychiatric medications: Lithium, Anticonvulsants, and Antipsychotics. There are other medications, also, that have been found to be effective in treating various symptoms of bipolar disorder. Generic and brand names (registered trademarks) are listed below.

Lithium: Lithobid, Eskalith

Anticonvulsant Mood Stabilizers:

Generic Name

Brand Name

Meets criteria for (hypo)mania + ≥3 of the following:

Meets criteria for depression + ≥3 of the following:

divalproex sodium

Depakote
carbamazepine Tegretol; Equetro
oxcarbazepine Trileptal (off-label)
lamotrigine Lamictal

Second-Generation Antipsychotics (SGA), also often referred to as Atypical Antipsychotics: This is the name commonly used for a class of more newly developed antipsychotic medications that treat psychotic symptoms and appear to have mood stabilizing effects as well:

Generic Name

Brand Name

olanzapine

Zyprexa

risperidone

Risperdal
ziprasidone Geodon
aripiprazole Abilify
quetiapine Seroquel
asenapine Saphris
lurasidone Latuda
cariprazine Vraylar
lumateperone Caplyta

Antidepressant and Atypical Antipsychotic Combination: Symbyax, a combination of Prozac and Zyprexa approved by the FDA for the treatment of acute depression or bipolar I disorder.

Benzodiazepines: These are also referred to as minor tranquilizers or anti-anxiety drugs. Only those most commonly used are listed; for the acute phase of treatment, they can be used as needed for very short periods, such as three to six weeks.

Generic Name

Brand Name

diazepam

Valium

clonazepam

Klonopin
lorazepam Ativan

Sleeping Pills: These medications can be used as needed to regulate a patient’s sleep for three to six weeks use.

Generic Name

Brand Name

zolpidem

Ambien

zaleplon

Sonata
eszopiclone Lunesta
ramelteon Rozerem
suvorexant Belsomra

Antidepressant medications are often used in treating bipolar disorders. However, their use often results in ineffective outcomes or the provoking of significant emergent symptoms, such as mania. Even though they are often prescribed, the current thinking is that they should rarely be used and only in treatment-resistant cases or a previous fair response without mood switching. There is a general lack of knowledge about whether antidepressants are even effective, but whether they can cause significant problems. There are a number of other medications that are used occasionally, including some experimental drugs, such as Omega-3 fatty acids, and Topamax, to help reduce weight gain. Topamax does not appear to be an effective antimanic medication. This course will provide a brief overview of standard treatment guidelines that have been developed primarily by the American Psychiatric Association and findings from the STEP-BD Program (Systematic treatment enhancement program for bipolar disorder).

Targets for Medication Treatment

There are two primary goals in medication treatment of bipolar disorder. The first goal is dealing with potentially dangerous acute phases of mood episodes of mania or depression by stabilizing patients. The second goal is the maintenance phase which includes relapse prevention. The choice of medications used will always be influenced by these goals. Of course, the medication choice will also be dictated by the need to minimize side effects.

Getting Started: Acute Treatments and Laboratory Tests

Sometimes, there is a need for emergency treatment, such as when a person is experiencing a sudden onset of severe manic agitation. This may include extreme restlessness, impulsivity, severely impaired judgment, and/or aggression or serious suicidal impulses during a depression or dysphoric manic episode. At such times, acute hospitalization may be necessary to ensure the safety of the patient and others.

Emergency medical treatments for agitation include the use of either benzodiazepines (anxiolytic medications, such as Ativan, Klonopin, and Valium) or antipsychotic medications (such as Zyprexa, Risperdal, Geodon, Abilify, or Seroquel, and even Haldol). These two classes of drugs are often very effective in rapidly reducing agitation. On occasion, there is a need for emergency medical treatment for very severe depression, such as where there is either a grave suicide risk or refusal to eat accompanied by severe weight loss. In such cases, Electro-Convulsive Therapy (ECT, also known as shock treatment) can be used successfully. ECT is also very effective for the emergency treatment of severe mania.

Laboratory tests need to be done prior to or during such treatment. This is done for two purposes. The first is to rule out the possibility that the mood symptoms may be caused by a primary medical illness, such as thyroid disease or substance abuse. The other reason has to do with the tendency for many of the bipolar medications to cause significant changes in a variety of bodily functions. Mood stabilizers, in particular, are known to affect a broad range of organs and glands, especially when they are taken for prolonged periods. Thus, pretreatment labs typically include measures of cardiac, kidney, liver, and thyroid function, as well as a complete blood count. Laboratory monitoring of blood levels of certain medications may also be required. This is routinely done for the following mood stabilizing medications: Lithium, Tegretol, Trileptal, and Depakote.

Medication Dosing and Blood Levels

“Too much drug…Too little drug”

For each psychiatric medication listed in the Appendix, you will see listed the typical adult daily doses. In many instances, the “therapeutic dosage range” is broad. For example, daily dosing with lithium is between 600 and 1,800 mg. It is important to know that the amount of medication required to effectively reduce and eliminate symptoms often has little to do with how severe the mood episode is. What matters is not so much how much is ingested but rather, how much of the medication enters the blood stream.

There are three primary factors that influence the amount of drug that finds its way into the blood stream. First is the rate of liver metabolism. Bipolar medications are absorbed through the walls of the stomach and intestines, and go directly to the liver. Here the drug molecules are acted upon by liver enzymes that begin a process generally referred to as biotransformation. Liver enzymes chemically alter the medication in ways that allow the drug to be more readily excreted from the body. The liver’s function is to detoxify the body. Thus, in this so-called first pass effect through the liver, a good deal of the drug is transformed and then rapidly excreted. However, some of the medication initially escapes this process, makes its way through the liver and into circulation, and is therefore allowed to begin accumulating in the blood stream. How rapidly the liver metabolizes drugs depends on a number of factors. This resulting blood level is what matters when it comes to reducing symptoms. (Note: two bipolar medications are not metabolized in the liver, Lithium and Neurontin [off-label medication]).

Genes play a significant role in this process. A small percentage of people are known as rapid metabolizers. They take certain drugs and then eliminate them very quickly. The result is that, even though they may be taking what seems like an adequate dose of the medication, little actually gets into the blood stream. Once it is discovered that someone is a rapid metabolizer, usually they are prescribed very high doses of medications, and eventually enough gets into the blood stream to be effective. Again, this has nothing to do with how severely ill the patient is – it’s just a matter of the liver’s metabolic rate. Conversely, some individuals are hypo-metabolizers (slow metabolizers). This small percentage of people has fewer than average liver enzymes. The effect is that they can take a very small dose of a medication, and on its trip through the liver, only small amounts are transformed and excreted. The result is often very high blood levels of the medication and severe side effects or toxicity. The ultimate solution for hypo-metabolizers is to use very small doses. Sometimes, when a person is first treated, they will experience serious side effects that may be due to slow/hypo-metabolizing. It is often hard to know ahead of time if this will happen with any one given individual. Thus, if your patient has experienced very intense side effects with other medications in the past, it may be anticipated that they are a slow/hypo-metabolizer, so initial dosing is done gradually; we tend to take a “start low and go slow” approach.

A second factor determining blood levels of medications is the functioning of the kidneys. Sometimes genetic factors play a role here too, but more often problems can occur due to kidney disease. For some bipolar medications, pretreatment labs will include an assessment of kidney functioning (this is especially important for patients being treated with Lithium).

Finally, a number of drugs can adversely affect liver metabolism and thereby alter blood levels. This is where drug-drug interactions can cause significant problems. This applies to some prescription drugs, over-the-counter drugs, herbal and dietary supplement products, and recreational drugs. The use of prescription drugs must be carefully monitored by the treating physician. In addition, even modest amounts of alcohol can have significant effects on the liver. St. John’s Wort, a popular herbal product for the treatment of depression, is known to cause some very significant changes in liver metabolism. Since marijuana has been legalized in some U.S. states, there are more and more people using it recreationally, and there are studies indicating that its use has diminished mood stabilizer efficacy and that it increases the risk of medication side effects.

Caution: The use of Tegretol, Trileptal, Topamax, Lamictal, or St. John’s Wort can interfere with the effectiveness of birth control pills. This is especially important to monitor since some mood stabilizers are known to cause birth defects.

Treatment Guidelines: Mania

The choice of medications used to treat core symptoms of mania is important and often complex. As noted above, there are several different symptoms of mania, and a considerable amount of research has been done to discover which medications are best suited for treating particular subtypes of mania. Dozens of large-scale research studies have been conducted in recent years, and specific treatment guidelines have been developed that are useful in helping physicians to decide on initial medication choices (see below). However, the fact is that each person will have a number of factors unique to themselves that will influence the choice of medications, such as age, gender, body weight, history of allergies to medications, liver metabolism rate, the presence or absence of other medical conditions, and other medicines being used to treat such conditions in the past.

Several classes of psychiatric medications have been found to be effective in treating acute manic episodes:

Treatment-Resistant Mania

For people who experience very severe mania that does not respond to more traditional treatments, there are a number of options.

The antipsychotic medication clozapine (brand name Clozaril) has been found to be effective in some cases of treatment-resistant mania. This drug has antipsychotic effects for treating hallucinations or delusions. It also is proving to be effective for treating not only mania but for relapse prevention. Unfortunately, clozapine can cause numerous side effects, some of which are potentially dangerous such as neutropenia and myocarditis. ECT (electro-convulsive therapy) is a safe and highly effective treatment for severe mania.

ECT: Electro-Convulsive Therapy

ECT (electro-convulsive therapy) was developed in the late 1930s and has experienced a checkered history. ECT involves the use of an electric current that is delivered by way of two electrodes placed on the frontal area of the skull. The electrical current produces a grand mal seizure and there is evidence that the seizure is responsible for rapidly altering the chemistry of the brain. The changes in brain chemistry are remarkably similar to that seen as a result of psychiatric medication treatments, although such changes typically occur after just a few days and a few treatments, while medications generally require a number of weeks to yield such changes.

In the early days, ECT was a very crude medical technology. The treatment, unfortunately, was administered in ways that resulted in a multitude of serious medical and neurologic consequences, including spinal fractures, cardiac arrests, and persistent memory problems. However, it was also clear from the outset that this was a powerful treatment that often resulted in rapid and significant improvement in patients suffering from very severe mania and depression.

There have been significant advances in the way ECT is administered. Currently, ECT is administered to the patient under a general anesthetic while being monitored by an anesthesiologist. The procedure is completely painless and is judged to be safe. Muscle relaxing drugs and the anesthesia help to prevent the medical problems encountered in the early days of ECT. Memory loss does occur following the treatments (primarily forgetfulness), but almost without exception, memory problems completely remit within six weeks after the final treatment. ECT can resolve acute, severe mood states; however, once the treatments end, most patients will slip back into a depression or mania within a few weeks, so it does need a maintenance ECT treatment in biweekly to monthly intervals. The preferred strategy is to give ECT while also administering mood-stabilizing medications; the drugs help to prevent acute relapse.

Unfortunately, ECT is currently considered a treatment of last resort, primarily because of the costs involved, but it remains an important and often lifesaving technique for treating both manias and severe depressions of bipolar illness.

Treatment Guidelines: Bipolar Depression

It is important to know that bipolar depressions are often difficult to treat. Treatment guidelines have been developed by the American Psychiatric Association. However, there is a significant amount of controversy in the field regarding the best approaches for treating this aspect of bipolar disorder. The biggest issue is that many treatments that ordinarily are effective in reducing depression (i.e., antidepressants) carry a risk of provoking manic episodes, a phenomenon referred to as switching, or causing cycle acceleration. This refers to a gradual, over-all worsening of bipolar disorder in which, over time, there is an increased frequency of episodes, and episodes tend to become more severe and more difficult to treat. Switching and cycle acceleration have been clearly documented with the use of antidepressants (see below) and thus these drugs are not advised in the treatment of bipolar depression (Ghaemi, et al. 2001; Post, et al. 2001; Goodwin & Jamison, 2007). Excessive bright light exposure, which can treat some types of seasonal depression, has also been associated with provoking manias. Additionally, three popular over-the-counter products that have antidepressant properties can, likewise, cause switching or cycle acceleration: 5-HTP, St. John’s Wort, and SAM-e.

When using an antidepressant for bipolar disorder patients, there are several factors that need to be considered: if the patient does not have a history of antidepressant-induced mania, has an absence of recent mania or hypomania, no rapid cycling, and absence of comorbid alcohol or substance use disorder. There are two antidepressants, Wellbutrin (bupropion) and Paxil (paroxetine), that have been shown to carry a lower risk of “switching” than other antidepressants. Monoamine Oxidase Inhibitors (MAOIs) have a lower switching rate as well.

Several classes of psychiatric medications are often used to treat bipolar depression:

Treatment Guidelines: Hypomania

For patients with hypomania, the treatment is required only if symptoms are prolonged, severe, and/or associated with significant functional impairment. We use mood stabilizers such as Lithium, Lamictal and/or an atypical antipsychotic.

Treatment Guidelines: Mixed Features

The mixed features are marked by the coexistence of depression and mania/hypomania symptoms (see Table 4), representing a more difficult-to-treat state. For patients with mixed features, most treatment guidelines favor using a combination treatment, (e.g., an atypical antipsychotic plus Depakote) to adequately address symptoms, although initial monotherapy with an antipsychotic may be considered while at the same time tapering and discontinuing any current antidepressant medications (Fountoulaki et al., 2013).

Treatment Guidelines: Rapid Cycling

In only about 2% of people is rapid cycling (four or more mood episodes in a one-year period) continuous for very prolonged periods. Three factors account for the majority of cases of rapid cycling: substance abuse (including alcohol), the use of certain prescription medications (e.g. antidepressants, steroids, or stimulants), or disorders of the thyroid gland. Thus, it is very important to determine whether any of these factors is present and to take appropriate action to ameliorate them. Special attention must be taken to stabilize the patient’s lifestyle, making sure that there is regularity of sleep patterns and making every attempt to reduce or avoid sleep deprivation (e.g., establishing regular sleeping and awakening times; completely avoiding sleep-destroying substances such as caffeine, alcohol, and decongestants; no all-nighters cramming for exams; no late-night partying).

The treatment approach to patients having rapid cycling requires planning and patience. Mood shifting may occur suddenly, and treatment of the current individual episode may be counterproductive. Rapid cycling bipolar disorder is well known for its relative resistance to most monotherapies, usually requiring combinations of mood stabilizers, so that patients may need to take two or three medications. Lithium, Depakote, Zyprexa, and Seroquel have demonstrated efficacy as maintenance treatments and are therefore reasonable to consider as first-line options (Yatham et al., 2018). Finally, the most common mood symptoms seen in rapid cycling are depression or a combination of depression and irritability. Unfortunately, antidepressants can contribute to cycle acceleration and rapid switches in mood. Thus, the use of antidepressants in rapid cycling is not recommended, at least not without caution.

Treatment Guidelines for Maintenance Treatment

As a general rule, if a patient has responded to a particular medication in the acute phase of treatment, treatment with that particular drug should be continued. Monotherapy is recommended, such as with Latuda, Caplyta, Vraylar, Seroquel, Lithium, or Lamictal. Seroquel appears to be particularly protective against relapse into depression (Yatham et al., 2018). Lithium is another good option for maintenance treatment in bipolar II disorder, which shows that it reduces the time spent in episodes of both hypomania and depression by over 50%, and is supported by guidelines internationally (Young et al., 2014).

Clinically, we see that when patients are feeling better after being stabilized, they tend to stop taking their medication. If medication is then discontinued, the acute relapse rate can be as high as 85%. Therefore, for a period of several months, medication treatment is typically continued. This phase of treatment is appropriately called maintenance treatment, in which a focus of treatment is on the prevention of recurrent episodes. Often, if a person has been receiving Lithium, the dose is gradually reduced (which often results in fewer side effects). The doses of other medications may also be reduced. However, such a decision is highly individualized and is influenced by a number of factors, including a person’s clinical history and the presence of particular side effects. Despite the fact that there have been decades of experience in treating bipolar illness, there are no good long-term studies on relapse prevention (the longest studies available only extend to about a year). Yet this is a lifelong illness, and all experts agree that lifelong treatment is required. It is important to know that most medications used to treat bipolar disorder do have side effects that may emerge with very long-term use, thus necessitating periodic lab tests to monitor blood and liver and kidney function. It is clear that failure to treat or adequately treat, bipolar disorder almost always leads to disaster.

During this period of treatment, psychoeducation on treatment adherence becomes essential in order to prevent another episode of mania, hypomania, or depression. Many people become concerned about the long-term use of medication and feel ashamed due to the stigma of being on medication. Patients must attend the follow-up visits with psychiatrists and report any side effects from medications. Psychiatrists can order lab tests and/or adjust medication dosage or change medications. Patients also need to see a therapist to learn coping skills and figure out the potential triggers for their mood changes. If it is possible, we need to involve patients’ family members who can help them comply with their medication treatment. Getting better and improving their functioning is a team effort.

Here is the truth – the pathway to recovery and good outcomes, more often than not, is complicated. The rule, not the exception, is that people will be tried on several, if not many, medications in the search for the right drug or medication combination. It is very important to help patients understand this so that they don’t conclude that the frequent changes in medications are necessarily a reason for concern. The fact is that bipolar disorder is challenging to treat and often requires a considerable amount of time systematically trying various medications before the right medication combinations are found. As mentioned earlier 90% of people being treated for bipolar disorder ultimately must take two or more medications at the same time to adequately treat their symptoms.

Other Adjunctive/Experimental Treatments for Bipolar Disorder

Bright light therapy Using a commercially available light box that generates 10,000 lux of light intensity for 10-30 minutes a day or going outside into natural sunlight without wearing sunglasses, has been used for treating bipolar depression, especially for those who routinely have winter depressions or who work the night shift. This treatment is typically combined with medication treatments and, like all treatments for depression, it too, carries a risk of provoking mania in some people with bipolar I disorder. Current studies indicate that light therapy is possibly useful in decreasing the severity of depression.

Exercise therapy has recently been shown to be effective in treating unipolar major depression, however, there are few studies of this approach in treating bipolar depression. Despite the lack of literature on exercise and physical activity in bipolar disorder, there is preliminary evidence that exercise may be a double-edged sword for patients with bipolar disorder due to its potentially polar-specific effect.(Wright et al. (2012).

Repetitive Transcranial Magnetic Stimulation (rTMS): TMS is approved by the FDA in 2008 to treat refractory depression.An electromagnetic coil is placed against the scalp of the patient’s head. This coil delivers magnetic pulses that stimulate nerve cells in the region of the brain involved in mood control and depression. It's thought to activate regions of the brain that have decreased activity during depression. Treatments generally last from 10 to 20 minutes during which an electromagnet is placed next to the left frontal part of the skull or the right frontal part or both sides. The treatment duration is Monday to Friday for 6 weeks. During the treatment, a train of magnetic pulses is delivered for many milliseconds to several seconds at a frequency of 1-25 Hz. This treatment causes virtually no side effects (the exception is that about 1.5% of people experience a seizure). There is no loss of consciousness. The literature on rTMS suggests that it is a rapid and effective treatment not only for some cases of severe depression, but also for people whose bipolar disorder is concurrently treated with mood stabilizers. This is a promising new approach, but it is still considered experimental and it has been approved for treatment-resistant depression only, not bipolar disorder.

Herbs and Supplements: Omega-3 Fatty Acids, dietary supplements that have some limited research support as effective agents in reducing the severity of bipolar mood swings (Stoll, et al., 1999). It should be noted that Omega-3 treatments appear to be more effective as an adjunct to the treatment of unipolar depression. Studies with bipolar disorder have been much less robust and remain equivocal. Other herbs and supplements reported to help minimize some symptoms of bipolar disorder include chromium, coenzyme Q-10, and alpha-lipoic acid.

Ketamine Therapy: Ketamine infusion has shown some promising signs to help bipolar disorder; it helps to improve anxiety, agitation, and irritability in bipolar patients. (McIntyre, et al., 2020). However, it is not FDA approved treatment for any mental illness yet.

Chronotherapy (targeting stabilization of the circadian rhythm): Partial sleep deprivation therapy (sleeping for four hours and then being awakened and kept awake until 9:00 pm) and dawn simulation (waking up at the same time each day) have been used for many years in Europe as an augmenting strategy aimed at stabilizing the circadian rhythm.

Other Issues

Pregnancy: If a patient with bipolar disorder is pregnant, she needs to see a psychiatrist who specializes in managing mood disorders during pregnancy. The common recommendations for management of bipolar disorder during pregnancy include avoiding medication, if possible, particularly during the first trimester, depending on the patient’s individual risk for recurrence, and, when medications are required, prescribing the lowest effective doses of monotherapy (Patorno, et al., 2013) (Medical Product Alert, 2023). Depakote cannot be used because it has a high risk of birth defects (including neurol tube defects). Lithium increases the risks of Ebstein anomaly 20-fold according to some studies, with particular risk conferred by lithium use during weeks two to six after conception (Merikangas et al.,2011). Lamictal and Latuda have carried low risks. ECT may also be indicated during the pregnancy if it is an emergent need.

Childhood-onset Bipolar Disorder: The treatment of childhood-onset bipolar disorder is beyond the scope of this CE course; however, a few brief comments will be made. At the outset, in must be acknowledged that there are not well-established guidelines for diagnosing pre-adolescent bipolar disorder. Mood instability is seen in many other disorders and some experts have commented that bipolar disorder in children is often misdiagnosed.

When mania occurs in pre-pubertal children, it most commonly presents as a form of mixed mania with rapid cycling and marked irritability. With adults, the general strategy is to begin treatment with one mood stabilizer and only later add additional medicines if they are needed. This is done with the intention of avoiding unnecessary side effects that occur when multiple drugs are prescribed. Obviously, there are compelling reasons for wanting to minimize side effects in children as well. However, preliminary research has rather strongly indicated that most children suffering from mania ultimately end up taking two or more mood stabilizers. This is required for most to effectively eliminate manic symptoms. Thus, there currently is a trend to begin treatment with children using two mood stabilizers (often this combination is Depakote and lithium). It is generally felt that the much higher success rate with two mood stabilizers outweighs the added side effects of using two drugs. In addition, it is felt that the earlier a lid can be put on mania and its development, the better – to do so matters not only in regard to the current episode but may also have a positive effect on reducing the severity of future episodes.

Lifestyle Management for Bipolar Disorder

People with bipolar illness have very unstable and fragile neurobiological mechanisms for affect regulation. Extreme emotional lability and mood episodes can be triggered by a number of environmental, psychological, and physiological stressors. It is especially important for the person to regulate their lifestyle closely – without this, medical treatments are often only partially effective (Malkoff-Schwartz, et al.,1998). Important concerns are:

Medications for Bipolar Disorder: Reference Guide

Note: To the best of my knowledge, doses and side effects listed below are accurate. However, this is meant as a general reference only and should not serve as a guideline for prescribing medications. Brand names are registered trademarks.

Mood Stabilizers

Lithium

Facts

Brand Names

Uses

Treats bipolar I disorder, acute manic/mixed, bipolar II disorder, maintenance treatment, and schizoaffective disorder (off-label)

Typical Adult Daily Doses

Eskalith or Lithobid are most commonly prescribed: 600-1,800 mg per day. Note: what matters with lithium treatment is not the dose, per se, but the blood level (which is carefully monitored). A lithium level between 0.8 and 1.2 mEq/L (mEq/L is the technical designation for what is commonly called the lithium level) is generally felt to be in the therapeutic range for treating mania. Once the manic episode is resolved, then it is common practice to lower the dose to establish a blood level somewhere between 0.6 and 0.8 mEq/L. Blood levels above 1.2 are associated with significant side effects, and levels above 2.0 can be dangerous.

Onset of Effects (how long it takes to start working)

Generally, 7-10 days

Laboratory Tests

Prior to starting treatment with some medications, laboratory tests are required to establish baseline measures of the functioning of certain bodily systems. The following are typically required prior to starting treatment:

ECG (EKG), electrolytes, complete blood count, kidney function tests (BUN, creatinine, urinalysis), thyroid tests, calcium, lipid profile, pregnancy test (for reproductive females)

Laboratory Tests Routinely Done on an Ongoing Basis

Those tests flagged above with an asterisk are repeated periodically. In addition, it is necessary to periodically check lithium blood levels. This is done frequently during the first weeks of treatment and when there are significant changes in dosage. Initial monitoring: Every one to two weeks until desired serum concentration is achieved, then every two to three months for the first six months. Stable monitoring is every 6 to 12 months.

Lithium can cause weight gain, so we need to monitor body mass index (BMI).

Common Side Effects

Less Common Side Effects (these should be reported to prescribing physician immediately)

Rare or Potentially Dangerous (if these occur, immediately contact prescribing physician)

Habit-forming / Addiction Potential

None

Interactions with Other Medications

Here are only the most common medications with which the drug may cause adverse interactions:

Safety During Pregnancy

A rare birth defect (Ebstein’s anomaly, a heart defect) if taken during the first trimester. This occurs in 0.1%-0.2% of fetuses exposed to lithium. If the patient is planning to get pregnant or suspects that she may be pregnant, contact the prescribing physician.

Breast-feeding

Not recommended when taking lithium

Special Concerns

Lithium is a very dangerous drug if taken in an accidental or intentional overdose. It is called “lithium toxicity” and is a life-threatening event, so seek immediate medical attention.

Anticonvulsant Mood Stabilizers

Facts

Anticonvulsants are medications originally developed to treat epilepsy. It was only by accident that it was discovered that some anticonvulsants also have the ability to treat mania. Despite the lack of evidence, we use Lamictal clinically for bipolar depression. Please note: Lamictal has failed clinical trials to treat bipolar depression and it has not been approved for bipolar depression by the FDA. Topamax can be used off-label for weight gain, and Neurontin for anxiety, and insomnia caused by other mood stabilizers.

Anticonvulsant Mood Stabilizers: Generic and Brand Names and Typical Adult Daily Doses

Generic Name

Brand Name

Brand Name

divalproex sodium

Depakote

750-1,500 mg

carbamazepine

Tegretol, Equetro

800-1,600 mg

oxcarbazepine (off-label)

Trileptal

600mg-1,200mg

lamotrigine

Lamictal

50-200 mg

Uses

Treatment of bipolar disorder and acute mania, except Lamictal does not have antimanic effects and rather is used to treat bipolar depression. Research evaluating the ability for anticonvulsants to help prevent recurrences of mania and bipolar depression is not yet conclusive. Depakote and Tegretol help to prevent recurrences of mania, and Lamictal reduces the recurrence of bipolar depression.

Therapeutic Blood Levels

Two of the anticonvulsant mood stabilizers must be periodically monitored to check the levels of medication present in blood

Depakote blood levels

50-125 mcg/ml

Tegretol blood levels

4-12 mcg/ml
Trileptal blood levels not yet established
Lamictal blood levels not necessary to monitor

Onset of Effects

Generally, 7-10 days (one exception: if high doses of Depakote are administered, the loading dosage is 50mg/kg, the effects can be seen in less than five days)

Laboratory Tests

Required for: Depakote, Tegretol, and Trileptal. Specific tests depend on which drug is used, but often include:

Complete blood count, platelets, electrolytes, cholesterol, triglycerides, sonogram of ovaries (optional for females under the age of 20 treated with Depakote), liver function tests, ECG (EKG), and pregnancy test. For Topamax, kidney function tests (BUN and creatinine).

Pretreatment labs are generally not required for Neurontin or Lamictal.

Laboratory Tests Routinely Done on an Ongoing Basis

Tegretol and Depakote blood levels must be monitored (especially during the initial weeks of treatment). Generally, once a person is stabilized on Depakote, blood level monitoring is not necessary. However, those treated with Tegretol must have periodic and ongoing monitoring of Tegretol levels.

Ongoing lab tests are generally not required for Lamictal.

Common Side Effects 

Each medication has specific side effects, however listed here are side effects that can be seen with most of the anticonvulsants:

Less Common Side Effects 

Rare or Potentially Dangerous Side Effects

If these occur, immediately contact prescribing physician:
Skin rash-mild rashes are fairly common, but a rash that is severe and rapidly increases in severity, especially with Lamictal or the combined use of Lamictal and Depakote, should be reported to the prescribing physician immediately. It can be a black box warning side effect called Stevens-Johnson syndrome, such rashes are extremely rare, but lethal. If the treatment employs a gradual dosing schedule, we can detect it earlier and stop medication right away to avoid this life-threatening side effect.

Confusion

Habit-forming / Addiction Potential

None

Interactions with Other Medicines (varies depending on the specific drug)

Safety During Pregnancy

There is a risk of birth defects when taking anticonvulsant mood stabilizers during pregnancy, especially in the first trimester; significant birth defects are seen most commonly in treatment with Depakote. Lamictal is a relatively safe medication during pregnancy.

Breast-feeding

Not recommended when taking anticonvulsants

Antipsychotic Medications

Facts

Antipsychotic medications were first developed to treat psychotic symptoms such as hallucinations and thought distortion, mainly for schizophrenia and schizoaffective disorder. The first such drugs were found to be effective in reducing psychotic symptoms, but they were notoriously “dirty” drugs, causing significant side effects. Since the mid-1990s, new and improved antipsychotics have been developed and marketed. These newer generation medications are not side effect-free, but they are considerably safer and better tolerated. The newer drugs are commonly referred to as atypical antipsychotics or second-generation antipsychotics (SGAs).

Although atypical antipsychotic medications are highly effective in treating psychotic symptoms, it has been found that they are also good treatments for mania and possibly for mood stabilization in general. They also have a role in treating aggression and agitation. Thus, these medications are currently being widely used to treat bipolar disorder even in individuals who have no psychotic symptoms.

Atypical Antipsychotic Medications: Generic and Brand Names and Typical Adult Daily Doses:

Generic Name

Brand Name

Typical Adult Daily Dose

olanzapine

Zyprexa

5-20 mg

risperidone

Risperdal

2-6 mg

quetiapine

Seroquel

200-800 mg for bipolar I disorder, manic and 300mg for bipolar depression

ziprasidone

Geodon

40-160 mg with food
aripiprazole Abilify 15-30 mg
asenapine Saphris 5-20 mg
lurasidone Latuda 20-120mg with food
cariprazine Vraylar 3-6 mg
lumateperone Caplyta 21-42mg

Another antipsychotic medication, Clozaril (brand name), clozapine (generic), is an important medication that can often successfully treat those people who have not responded to more traditional mood stabilizers and who have persistent suicidal thoughts. The typical adult daily doses for Clozaril are 300-900 mg.

First-generation antipsychotic medications, such as Haldol and Thorazine, have significant side effects (e.g., dry mouth, constipation, sedation, seizures, excessive salivation, blurred vision, nausea, heartburn, and weight gain) and have been associated with a serious blood disorder, agranulocytosis, which causes soreness of the mouth, throat, and gums and a high fever. Thus, it is never considered a first-line medication choice. However, despite the problematic side effects, we do use them for agitation management.

Please note that all of the following information regarding antipsychotics pertains to the atypical antipsychotics or SGAs (not Clozaril).

Uses

Treats mania and agitation, mixed features, rapid cycling, hypomania, and depression.

Onset of Effects

Antipsychotic medications are used to treat mania and can begin to reduce severe agitation within a few hours to a few days, however, the reduction of more pronounced manic symptoms is similar to that seen with other mood stabilizers such as lithium and anticonvulsants (7-10 days or longer).

Laboratory Tests

All SGAs can cause metabolic syndrome. Metabolic syndrome is a group of symptoms, such as overweight, high triglycerides and low HDL, high blood pressure and high sugar level which can increase the risks of developing heart disease, diabetes and other health problems. SGAs is one of the medication groups that can pose the risk of this syndrome. Therefore, periodic measures of blood glucose, triglycerides, cholesterol, weight, and body mass index (BMI) should be done at the beginning of treatment, every three to six months, and yearly afterward.

Common Side Effects for SGAs or Atypical Antipsychotics

Less Common Side Effects (these should be reported to prescribing physician)

Rare or Potentially Dangerous Side Effects (if these occur, patient should immediately contact prescribing physician)

Habit-forming / Addiction Potential

None

Interactions with Other Medications (varies depending on the specific drug)

Safety During Pregnancy

SGAs (atypical antipsychotics) are generally considered to be cautiously used during pregnancy.

Breast-feeding

Antipsychotic medications are secreted in breast milk. Since these are recently developed medications, there is inadequate information regarding safety for infants.

Special Concerns

Antidepressant Medications

Note: Not recommended in the treatment of bipolar disorder. The following list is offered simply as a general reference. They are Selective serotonin reuptake inhibitors (SSRIs), Serotonin and norepinephrine reuptake inhibitors (SNRIs), Norepinephrine and dopamine reuptake inhibitors (NDRI), Serotonin antagonist and reuptake inhibitor (SARI) and Noradnergic and specific serotonergic antidepressant (NaSSA) and Serotonin modulators.

New Generation Antidepressants: Generic and Brand Names and Typical Adult Daily Doses

Generic Name

Brand Name

Typical Adult Daily Dose

trazodone

Desyrel

50-400 mg

fluoxetine

Prozac

20-80 mg

bupropion

Wellbutrin XL/SR

100-450 mg

sertraline

Zoloft

50-200 mg

paroxetine

Paxil, Paxil CR

20-50 mg

venlafaxine

Effexor, Effexor XR

75-225 mg

nefazodone

Serzone

100-600 mg

fluvoxamine

Luvox

50-300 mg

mirtazapine

Remeron

15-45 mg

citalopram

Celexa

10-40mg

escitalopram

Lexapro

5-20 mg

duloxetine

Cymbalta

20-80 mg

desvenlafaxine

Pristiq

50-400 mg

vilazodone

Viibryd

10-40 mg

vortioxetine

Trintellix

5-20 mg

levomilnacipran

Fetzima

40-120 mg

Dextromethorphan/bupropion

Auvelity

45mg/105mg to 90mg/210mg

Antidepressants are effective in treating depression, anxiety, panic attacks, and obsessive-compulsive disorder (OCD).

Uses

Generalized anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), and major depressive disorder.

Onset of Effects

Generally, two to six weeks

Laboratory Tests

Not required

Common Side Effects

Rare Side Effects (if these occur, patient should immediately contact prescribing physician)

Habit-forming / Addiction Potential

None

Interactions with Other Medications (vary depending on the drug)

Safety During Pregnancy

Most experts agree that some new generation antidepressants are safe for use during pregnancy (e.g., Prozac, Zoloft, and Wellbutrin). Note: the following antidepressants have only recently come to market, and there is inadequate data to evaluate safety during pregnancy: Cymbalta, Strattera, Lexapro, Celexa, Serzone, Pristiq, and Remeron. High doses of Desyrel should not be used during pregnancy. In addition, recent data suggests that Paxil is less safe for use during pregnancy. If you want to know the safety of psychotropic medications used during the pregnancy, please check out: womensmentalhealth.org.

Breast-feeding

Antidepressants are secreted in breast milk, but the amounts are extremely low. Most experts agree that it is safe to breast feed while taking new generation antidepressants, however we need to use it with caution.

Special Concerns

If someone has been taking antidepressants for a period of six weeks or more and abruptly stops taking the medications, there can be withdrawal symptoms (this can occur with any of the antidepressants with the exception of Prozac due to its long half-life). Withdrawal symptoms include nausea, stomach upset, nervousness, flu-like symptoms, and a peculiar sensation described by patients as electrical shocks going through one’s head or extremities. Withdrawal symptoms are very unlikely if one has been taking the medication for less than six weeks. Moreover, withdrawal symptoms can be avoided almost 100% of the time by reducing the dose gradually over a period of several weeks.

Combination Drug: Symbyax (Prozac and Zyprexa) FDA approved for the treatment of bipolar depression. Common side effects are those seen with other SSRIs and Zyprexa (e.g., weight gain, increased risk of type II diabetes, hyperglycemia, and elevations in LDL cholesterol and triglycerides)

Benzodiazepines

Facts

Benzodiazepines are also commonly referred to as minor tranquilizers or anti-anxiety medications (anxiolytics).

Benzodiazepines: Generic and Brand Names and Typical Adult Daily Doses

Generic Name

Brand Name

Typical Adult Daily Dose

diazepam

Valium

5-10 mg

clonazepam

Klonopin

0.5-4.0 mg

lorazepam

Ativan

2-10 mg

Note: alprazolam (Xanax) can provoke mania in bipolar patients.

Benzodiazepine-like Z drugs Used for Sleep

Generic Name

Brand Name

Typical Adult Daily Dose

zolpidem

Ambien

5-10 mg

zaleplon

Sonata

5-10 mg

eszopiclone

Lunesta

1-3 mg

Note: There are two non-benzodiazepine prescription sleeping pills, suvorexant (Bellsomra,10 mg-20 mg) and ramelteon (Rozerem, 8 mg)

Uses

Treats acute anxiety and insomnia during episodes of mania. Also used as an adjunct treatment to treat anxiety disorders (such as panic disorder, social anxiety, and generalized anxiety disorder). In the treatment of mania, benzodiazepines are generally used only for the first few days of treatment to reduce agitation; only rarely are these drugs used beyond a couple of weeks.

Onset of Effects

30-60 minutes

Laboratory Tests

None required

Common Side Effects

Less Common Side Effects

Habit-forming / Addiction Potential

Significant risk for people with a prior personal or family history of alcoholism or other forms of serious drug abuse. Belsomra and Rozerem have a less habit-forming character.

Interactions with Other Medications

When taking benzodiazepines, any other type of medication that causes drowsiness or impaired alertness and reaction time can be potentially dangerous, especially if one has to drive an automobile. In addition, alcohol should not be consumed when taking benzodiazepines and/or sleeping pills.

Safety During Pregnancy

Benzodiazepines typically are not to be used during pregnancy, they can potentially cause facial clefts and cardiac malformation.

Breast-feeding

Benzodiazepines are secreted in breast milk and should not be used when breast-feeding.

Special Concerns

If benzodiazepines are being taken on a regular basis, the body develops a tolerance for the medication. When this happens, the drugs continue to work to reduce anxiety, but the problem when there is tolerance is that sudden cessation of the medication can lead to withdrawal symptoms. Withdrawal symptoms usually include nervousness, agitation, difficulty falling asleep, and on occasion can produce seizures. This needs to be taken very seriously. If a person has been taking a benzodiazepine on a daily basis for more than six weeks, and especially if the dose is moderate to high, withdrawal reactions are a very real risk. The patient should never abruptly stop taking the medication without first consulting with their doctor.

Calcium Channel Blockers

Calcium channel blockers are medications that are often used to treat certain cardiovascular diseases and hypertension. One of these drugs has been found to be effective in the treatment of mania in some studies, specifically for women, and possibly as a treatment to prevent the recurrence of mood episodes in a few studies. However, they are not approved by the FDA to treat bipolar disorders.

Generic Name

Brand Name

Typical Adult Daily Dose

verapamil

Calan SR

120 mg. given 3 or 4 times a day, thus total daily: 80-480 mg

nimodipine

Nimotop

Still considered to be experimental. Clinical doses are not yet well established.

Uses and General Considerations

For people who cannot tolerate lithium, for rapid cycling bipolar, or for use during pregnancy (verapamil is considered the safest mood stabilizing medication for the treatment of bipolar disorder during pregnancy). Like most other mood stabilizers, it generally takes 7-10 days to begin reducing symptoms.

One additional calcium channel blocker is used occasionally to treat mania – nimodipine (brand name: Nimotop). This medication looks promising in terms of efficacy; however, it is very expensive and to date, although there are positive case reports, there are no well-controlled studies, so they are not a standard of care.

Miscellaneous / Other Medications that are Occasionally Used to Treat Bipolar Disorder

The following medications are used less often in the treatment of bipolar disorder and thus will be discussed only briefly.

Omega-3 Fatty Acids

Approximately 60% of the human brain is composed of lipids (fats), and between 30% and 35% of brain mass is made up of omega-3 fatty acids. These molecules are important in forming cell membranes and synapses, and in facilitating nerve cell actions. The most abundant dietary sources of omega-3 fatty acids are fish and shellfish. In cross-cultural studies, it has been found that in countries where people eat a lot of fish and other seafood, the severity of mood disorders is less. This interesting finding led researchers to carefully evaluate the impact of diet on mood. During the past ten years, a number of studies have been conducted with people suffering from bipolar disorder and also with those with major depression. Preliminary findings suggest that adding omega-3 fatty acids to the diet can have a positive effect on reducing the severity of depression (unipolar depression), however, results in use with bipolar patients have been minimal at best. In all studies to date, omega-3 fatty acids have been added to traditional medications (i.e., antidepressants) and omega 3 derived from fish oil has greater bioavailability in the central nervous system than that derived from seed or nut oils.

Uses and General Considerations

Omega-3 fatty acids are not effective in treating severe episodes of mania or depression. However, their role appears to be in reducing the severity of episodes and possibly having a positive impact on preventing recurrences (evidence more strongly supports the use with unipolar depression and less positive effects have been seen with bipolar disorder). Studies have found that people treated with omega-3 fatty acids must take these dietary supplements on a daily basis and over a prolonged period (i.e., building this in to an ongoing diet). As noted above, the main sources of omega-3 fatty acids are fish and shellfish and presumably adding more fish to the diet may be a way to enrich levels of these molecules in the brain. However, all of the studies that have had positive results have used dietary supplement capsules (available from health food stores). There are three types of omega-3 fatty acids: LNA (derived from seed and nut oils, principally from flax seed oil), EPA, and DHA (both from fish oil). Most studies have demonstrated that EPA is the most effective type of omega-3 fatty acids used to treat bipolar disorder. The early studies used mega-doses of omega-3 (nine grams per day). However, it appears that much lower doses may be effective (for example, 500 mg. taken twice a day). There are also indications that what may also be involved is achieving a balance between omega-3 and omega-6 fatty acids (the main omega-6 is arachidonic acid). Unfortunately, dietary habits in the United States are notoriously poor, and lots of processed foods as well as snack and junk foods contain significant amounts of omega-6 fatty acids; especially due to the widespread use of corn oil in many processed foods that may throw things out of balance. Thus, a recommended strategy is to reduce sources of omega 6 and add omega-3 fatty acids. Omega-3 fatty acids (especially at lower doses) have few if any side effects and are well tolerated. High doses can cause gastrointestinal discomfort. The patient should talk with their prescribing physician about the possibility of adding omega-3 fatty acids to existing prescription medications (Stoll, et al., 1999).

Older Generation Antipsychotics

As noted above, newer generation antipsychotics have been developed during the past few decades. The newer drugs are considerably safer and have significantly fewer side effects than older-generation antipsychotic medications. We are simply mentioning these medications here just as a point of information since in rare instances, some people may be treated with these drugs (brand names): Thorazine, Mellaril, Serentil, Moban, Trilafon, Loxitane, Stelazine, Prolixin, Navane, Orap, and Haldol. Of these, the most common drugs that are still used these days are Haldol (often useful to initially treat very severe agitation seen in some types of mania) and Thorazine.

Anticholinergic Medications

This class of medications is used occasionally to combat side effects of some antipsychotic drugs (such as muscle rigidity or spasms, restlessness, and tremor). Again, we will only list these medications (brand names): Cogentin, and Artane. Anticholinergic drugs have their own set of side effects including constipation, blurred vision, dry mouth, difficulty beginning urination, and occasionally memory loss, confusion, and delirium.

Suggested Readings

Goodwin, F. K. & Jamison, K. R. (2007) Manic-depressive Illness. Oxford Press.

Preston, J. D., O'Neal, J., & Talaga, M. (2017) Handbook of Clinical Psychopharmacology for Therapists (8th Ed.). New Harbinger.

Diagnostic And Statistical Manual of Mental Disorders: DSM-5-TR, American Psychiatric Association.

References

American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

American Psychiatric Association (2022). Diagnostic and statistical manual of mental disorders (5th ed.). Text Revision.

Bauer, N., Alda, M., Priller, J., & Young, L. T. (2003). Implications of the neuroprotective effects of lithium for the treatment of bipolar and neuro-degenerative disorders. Pharmacopsychiatry, 36(3) S 50-254. doi: 10.1055/s-2003-45138

Bottern, K. N., Raichle, M. E., Drevets, W. C., Heath, A. C., & Todd, R. D. (2002). Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biological Psychiatry, 51(4), 324-344.

Bowden, C. L., & Singh, V. (2005) Long-term management of bipolar disorder. In T. Ketter (Ed.), Advances in the Treatment of Bipolar Disorder (p. 135), American Psychiatric Publishing, Inc.

Fountoulak,i K. N., Kontis, D., Gonda, X., & Yatham, L. (2013). A systematic review of the evidence on the treatment of rapid cycling bipolar disorder. Bipolar Disorders, Mar. 15(2), 115-37. doi: https://doi.org/10.1111/bdi.12045

Ghaemi, S. N., Lennox, M. S., & Baldessarini, R. J. (2001). Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. Journal of Clinical Psychiatry, 62(7), 565-569.

Gitlin, M. (2002). Depression Myths and Contrary Realities. Continuing Education Series, UCLA.

Goodwin, F. K. (2002). Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. Journal of Clinical Psychiatry, 63 (Suppl. 10), 5-12.

Harvard Medical School. National Comorbidity Survey (NSC). (2017, August 13).

Hirschfeld, R. M. A., Bowden, C. L., Perlis, R. H., et al. (2002). Practice Guideline for patients with Bipolar Disorder. American Journal of Psychiatry, 159, 1-50.

Jawad, M., et al. (2023). The role of ketamine in the treatment of bipolar depression: A scoping review. Brain Science Jun 4, 13(6):909.https://pubmed.ncbi.nlm.nih.gov/37371387/

Judd, L., Akiskal, H. S., Schettler, P. J., Endicott, J., Maser, J., Solomon, D., et al. (2002). The long-term natural history of the weekly symptomatic status of bipolar I disorder. Archives of General Psychiatry, 59, 530-537.

Malkoff-Schwartz, S., Frank, E., Anderson, B., Sherrill, J. T., Siegel, L., Patterson, D., et al. (1998). Stressful life events and social rhythm disruption in the onset of manic-depressive bipolar episodes: A preliminary investigation. Archives of General Psychiatry, 55, 702-707.

McIntyre, et al. (2020) Bipolar disorders; The Lancet. 22:8310.

Medical product alert, (2023). Statement on the risks associated with use of valproic acid (sodium valproate) in women and girls of childbearing potential. World Health Organization, May 2.

Medina, J. (2003). Lithium and neural interiors. Psychiatric Times, October, 86-89.

Medina, J. (2003). Intracellular signaling and mood stabilizers. Psychiatric Times, November, 32-34.

Merikangas, K. (2011). Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative. Archives of General Psychiatry, 68:241.

National Institute for Health and Care Excellence (2020). Bipolar disorder: assessment and management. www.nice.org.uk/guidance/cq185.

https://www.nice.org.uk/guidance/indevelopment/gid-ng10380

Patorno, E, Huybrechts, K. F., Bateman, B. T., et al. (2017) Lithium use in pregnancy and the risk of cardiac malformations. New England Journal of Medicine June 8; 376(23) 2245-54.

Pope, M., & Scott, J. (2003). Do clinicians understand why individuals stop taking lithium? Journal of Affective Disorders, 74, 287-291.

Post, R. M., Altshuler, L. L., Frye, M. A., Suppes, T., Rush, A. J., Keck, P. E., et al. (2001). Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disorders, 3, 259-265.

Preston, J. D., O'Neal, J., & Talaga, M. (2017). Handbook of Clinical Psychopharmacology for Therapists (8th ed.) New Harbinger Publications.

Stern, T., Herman, J, & Rubin, D. (2021). Massachusetts General Hospital Psychiatry Update & Board Preparation (4th ed.).

Stoll, A. L., Severus, W. E., Freeman, M. P., Reiter, S., Zboyan, H. A., Diamond, E., et al. (1999). Omega 3 fatty acids in bipolar disorder. A preliminary double-blind, placebo-controlled trial. Archives of General Psychiatry, 56, 407-412.

Suppes, T., Webb, A., Paul, B., Carmody, T., Kraemer, H., & Rush, A. J. (1999). Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment- resistant illness and a history of mania. American Journal of Psychiatry, 156, 1164-1169.

Swann, A. C., Bowden, C. L., Calabrese, J. R., Dilsaver, S. C., & Morris, D. D. (1999). Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. American Journal of Psychiatry, 156, 1264-1266.

Williams, R. S., Cheng, L., Mudge, A. W. & Harwood, A. J. (2002). A common mechanism of action for three mood-stabilizing drugs. Nature, 417, 292-295.

Wright, K., Armstrong, T., Taylor, A., & Dean, S. (2012). “It’s a double-edged sword”: a qualitative analysis of the experiences of exercise amongst people with Bipolar Disorder. Journal of Affective Disorders, 136, 634–642.

Yatham, L. N., Kennedy, S. H., Parikh S., et al. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patient with bipolar disorder. Bipolar Disorders. 20(2), 97-170.

Young, A.H., McElroy, S.L., Olausson, B, et al. (2014). A randomized, placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder. World Journal of Biological Psychiatry 15(2):96-112.

Resources for Families and for Patients with Bipolar Disorder

Miklowitz, D J. (2010). The Bipolar Disorder Survival Guide. Guilford Press

Fast, J. & Preston, J. (2012). Loving Someone with Bipolar Disorder: How to Help and Understand Your Partner (2nd Ed.). New Harbinger Publications.

Fast, J. & Preston, J. (2006). Taking Charge of Bipolar Disorder. Warner Books

 

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