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

2 CE Hours - $29

Last revised: 03/06/2018

Course content © copyright 2004-2018 by John Preston, Psy.D., ABPP All rights reserved.


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Learning Objectives

This is a beginning to 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. 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(e.g. offered by the American Psychiatric Association, and other groups), as of the current update, are significantly outdated. The material in this course is derived from such guidelines, but 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.

Introduction

Bipolar disorder is a common type of mood disorder affecting between 3.5-6% of the population (lifetime prevalence: Akiskal, et al. 2000). Previously, it was thought that the lifetime prevalence was 1-1.5% of the population; however, more recent epidemiological studies and new, refined diagnostic criteria have revealed the larger prevalence rate. 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. Bipolar disorders are a group of genetically transmitted illnesses that result in recurring episodes of depression and mania or hypomania (see below). This is a lifelong disorder that requires ongoing medical treatment. Mood-stabilizing medications can effectively reduce episode severity and frequency. Nevertheless, there is currently no cure for bipolar disorders.

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. Brand names are registered trademarks.

Diagnostic Issues

In adolescents and adults 60-70% of manic episodes are classic manias (i.e. euphoric mania). 30-40% are referred to as dysphoric or mixed mania (mania with mixed features: DSM-5).

Symptoms of Classic Mania

Symptoms of Mania with Mixed features

Hypomania is a milder version of mania that typically involves much less intense mood symptoms. The duration of hypomania is often only 2-4 days, (although it may last for longer periods of time) and is frequently not noticed as being a sign of illness by the person experiencing hypomania (although, in most cases, family members are more clearly aware of the mood changes and increased energy). During some hypomanias the person can feel highly motivated and productive, is witty, gregarious and “upbeat” (although there is often underlying irritability). One very common sign of hypomania is a decreased need for sleep with no daytime fatigue. DSM-5 requires a minimum of 4 days of hypomania to diagnose bipolar II disorder; however, the most common presentation of hypomanias is 2-3 days (Goodwin and Jamison, 2007). DSM-5 has a new category: Depressive Episodes with Short-duration Hypomania (requiring 2-3 days of hypomania). Experts working on the development of DSM-5 disagreed on the criterion for Bipolar II hypomania duration. For practical purposes, Bipolar II and Depressive Episodes with Short-duration Hypomanias can be seen as simply two versions of the same disorder.

There are five subtypes of bipolar disorder:

(Note: ICD: International Classification Diseases, does not use the terms Bipolar I or II. Rather, they have adopted terms: bipolar disorder current episode mania, bipolar disorders current episode mixed, bipolar disorder current episode mixed, and so forth. Most research studies and treatment guidelines still refer to the DSM nomenclature, [i.e., Bipolar I and Bipolar II]. DSM-5 terms are presented here because they are more familiar).

A complication of bipolar disorder affecting about 20% of suffers is called rapid cycling. This represents a time-limited worsening of the illness in which episodes occur with greater frequency (i.e., 4 or more episodes of depression, mania, or hypomania per year). 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/abuse. Rapid cycling has also been attributed to the use of antidepressants by bipolar patients. Antidepressants, as will be discussed shortly, are medications that 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.

Untreated or poorly treated bipolar illness leads to disaster. Careers and marriages are ruined, physical health problems abound, and there is a high rate of suicide (19-20% lifetime risk). If not treated, most cases of bipolar disorder become progressively worse, likely owing to kindling effects. The sooner this illness can be diagnosed and properly treated, the better.

Treatment must have a two-pronged focus: bringing to an end the current manic or depressive episode and relapse prevention. With proper medical treatment, most people can experience a marked decrease in episode frequency and severity.

Lifestyle Management

People with bipolar illness have very unstable and fragile neurobiologic 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 her lifestyle closely – without this, medical treatments are often only partially effective (Malkoff-Schwartz, et al. 1998). Important concerns are:

Medication Treatments: General Considerations

General references:

  1. Texas Department of Mental Health (2007) Texas Medication Algorithm Project: Bipolar Disorder Algorithms
  2. Ketter, T.A. (Editor) (2005) Advances in the Treatment of Bipolar Disorder: Washington, D.C.: American Psychiatric Publishing, Inc.
  3. National Institute of Mental Health (2006) STEP-BD Program
  4. Goodwin, F.K. and Jamison, K.R. (2007) Manic-Depressive Illness: Second Edition. Oxford: Oxford University Press.
  5. American Psychiatric Association: (2002) Bipolar Disorder Practice Guidelines: Second Edition.

Please note that official treatment guidelines listed above are dated. Updates are in progress. 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, the medication choice always must take into consideration the ultimate goal of preventing recurrences.

Currently, there are fourteen medications that are approved by the Food and Drug Administration (FDA) for the treatment of bipolar disorder: lithium, Thorazine, Depakote, Equetro, Lamictal, Symbyax, Risperdal, Seroquel, Geodon, Abilify, Latuda, Saphris, Rexulti, Vraylar, and Zyprexa. However, a number of other effective drugs are in common use. 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.

Recent surveys reveal that, in the United States, only 11% of people being treated for bipolar disorder are taking just a single drug (mono-therapy); 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 mono-therapy 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, often they are 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 certain 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 understandable: 1) the patients is plagued by unpleasant side effects and/or, 2) it’s the negative stigma associated with having a psychiatric condition, and/or 3) the person suffering from bipolar disorder concludes that the episode he experienced is not really bipolar disorder, but was just a single episode and that there will be no recurrence. This conclusion is borne of hopefulness that this is not really going to be a recurring illness (Pope and Scott, 2003). These reasons for discontinuing the medication are entirely understandable, but they almost invariably lead to the emergence of another episode (this 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. During mood episodes, there are often toxic levels of certain neurotransmitters (e.g. glutamate) and stress hormones (e.g. cortisol) that are released that 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 (e.g. lithium, Seroquel, Lamictal, and Depakote) appear to be “neuro-protective.”

Many side effects can be managed by dosage adjustments or by switching to other medications. This is one reason that most times 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 for the individual. Every effort should be made to find the right medication or medication combinations in an attempt to minimize side effects. Moreover, this is often something that can be accomplished. However, it is frequently the case that it takes 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 to not feel too discouraged if the first medications used are less than optimally effective or that there are problematic side effects. A sign of a competent and compassionate psychiatrist is her willingness to be persistent in carrying out systematic medication trials until the best treatment is finally identified. Sometimes side effects can be minimized; however, many people 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.

Medication Treatments: What are Realistic Outcomes?

Bipolar disorder is like a number of other chronic medical conditions (such as diabetes, asthma, arthritis). It is not a condition that can be cured by currently available medications. However, the medications discussed below are 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, and if the treatment is started during the first or second mood episode, about 30% of people will not experience recurrences. That is, in about one out of four people the medications are successful in preventing relapses (please note that if the first appropriate medical treatments begin after the second episode, typically treatment becomes somewhat more challenging and the outcomes are not quite as robust). However, for the majority of other 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, C.L. and 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

There are seven major classes of psychiatric medications that have been found to be effective in treating various symptoms of bipolar disorder. Generic and brand names (registered trademarks) are listed below.

Lithium: Eskalith, Lithonate

Anticonvulsants mood stabilizers:

Generic name

Brand Name

divalproex

Depakote

carbamazepine

Tegretol; Equetro

oxcarbazepine

Trileptal

lamotrigine

Lamictal

Second-Generation Antipsychotics (SGA)…also often referred to as: Atypical Antipsychotics (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

papliperidone Invega
iloperidone Fanapt
asenapine Saphris
lurasidone Latuda
brexpiprazole Rexulti
cariprazine Vraylar

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

Calcium Channel Blockers (FDA-approved to treat hypertension; can be used off label to augment other bipolar medications):

Generic name

Brand Name

verapamil

Calan, Isoptin

nimodipine Nimotop

Benzodiazepines (also referred to as minor tranquilizers or anti-anxiety drugs; only those in most common use are listed):

Generic name

Brand Name

diazepam

Valium

clonazepam

Klonopin

lorazepam

Ativan

alprazolam

Xanax

Sleeping Pills:

Generic name

Brand Name

temazepam

Restoril

triazolam

Halcion

zolpidem

Ambien

zaleplon

Sonata

eszopiclone

Lunesta

ramelteon

Rozerem

suvorexant Belsomra

In addition, antidepressant medications are often used in treating bipolar disorders. However, their use often results in ineffective outcomes or the provoking of significant emergent symptoms (e.g. provoking mania). In this course we will look at the controversies and risks of using antidepressants. Currently, even though they are often prescribed, the current thinking is that they should rarely be used and only in treatment resistant cases. There is a general lack of knowledge that antidepressants are ineffective and can cause significant problems. There are a number of other medications that are used occasionally, including some experimental drugs (e.g. Omega-3 fatty acids) and Topamax (to help reduce weight gain; note: Topamax does not appear to be an effective antimanic). This CE 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.

Targets for Medication Treatment

There are three primary goals in medication treatment of bipolar disorder: dealing with potentially dangerous emergency issues (e.g. extremely severe agitation or suicidal impulses), resolving the current episode (mania or depression), and relapse prevention. The choice of medications used will always be influenced by these goals. In addition, of course, the medication choice will also be dictated by the need to minimize side effects.

Getting Started with Medication Treatment: Emergency Medication 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 (which may include extreme restlessness, impulsivity, severely impaired judgment, and/or aggression) or serious suicidal impulses during a depression or dysphoric manic episodes. At such times, acute medical treatment may be necessary.

Emergency medical treatments for agitation include the use of either benzodiazepines (anti-anxiety tranquilizers, such as Ativan, Klonopin, and Valium) or antipsychotic medications (such as Zyprexa, Risperdal, Geodon, Abilify, Haldol, or Seroquel). 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 (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 treatments) can be used successfully. ECT is also very effective for the emergency treatment of severe mania.

If the situation is not extremely urgent, then it is commonplace to order some pre-treatment laboratory tests. 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 functioning, 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 2400 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).

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 he is 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. 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, she will experience serious side effects that may be due to 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 she is a hypo-metabolizer, so initial dosing is done gradually.

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.

Caution The use of Tegretol, Trileptal, Topamax, 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

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

Anticonvulsants:

Antipsychotic medications:

Calcium Channel Blockers:

Benzodiazepines (minor tranquilizers):

There are three stages in the medical treatment of mania:

  1. Reduce extreme agitation (the goal is to get agitation under control within a few hours). Severe agitation can be dangerous to the patient as well as to others around them, so this must be addressed as soon as possible.
  2. Reduce core manic symptoms such as restlessness, sleeplessness, rapid speech, paranoid ideas, etc.
  3. Begin treatment for relapse prevention.

Stage One: As mentioned above, antipsychotic medications and benzodiazepines (with the one exception of Xanax which can aggravate mania) are the best medications for treating acute agitation; they quickly produce substantial sedation, calming, or sleep. It is important to note that, although antipsychotic medications do successfully treat psychotic symptoms (such as hallucinations), the more recently developed drugs (i.e., atypical or second generation antipsychotics) have also been found to be effective mood stabilizers and are commonly used to treat mania. Most mood stabilizers require the 7-10 day period before symptom reduction, with one notable exception – the anticonvulsant mood stabilizer, Depakote, when given in large doses, can begin to show anti-manic effects in about 4 days. Once severe agitation has subsided, benzodiazepines are often gradually reduced and, within a few days, are discontinued. This may also be true for antipsychotic medications. However, there are times when antipsychotic drugs may continue to be used for a more prolonged period.

During stage one of treatment, as mentioned above, a number of lab tests are frequently done to monitor the early effects of the drugs.

Stage Two: The choice of medications used to treat core symptoms of mania is important and often complex. As noted above, there are several different types 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 him 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.

Patients must anticipate that it is extremely common for psychiatrists to make initial medication choices, begin treatment, and then during the following weeks or months make what are often frequent changes in the doses or medications prescribed. There is an important reason for emphasizing this. Many times people being treated for bipolar illness, or their family members, become worried as they begin to encounter side effects, or they must go through what seems like an endless number of lab tests or changes in medications or medication doses. Many people become concerned that these medication changes suggest that their doctor may not be competent or that their case of bipolar is especially treatment-resistant. This can lead to discouragement and feelings of pessimism. 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 combinations. It is so 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 medications combinations are found.

“Classic Mania” (with euphoria, expansiveness, upbeat mood, occasional irritability, etc.) has been found to respond best to treatment with lithium or Depakote (other anticonvulsant mood stabilizers or atypical antipsychotic medications often can treat classic mania, but in head-to-head comparisons, lithium and Depakote appear to be the best first-line medications for this type of mania). Generally, during stage two of treatment, especially if this is a person’s first episode of mania, just one of these medications will be prescribed. Assuming that the medication is tolerated (i.e., that side effects are mild or manageable), treatment will continue for a period of several weeks. 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 mania. Thus, it is possible that the one medicine initially prescribed may be tolerated and may eventually be effective. Decisions to increase the dose or to change or add another medication in the ensuing weeks will depend on tolerability and effectiveness. Since there are always possible drug-drug interactions, the generally recommended approach is to first optimize treatment with one medication (which means to progressively increase the dose while always being watchful for the emergence of side effects). What is hoped for is that the first signs of symptomatic change will occur during the initial 7-10 days, and that symptomatic improvement will continue to unfold over the next few weeks. Just how long it takes to fully resolve a manic episode varies from one individual to another. It should be noted that a current trend is to initiate treatment with one mood stabilizer, and then relatively soon add a second antimanic agent (e.g. lithium and a second generation antipsychotic) since it has been found that the use of two agents is often more effective and since this combination treatment can involve lower doses of each medication, there are often actually fewer side effects.

Should side effects be significant, there will typically be either a dosage adjustment or possibly a change to another medication. If side effects are mild to moderate and tolerable, but there is only partial improvement in symptoms after several weeks of treatment, then a decision will be made to either change to a different medication or to add another medication (the addition of medications is commonly referred to as augmentation). Medications typically used for augmentation include anticonvulsant mood stabilizers and/or antipsychotic medications.

Mania with Mixed Features: (agitation, decreased need for sleep, rapid speech, feelings of despair, hopelessness, etc.). There is some controversy regarding the treatment of mixed mania. However, most experts agree that the best first-line medication is Depakote. Many people experiencing mixed mania do have positive responses to lithium as a mono-therapy. Again, the use of just one medication initially is the typical strategy, and before adding or changing medications, the drug used will be optimized. As in the treatment of classic mania, we are looking for the first signs of improvement within the first 7-10 days.

If after several weeks of treatment, and if increased doses of the medication yield only partial symptomatic improvement, then augmentation can be used. Often the first augmentation strategy is to combine Depakote and lithium. If other medications are required, then the addition of the following are commonly prescribed: the anticonvulsants Tegretol, or Trileptal. The anticonvulsant, Neurontin, has been found to be ineffective as a mono-therapy, but it is often used as an augmenting agent, and is especially helpful in reducing anxiety. Other choices include atypical antipsychotics, also known as SGAs.

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.

Rapid Cycling

As mentioned above, rapid cycling generally is a period of time lasting anywhere from a few months to a year or year-and-a-half where there is a significant increase in the frequency and (often) severity of mood episodes. In only about 2% of people is rapid cycling 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, stimulants), or disorders of the thyroid gland. Thus, it is very important to determine whether any of these factors is present, and take appropriate action to ameliorate them. Special attention must be taken to stabilize the patient’s lifestyle, especially making sure that there is regularity to sleep patterns and making every attempt to reduce or avoid sleep deprivation (e.g. establishing regular bed and awakening times; completely avoiding sleep-destroying substances such as caffeine, alcohol and decongestants; no all-nighters cramming for exams; no late night partying).

Beyond these approaches, the following medication strategies have been found to be helpful. Preferred mood stabilizers include Lamictal, Depakote, and Tegretol. Atypical antipsychotic medications are also frequently prescribed. 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 indicated.

Treatment-Resistant Mania

For people that 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 (e.g. for treating hallucinations, delusions). It also is proving to be effective for treating not only mania but for relapse prevention. Unfortunately, Clozaril is plagued by numerous, significant side effects, some of which are potentially dangerous. 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 only a few days and a few treatments, when 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. The preferred strategy is to give ECT while also administering mood-stabilizing medications; the drugs help to prevent acute relapse.

ECT is 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.

Stage Three: Relapse prevention

Once the current manic episode is completely controlled, it is common practice to continue medications, even though there are no obvious symptoms. This is necessary because it is clear that once symptoms subside, 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, often at the same doses used during treatment of the acute phase of the episode. This phase of treatment is appropriately called continuation treatment. After several months, assuming there have been no “breakthrough” symptoms, then the next stage of treatment – maintenance treatment – begins. Here, the 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 individual and is influenced by a number of factors including a person’s clinical history and the presence of particular side effects.

In general, the medications used to treat mania are considered very effective for most people experiencing a manic episode (note: this is true for bipolar mania seen in patients who have a late adolescent or adult-onset illness. Mania in pre-pubertal children is significantly more difficult to treat). However, the more long-term goal of preventing recurrences is more challenging. 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 various glandular and organ system functioning. It is clear that failure to treat (or to adequately treat) bipolar disorder almost always leads to disaster.

The medications for which the best data exist for long-term maintenance treatment are the following mood-stabilizers: lithium (the best data), Depakote, Tegretol, and Zyprexa. Most people on maintenance treatment will continue to take several medications. However, longer-term treatments generally do not include treatment with benzodiazepines.

Treatment Guidelines: Bipolar Depression

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

The combination drug, Symbyax (Prozac and Zyprexa), is FDA approved for the treatment of bipolar depression.

The anticonvulsant, Lamictal, has antidepressant actions and is FDA approved for preventing recurrence of bipolar depression.

The atypical antipsychotics (SGAs), Seroquel, Abilify, and Latuda, have antidepressant actions.

Monoamine Oxidase Inhibitors (MAOIs), though rarely used, this is the one class of antidepressants that appears to have some efficacy in treating 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 and 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.

There are also three stages in the treatment of bipolar depression.

Stage One: In the event of life threatening symptoms such as strong suicidal impulses or refusal to eat, ECT is a highly effective treatment. The treatment approach is much the same as used to treat acute mania (see previous box titled ECT: Electro-Convulsive Therapy). The other emergency treatment is hospitalization. Unfortunately, aside from ECT most approaches to treating depression require several weeks before one is likely to see symptomatic improvement.

Stage Two: Start with a medication that has been found to have antidepressant actions. The five drugs that have the best track record of effectiveness are lithium, Seroquel, Latuda, Symbyax and Lamictal (however, there is an important consideration when using Lamictal – once treatment is begun, it is required that Lamictal be given in small doses and that dosage changes are done very gradually during the first 4-6 weeks of treatment. This is to avoid inducing a potentially dangerous rash [Stevens-Johnson syndrome] that is more common if there is rapid dose escalation. Since this more gradual titration schedule has been developed, the incidence of serious rashes has been extremely low; it should be noted that the use of Lamictal in pre-adolescent children still carries a risk of Stevens-Johnson syndrome). Of these five choices, Seroquel appears to be the most effective, first-line medication choice.

If treatment with one of these medications has not been successful or there is a partial response then there are several options:

  1. Combine Lamictal, Symbyax, Latuda, and/or Seroquel
  2. Add lithium. Lithium generally is not a first-line medication choice for bipolar depression. It is often effective, but it requires significant laboratory monitoring and thus is more difficult to manage. Additionally, even though lithium has been shown to significantly reduce suicide (with chronic use), during the initial phase of treatment when a person may be feeling suicidal, lithium can be very dangerous owing to its high level of toxicity (e.g. if taken in even small over-doses, it is often fatal). Thus, lithium may make sense as an add-on drug once the patient is recovered enough to be judged to have a low risk of suicide.
  3. ECT

The addition of an antidepressant to treatment resistant Bipolar II patients can at times be beneficial (when combined with a mood stabilizer). This almost never should be the first line treatment, but only if other treatments fail. However, the use of antidepressant augmentation for the treatment of Bipolar I is not indicated.

Adjunctive Therapies:

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.

Exercise therapy has recently been shown to be effective in treating unipolar major depression, however, there are no studies of this approach in treating bipolar depression.

Stage Three: This is much the same as stage three treatments for mania. Among the mood stabilizers that have the best record of effectiveness in the prevention of depressive episodes, Lamictal appears to be the front-runner.

Experimental treatments

There are three experimental treatments under investigation:

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 equivocal.

Repetitive Trans-Cranial Magnetic Stimulation (rTMS): a technology that uses a powerful electromagnet, which is able to stimulate the brain. Treatments generally last from 10-20 minutes during which an electromagnet is placed next to the left frontal part of the skull. During the treatment, approximately 1,000 surges of powerful magnetic energy are delivered, penetrating the skull and affecting metabolic functioning in the brain tissue in the underlying left frontal lobe. 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. Like ECT, treatments are given three times a week for 3-4 weeks. The literature on rTMS suggests that it is a rapid and effective treatment for some cases of severe depression. As with ECT, acute relapses do occur after the rTMS treatments stop so people are concurrently treated with mood stabilizers or antidepressants to avoid relapse. This is a promising new approach, but it is still considered experimental.

Vagus Nerve Stimulation: a technique that was initially developed to treat some forms of severe epilepsy, it has been found to be effective in successfully treating about 50-60% of people who suffer from highly treatment-resistant depressions. A pacemaker-like device is implanted in the chest wall (beneath the collarbone) and a wire extends up into the neck where it is wrapped around the vagus nerve. Periodically, a mild electrical stimulation is delivered to the vagus nerve, which causes nerve activity that enters the brain. This also appears to be a promising new treatment for some cases of severe depression, but as yet, it has not been studied for use in treating bipolar disorder.

Chronotherapy (targeting stabilization of the circadian rhythm): Partial sleep deprivation therapy (sleeping for 4 hours and then 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.

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 mania, bipolar depression, and to reduce recurrences of mania and depression

Typical Adult Daily Doses (Eskalith or Lithonate are most commonly prescribed): 600-2400 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*, pregnancy test (optional).

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. Once a person is stabilized on lithium for several months, lithium levels will then be checked less often (e.g. 3-4 times a year).

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: Lithium is generally considered to be safe for use during pregnancy, however there is a slight risk for 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 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. In the event of an overdose, 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. The anticonvulsant Lamictal is used to treat rapid cycling and bipolar depression. Please note: Lamictal, if used as a monotherapy, may provoke mania in Bipolar I patients.

Anticonvulsant Mood Stabilizers: Generic and Brand Names and typical adult daily doses.

Generic name

Brand Name

Typical Adult Daily Dose

divalproex

Depakote

750- 1500 mg

carbamazepine

Tegretol, Equetro

600-1600 mg

oxcarbazepine

Trileptal

1200-2400 mg

lamotrigine

Lamictal

50-200 mg

Uses: treatment of mania. 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, effects can be seen in four 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), 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, Depakote, and Trileptal blood levels must be monitored (especially during the initial weeks of treatment). Generally, once a person is stabilized on Depakote or Trileptal, blood level monitoring is not necessary. However, those treated with Tegretol must have periodic and ongoing monitoring of Tegretol levels.

Ongoing lab test 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 in most of the anticonvulsants).

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

Infertility problems (seen with some women under the age of 20 treated with Depakote), accompanied by menstrual irregularities.

Rare or potentially dangerous (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. Such rashes are extremely rare if the treatment employs a gradual dosing schedule)

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 seen most commonly in treatment with Depakote). Most psychiatrists do not prescribe these medications during pregnancy.

Breast feeding: not recommended when taking anticonvulsants

Antipsychotic Medications

Facts:

Antipsychotic medications were first developed to treat psychotic symptoms such as hallucinations. 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.

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. Thus, these medications are currently being widely used to treat BD 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

4-10 mg

quetiapine

Seroquel

150-400 mg

ziprasidone

Geodon

60-160 mg

aripiprazole

Abilify

15-30 mg

paliperidone Invega 3-12 mg
iloperidone Fanapt 12-24 mg
asenapine Saphris 10-20 mg
lurasidone Latuda 40-80 mg
brexpiprazole Rexulti 1-4 mg
cariprazine Vraylar 1.5-6 mg

Another antipsychotic medication that is used occasionally is clozapine (generic), Clozaril (brand name).

This older-generation antipsychotic medication has significant side effects (e.g. dry mouth, constipation, sedation, seizures, excessive salivation, blurred vision, nausea, heartburn and weight gain) and has 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, Clozaril is an important medication that can often successfully treat those rare people who have not responded to more traditional mood stabilizers. The typical adult daily doses for Clozaril are 300-900 mg.

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

Uses: treat mania and agitation; treat psychotic symptoms associated with both manic and depressive episodes and schizophrenia. The effectiveness of antipsychotic medications in the long-term prevention of recurrences is as yet inconclusive.

Onset of effects: Antipsychotic medications 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: periodic measures of blood glucose, triglycerides, cholesterol, weight, and body mass index should be done with all of the newer antipsychotics.

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 safe during pregnancy

Breast-feeding: antipsychotic medications are secreted in breast milk. Since these are recently developed medications, there is inadequate information regarding safety to infants.

Special Concerns:

Antidepressant Medications

Note: Not recommended in the treatment of bipolar disorder. The following list is offered simply as a general reference.

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, Sarafem

20-80 mg

bupropion

Wellbutrin

150-400 mg

sertraline

Zoloft

50-200 mg

paroxetine

Paxil, Pexeva

20-50 mg

venlafaxine

Effexor

75-350 mg

nefazadone

Serzone

100-500 mg

fluvoxamine

Luvox

50-300 mg

mirtazapine

Remeron

15-45 mg

citalopram

Celexa

10-60 mg

escitalopram

Lexapro

5-20 mg

duloxetine

Cymbalta

20-80 mg

atomoxepine

Strattera

60-120 mg

desvenlafaxine

Pristiq

50-400 mg

vilazodone Viibryd 10-40 mg

vortioxetine

Trintellix

10-20 mg

levomilnacipran Fetzima 40-120 mg

Antidepressants (all except Wellbutrin) are effective in treating severe anxiety, panic attacks, and obsessive-compulsive disorder (OCD).

Uses: anxiety, obsessive-compulsive disorder (OCD), and unipolar depression

Onset of Effects: generally 2-6 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, Effexor, Wellbutrin, and Luvox). Note: the following antidepressants have been only recently come to market, and there is inadequate data to evaluate safety during pregnancy: Vestra, 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 not safe for use during pregnancy.

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.

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). 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.

Benzodiazepines: Generic and Brand Names and Typical Adult Daily Doses:

Generic name

Brand Name

Typical Adult Daily Dose

diazepam

Valium

4-30 mg

clonazepam

Klonopin

0.5-2.0 mg

lorazepam

Ativan

2-6 mg

alprazolam

Xanax

1-4 mg

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

Benzodiazepine and benzodiazepine-like used for sleep: Typical Adult Nighttime Doses:

Generic name

Brand Name

Typical Adult Daily Dose

temazepam

Restoril

15-30 mg

triazolam

Halcion

0.25-0.5 mg

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, 15-40 mg) and ramelteon (Rozerem, 4-16 mg)

Uses: treats acute anxiety, agitation, and insomnia during episodes of mania. Also used 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. The use of Xanax during manic episodes should be avoided (may increase manic symptoms).

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. Rozerem is non-habit forming. At the time of this printing Belsomra is still being evaluated for the potential of being habit-forming).

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.

Safety During Pregnancy: Benzodiazepines typically are not to be used during pregnancy.

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 to sleep, 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 6 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 his doctor. It is also a good idea to be especially careful to monitor his supply of the medications so that refills can be requested in a timely fashion. Many people find it helpful to keep at least a two-day supply on hand in the event that it takes longer than usual for a prescription to be refilled.

Calcium Channel Blockers

Calcium channel blockers are medications that are often used to treat certain cardiovascular diseases. One of these drugs has been found to be effective in the treatment of mania, and possibly as a treatment to prevent the recurrence of mood episodes.

Generic name

Brand Name

Typical Adult Daily Dose

verapamil

Calan, Isoptin

120 mg. given 3 or 4 times a day, thus total daily: 360-480 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.

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 briefly.

Omega-3 Fatty Acids

Approximately 60% of the human brain is composed of lipids (fats), and between 30-35% 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. The early studies used mega-doses of omega-3 (9 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 omgea-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 wide-spread 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 his/her 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 ten years. 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 Trilafon.

Anticholinergic Medications

This class of medications is used occasionally to combat side effects of some antipsychotic drugs (such as muscle rigidity or spasms, restlessness, tremor). Again, we will only list these medications (brand names): Cogentin, Akineton, 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. And Jamison, K.R. (2007) Manic-depressive Illness. Oxford: Oxford Press.

Preston, J.D., O'Neal, J. and Talaga, M. (2017) Handbook of Clinical Psychopharmacology for Therapists: 8th Edition. New Harbinger: Oakland.

References

Akiskal, H.S., Bourgeois, M.L., Angst, J., Post, R., Moller, H.J., & Hirschfeld, R.M.A. (2000). Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J. Affective Disorders, 59, Suppl, S5-530.

Bauer, N., Alda, M., Priller, J., and Young, L.T. (2003) Implications of the neuroprotective effects of lithium for the treatment of bipolar and neuro-degenerative disorders. Pharmacopsychiatry, 36(3): S 250-254.

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

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

Ghaemi, S.N., Lennox, M.S., & Baldessarini, R.J. (2001). Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. Journal of Clin. 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.

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

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. Arch Gen 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 Gen. Psych., 55, 702-707.

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.

Pope, M. & Scott, J. (2003). Do clinicians understand why individuals stop taking lithium? J. 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., and Talaga, M. (2017). Handbook of Clinical Psychopharmacology for Therapists: 8th Edition. Oakland: New Harbinger Publications.

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. Arch Gen Psychiatry, 56, 407-412.

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Resources for Families and for Patients with Bipolar Disorder

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

Loving Someone with Bipolar Disorder: How to Help and Understand Your Partner; Second Edition. By Julie Fast and John Preston. New Harbinger Publications, (2012)

Taking Charge of Bipolar Disorder. By Julie Fast and John Preston. Warner Books: New York (2006)

Consumer’s Guide to Psychiatric Medications by John Preston, John O’Neal and Mary Talaga. Penguin Books (2009)

Free Online Downloads - www.Psyd-Fx.com

Bipolar Medications. A concise Guide to Medication Treatments for Adolescents and Adults (2018) by John Preston

Detailed information on medications, drug interactions, addiction potential, safety during pregnancy, etc. Appropriate for clinicians

Quick Reference to Psychiatric Medications (2018) by John Preston. Updated annually.

 

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