Bipolar disorder

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

• The connection between mania and melancholia dates back to the 2nd Century CE.
  • Soranus of Ephesus (98-177 CE), a Greek physician, characterized mania and melancholia as separate illnesses.
• German psychiatrist Emil Kraepelin (1856–1926) examined and classified the natural course of patients with untreated bipolar disorder years prior to the discovery of mood stabilizers.
  • In 1902, Kraepelin created the term manic depressive psychosis to describe these patients.
• In 1957, Karl Leonhard, a German psychiatrist, coined the terms bipolar and unipolar to describe subclassifications of manic depressive psychosis (bipolar disorder).
  • Bipolar was used to describe cases with manic episodes.
  • Unipolar was used to describe cases characterized by the presence of depressive episodes and the lack of manic episodes.

• Humans have experienced cycles of varying moods and energy levels for thousands of years.
• The terms melancholia and mania originated in Ancient Greece.
  • Melancholia originates from the Greek words melas and chole, meaning “black” and “bile” or “gall”^[1] respectively.
  • Mania originates from the Greek words ania and manos, meaning “to produce great mental anguish” and “relaxed or loose” respectively.
• Both mania and melancholia were thought to arise from imbalances in the body’s humors. Mania was thought to result from excess amounts of yellow bile, while melancholia was thought to result from excess black bile.
• The connection between mania and melancholia dates back to the 2nd Century CE.^[2]
  • Soranus of Ephesus (98-177 CE), a Greek physician, characterized mania and melancholia as separate illnesses^[3] during a period where many viewed melancholia as a type of mania.
  • Aretaeus of Cappadocia, a medical philosopher who lived between the years 30 and 150 CE, is credited with the earliest accounts of a connection between melancholia and mania. Aretaeus wrote many texts that survive today in which he described manic-depressive disease that he believed originated in black bile.
• Early Chinese authors established clear classification of bipolar disorder as a mental illness. For example, author and encyclopedist Gao Lian (c. 1583) described the disorder in Eight Treatises on the Nurturing of Life.^[4]
• The modern psychiatric understanding of manic-depressive illness is often traced to the 1850s.
  • On January 31, 1854, French psychologist Jules Baillarger presented a description of a biphasic mental illness characterized by alternating periods of mania and depression to the French Imperial Academy of Medicine. Baillarger termed the illness “folie à double forme” (dual-form insanity).
• German psychiatrist Emil Kraepelin (1856-1926) examined and classified the natural course of patients with untreated bipolar disorder years prior to the discovery of mood stabilizers.
  • In 1902, Kraepelin created the term manic depressive psychosis to describe these patients.
  • He observed that periods of acute illness (manic or depressive) were often preceded and followed by symptom-free periods in which patients were able to function normally.^[2]
• Following the Second World War, Australian psychiatrist Dr. John Cade conducted research on the effectiveness of different compounds in treating veterans with manic-depressive illness. Through his research, Dr. Cade found that lithium carbonate was effective at treating manic-depressive illness^[3]. Lithium was not widely used as a treatment immediately following Dr. Cade’s discovery as many held fears of its toxicity. However, following the use of lithium in the treatment of manic-depressive disorder in some hospitals beginning in the 1950s and reports of the benefits of lithium treatment in medical journals in the 1960s, the Food and Drug Administration approved the use of lithium as a treatment for manic-depressive illness in 1970^[4].
• In 1952, the phrase “manic-depressive reaction” was included in the first American Psychiatric Association Diagnostic Manual, demonstrating the belief that the disease was a result of a reaction of biogenetic factors to social/environmental factors.^[5]
• In 1957, Karl Leonhard, a German psychiatrist, coined the terms bipolar and unipolar to describe subclassifications of manic depressive psychosis (bipolar disorder).^[6]
  • Bipolar was used to describe cases with manic episodes.
  • Unipolar was used to describe cases characterized by the presence of depressive episodes and the lack of manic episodes.
• In 1968, ICD-8 and DSM-II both called the condition “manic-depressive illness,” demonstrating the increasing biological thinking surrounding the condition.^[7]
• The current term for the condition, bipolar disorder, recently became popular, though some prefer the old nosology and claim that “manic-depressive illness” better described the multifaceted illness.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

Bipolar disorder is commonly categorized as either bipolar type I, where an individual experiences full-blown mania, or bipolar type II, in which the hypomanic “highs” do not go to the extremes of mania, and cyclothymic disorder where mood cycles between episodes of hypomania and dysthymia. The latter two are much more difficult to diagnose, since the hypomanic episodes may simply appear as a period of successful high productivity and is reported less frequently than a distressing depression. Psychosis can occur, particularly in manic periods. There are also ‘rapid cycling’ subtypes. Because there is so much variation in the severity and nature of mood-related problems, the concept of a bipolar spectrum is often employed. There is no consensus as to how many ‘types’ of bipolar disorder exist. Bipolar disorder can also be classified based on the phase of illness the patient may be in.^[1] Many people with bipolar disorder experience severe anxiety and are very irritable (to the point of rage) when in a manic state, while others are euphoric and grandiose.

The bipolar disorder spectrum includes the following:

• Bipolar I Disorder
• Bipolar II Disorder
• Cyclothymic Disorder
• Substance/Medication-Induced Bipolar Disorder
• Bipolar Disorder Due to Another Medical Condition
• Other Specified Bipolar Disorder Due to Another Medical Condition
• Unspecified Bipolar Disorder

Bipolar I disorder is a mood disorder that is characterized by at least one manic or mixed episode. There may be episodes of hypomania or major depression as well. It is a sub-diagnosis of bipolar disorder, and conforms to the classic concept of manic-depressive illness. The essential feature of bipolar I disorder is a clinical course that is characterized by the occurrence of one or more manic episodes or mixed episodes. Often individuals have also had one or more major depressive episodes. Episodes of substance-induced mood disorder (due to the direct effects of a medication, or other somatic treatments for depression, a drug of abuse, or toxin exposure) or of mood disorder due to a general medical condition do not count toward a diagnosis of bipolar I disorder. In addition, the episodes are not better accounted for by schizoaffective disorder and are not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder not otherwise specified.

Bipolar II Disorder is a bipolar spectrum disorder characterized by at least one hypomanic episode and at least one major depressive episode; with this disorder, depressive episodes are more frequent and more intense than manic episodes. The presence of a hypomanic episode is used mainly to differentiate it from unipolar depression. It is believed to be underdiagnosed because hypomanic behavior often presents as high-functioning behavior. Patients with bipolar II disorder are less likely to seek help from providers. Although a patient may be depressed, it is very important to find out from the patient or patient’s family or friends if hypomania has ever been present using careful questioning.

Cyclothymia is a mood disorder. This disorder is a milder form of bipolar II disorder consisting of recurrent mood disturbances cycling between hypomania and dysthymic mood. A single episode of hypomania is sufficient to diagnose cyclothymic disorder; however, most individuals also have dysthymic periods. The diagnosis of cyclothymic disorder is never made when there is a history of mania or major depressive episode or mixed episode.

Signs and symptoms of the depressive phase of bipolar disorder include: persistent feelings of sadness, anxiety, guilt, anger, isolation and/or hopelessness, disturbances in sleep and appetite, fatigue and loss of interest in usually enjoyed activities, problems concentrating, loneliness, self-loathing, apathy or indifference, depersonalization, loss of interest in sexual activity, shyness or social anxiety, irritability, chronic pain (with or without a known cause), lack of motivation, and morbid/suicidal ideation.^[2]

Mania is generally characterized by a distinct period of an elevated, expansive or irritable mood state. People commonly experience an increase in energy and a decreased need for sleep. A person’s speech may be pressured, with thoughts experienced as racing. Attention span is low and a person in a manic state may be easily distracted. People may feel they have been ‘chosen’, or are ‘on a special mission’, which are considered grandiose or delusional ideas. At more extreme phases, a person in a manic state can begin to experience psychosis, or a break with reality, where thinking is affected along with mood. In order to be diagnosed with mania according to DSM-IV, a person must experience this state of elevated or irritable mood as well as other symptoms for two or more weeks.

Hypomania is generally a less extreme state than mania, and people in the hypomanic phase generally experience fewer of the symptoms of mania than those in a full-blown manic episode. During an episode of Hypomania, one might feel an uncontrollable impulse to laugh at things he or she does not normally find funny. The duration is usually also shorter than in mania. This is often a very ‘artistic’ state of the disorder, where there is a flight of ideas, extremely clever thinking, and an increase in energy.

In the context of bipolar disorder, a mixed state is a condition during which symptoms of mania and clinical depression occur simultaneously (for example, agitation, anxiety, aggressiveness or belligerence, confusion, fatigue, impulsiveness, insomnia, irritability, morbid and/or suicidal ideation, panic, paranoia, persecutory delusions, pressured speech, racing thoughts, restlessness, and rage).^[3] Mixed episodes can be the most volatile of the bipolar states, as moods can easily and quickly be triggered or shifted. Suicide attempts, substance abuse, and self-mutilation may occur during this state.

Rapid cycling, defined as having four or more episodes per year, is found in a significant fraction of patients with bipolar disorder. It has been associated with greater disability or a worse prognosis, due to the confusing changeability and difficulty in establishing a stable state. Rapid cycling can be induced or made worse by antidepressants, unless there is adjunctive treatment with a mood stabilizer.^[4][5] The definition of rapid cycling most frequently cited in the literature is that of Dunner and Fieve: at least four major depressive, manic, hypomanic or mixed episodes are required to have occurred during a 12-month period. ^[6] There are references that describe very rapid (ultra-rapid) or extremely rapid ^[7] (ultra-ultra or ultraradian) cycling. One definition of ultra-ultra rapid cycling is defining distinct shifts in mood within a 24-48 hour period.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2]

A number of factors can be involved in bipolar disorder including genetic, biochemical, psychodynamic, and environmental factors. paternal age increase the risk of bipolar disorder in one’s offspring that could be due to increased genetic mutations during spermatogenesis. Stressful life events may be associated with onset of bipolar disorder and a more severe course of illness.The disorder runs in families. More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression. Bipolar disorder is associated with immune system dysregulation.

• Paternal age increase the risk of bipolar disorder in offspring due to increased genetic mutations during spermatogenesis. As an example, a national registry study found that the risk of bipolar disorder in offspring of fathers 45 years and older was six times greater.^[1]

• Stress and a history of childhood physical abuse associated with onset of bipolar disorder and a more severe course of illness.^[2][3]

• More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression.[4][./Bipolar_disorder_causes#cite_note-4 [4]]
• Genes that are involved in bipolar disorder have been studied, but no single gene has been identified.^[5] it may involve many genes with small effects.^[6]
• Studies found several genetic variants are associated with bipolar disorder. One possible locus is CACNA1C, which codes for a calcium channel that is involved in channel gating.^[7][8] other genes are ANK3, and CLOCK genes especially bipolar type I disorder.^[9][10]
• A meta-analysis suggests that other biologic pathways are cardiac β-adrenergic signaling, cardiac hypertrophy signaling, corticotropin releasing hormone signaling, endothelin 1 signaling, glutamate signaling, and phospholipase C signaling.^[11]
• In addition, a meta-analysis studies identified three single-nucleotide polymorphisms on chromosomes 3 and 10. One of them is located on a brain expressed gene that encodes calcium channel subunits; calcium signaling regulates neuronal growth and development.^[12][13]

• Bipolar disorder is associated with immune system dysregulation. Cytokines (eg, interleukin-4 and tumor necrosis factor-alpha) and cytokine receptors are elevated in patients with bipolar disorder^[14]
• A meta-analysis found that levels of C reactive protein were higher in patients than controls, and the difference was small to moderate.^[15]

• A number of neurotransmitters have been linked to this disorder.
• Catecholamine hypothesis, state that increase in epinephrine and norepinephrine causes mania and a decrease in epinephrine and norepinephrine causes depression.
• Drugs that increase levels of monoamines, including serotonin, norepinephrine, or dopamine, can all potentially trigger mania for instance drug of abuse like cocaine.^[16]
• Patients with substance use-induced psychosis may develop schizophrenia or bipolar disorder within five years.^[17]
• A postmortem study of the frontal lobes of individuals with these disorders revealed that the glutamate levels were increased^[18].

• A meta-analysis shows that decreased activation of gray matter in a cortical-cognitive brain network, which has been associated with the emotion regulation in patients with bipolar disorder. ^[19]
• There is functional and anatomic alterations in brain networks. for instance, there is activation in ventral limbic brain regions that mediate the experience of emotions. ^[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Bipolar disorder must be differentiated from cyclothymic disorder, major depressive disorder, schizophrenia, and substance abuse.^[1]

Bipolar disorder must be differentiated from:^[1]

• Anxiety disorders
• Attention-deficit/hyperactivity disorder
• Cyclothymic disorder
• Major depressive disorder
• Panic disorder
• Personality disorders
• Schizophrenia spectrum and other related psychotic disorders
• Substance abuse
• Intoxication induced delirium
• Medication side effects

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2]

The estimated lifetime prevalence of bipolar disorder among adults worldwide is 1 to 3 percent, and the lifetime prevalence of bipolar I and bipolar II disorder was 2.8 percent. The mean age of onset for bipolar I disorder is 18 years and for bipolar II disorder 20 years. The one-year prevalence of bipolar I disorder in people aged 65 years and older is approximately 0.4 percent and the lifetime rate is 0.8 percent. These rates were less than rates in younger individuals.

• The estimated lifetime prevalence of bipolar disorder among adults worldwide is 1 to 3 percent^[1], and the lifetime prevalence of bipolar I and bipolar II disorder was 2.8 percent^[2]
• The mean age of onset for bipolar I disorder is 18 years and for bipolar II disorder 20 years^[3]. The ratio of men to women who develop bipolar disorder is approximately 1:1.
• In the United States, the estimated lifetime prevalence of bipolar I disorder was 1 percent, and bipolar II disorder 1.1 percent. The mean age of onset for bipolar I and bipolar II disorder was 18 and 20 years.^[4]
• Bipolar disorder is the 18^th leading cause of disability in the United States.^[5]
• Individuals with manic or hypomanic episodes, psychosocial functioning is severely impaired in 70 percent; in 90 percent of the affected individuals functioning is severely impaired during episodes of major depression.^[4]
• The one-year prevalence of bipolar I disorder in people aged 65 years and older is approximately 0.4 percent and the lifetime rate is 0.8 percent. These rates were less than rates in younger individuals.^[6]
• Geriatric bipolar patients are predominantly female; 69 percent of late-life bipolar patients were women.^[7]
• The prevalence of bipolar spectrum disorders in children and adolescents is approximately 2 percent.^[8] However it is not well established because several factors make the diagnosis of bipolar disorder in pediatric complex and controversial.^[9]
• Pediatric bipolar disorder is characterized by high rates of comorbidity.^[8]
• Community studies suggest that the prevalence of bipolar disorder may be greater among adolescents (age 13 to 18 years) than children (age ≤12 years)^[10][11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Risk factors for bipolar disorder include genetic predisposition and problems in the relationship status such as divorce, separation, or becoming a a widow.^[1]

• Divorce
• Genetic predisposition
• Separation
• Being a widow^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2]

Lifelong outcome has rarely been studied, and precise data on the natural outcome are scarce. Some studies demonstrate that most patients continue to suffer from residual depressive or hypomanic symptoms between episodes, and many are functionally impaired. Bipolar disorder, has significant morbidity and mortality rates. Often, the cycling between depression and mania accelerates with age. The main complications of bipolar disorder are suicide, homicide, and addictions.

• In bipolar disorder the lifetime proportions of mania and depression remain stable into old age. Bipolar female subjects manifest more depression than bipolar male; and they have a poorer prognosis than other bipolar conditions, with slower remissions and higher risk for chronicity.^[1]
• The natural length of bipolar disorder episode has not changed over the past 120 years. Patients responding to antidepressants still require a maintenance treatment throughout the underlying episode. The median length of episodes is 3 to 6 months. The recurrence of bipolar disorder is the rule; there is some initial shortening of intervals/cycles, followed by an irregular persistent recurrence, with a median cycling of 18 months.^[2]
• Lifelong outcome has rarely been studied, and precise data on the natural outcome are scarce. Some studies demonstrate that most patients continue to suffer from residual depressive or hypomanic symptoms between episodes, and many are functionally impaired.^[1]
• The natural history of bipolar illness shows that it has a poor prognosis, as reflected by high recurrence, chronicity of episodes and premature death by suicide and somatic disorders.^[1]
  

• Stopping medication or taking it the wrong way can cause your symptoms to come back, and lead to the following complications:
  • Alcohol and/or drug abuse
  • Problems with relationships, work, and finances
  • Suicidal thoughts and behaviors, suicidal patients remain at risk for suicide. Patients emerging from a depression are thought to be at an increased risk for suicide. men with bipolar disorder are at higher risk for suicide.^[3]
  • Homicide often in the manic phase can be very demanding and grandiose. These individuals can become homicidal by acting on delusions.
  • Bipolar disorder type I results in diminished quality of life as measured by health utility and utility-based health-related quality of life. The patients with depression sustained the greatest loss in QOL.^[4]

A good prognosis results from good treatment, which, in turn, results from an accurate diagnosis. Because bipolar disorder continues to have a high rate of both under-diagnosis and misdiagnosis, it is often difficult for individuals with the condition to receive timely and competent treatment.

Bipolar disorder can be a severely disabling medical condition. However, with appropriate treatment, many individuals with bipolar disorder can live full and satisfying lives. Persons with bipolar disorder are likely to have periods of normal or near normal functioning between episodes.

Ultimately one’s prognosis depends on many factors, which are, in fact, under the individual’s control: the right medicines; the right dose of each; a very informed patient; a good working relationship with a competent medical doctor; a competent, supportive and warm therapist; a supportive family or significant other; and a balanced lifestyle including a regulated stress level, regular exercise and regular sleep and wake times.

There are obviously other factors that lead to a good prognosis as well, such as being very aware of small changes in one’s energy, mood, sleep and eating behaviors, as well as having a plan in conjunction with one’s doctor for how to manage subtle changes that might indicate the beginning of a mood swing. Some people find that keeping a log of their moods can assist them in predicting changes.

Even when on medication, some people may still experience weaker episodes, or have a complete manic or depressive episode. In fact, a recent study found bipolar disorder to be “characterized by a low rate of recovery, a high rate of recurrence, and poor interepisodic functioning.” Worse, the study confirmed the seriousness of the disorder as “the standardized all-cause mortality ratio among patients with BD is increased approximately 2-fold.” Bipolar disorder is currently regarded “as possibly the most costly category of mental disorders in the United States.”^[5]

The following behaviors can lead to depressive or manic recurrence:

• Discontinuing or lowering one’s dose of medication, without consulting one’s physician.
• Being under- or over-medicated. Generally, taking a lower dosage of a mood stabilizer can lead to relapse into mania. Taking a lower dosage of an antidepressant, may cause the patient to relapse into depression, while higher doses can cause destabilization into mixed-states or mania.
• Taking hard drugs—recreationally or not—such as cocaine, alcohol, amphetamines, or opiates. These can cause the condition to worsen.
• An inconsistent sleep schedule can destabilize the illness. Too much sleep (possibly caused by medication) can lead to depression, while too little sleep can lead to mixed states or mania.
• Caffeine can cause destabilization of mood toward irritability, dysphoria and mania. Anecdotal evidence seems to suggest that lower dosages of caffeine can have effects ranging from anti-depressant to mania-inducing.
• Inadequate stress management and poor lifestyle choices. If unmedicated, excessive stress can cause the individual to relapse. Medication raises the stress threshold somewhat, but too much stress still causes relapse.
• Often bipolar individuals are subject to self-medication, the most common drugs being alcohol, and marijuana. Sometimes they may also turn to hard drugs. Studies show that tobacco smoking induces a calming effect on most bipolar people, and a very high percentage suffering from the disorder smoke. [3]

Recurrence can be managed by the sufferer with the help of a close friend, based on the occurrence of idiosyncratic prodromal events.^[6] This theorizes that a close friend could notice which moods, activities, behaviours, thinking processes, or thoughts typically occur at the outset of bipolar episodes. They can then take planned steps to slow or reverse the onset of illness, or take action to prevent the episode from being damaging. ^[7]

“Mortality studies have documented an increase in all-cause mortality in patients with BD. A newly established and rapidly growing database indicates that mortality due to chronic medical disorders (eg, cardiovascular disease) is the single largest cause of premature and excess deaths in BD. The standardized mortality ratio from suicide in BD is estimated to be approximately 18 to 25, further emphasizing the lethality of the disorder.”^[8]

Although many people with bipolar disorder who attempt suicide never actually complete it, the annual average suicide rate in males and females with diagnosed bipolar disorder (0.4%) is 10 to more than 20 times that in the general population.^[9]

Individuals with bipolar disorder tend to become suicidal, especially during mixed states such asdysphoric mania and agitated depression. Persons suffering from Bipolar II have high rates of suicide compared to persons suffering from other mental health conditions, including Major Depression. Major Depressive episodes are part of the Bipolar II experience, and there is evidence that sufferers of this disorder spend proportionally much more of their life in the depressive phase of the illness than their counterparts with Bipolar I Disorder (Akiskal & Kessler, 2007).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Bipolar disorder is treatable. The emphasis of the treatment of bipolar disorder is on effective management of the long-term course of the illness, which can involve treatment of emergent symptoms. Treatment methods include pharmacological and psychological techniques.

A variety of medications are used to treat bipolar disorder; most people with bipolar disorder require combinations of medications. There is little evidence, however, that alternative or complementary treatments used alone work well for the long-term treatment of the disorder.

Medications called mood stabilizers are used to prevent or mitigate manic or depressive episodes. Mood stabilizing medications with demonstrated efficacy include lithium, and anticonvulsants such as Depakote, carbamazepine, and lamotrigine. The atypical antipsychotics are all FDA approved for acute treatment of mania (quetiapine, olanzapine, risperidone). Generally speaking, mood stabilizing medications are more effective at treating or preventing manic episodes associated with bipolar disorder; however, some medications (i.e. lamotrigine, fluoxetine, quetiapine) have demonstrated efficacy for the treatment of bipolar depression.

In medicine, every medication has its side effects: bipolar disorder medications are no exception. It is important to point out that each medication is associated with a unique side effect profile.

Lithium may be associated with gastrointestinal upset (e.g. nausea, diarrhea), memory problems, weight gain and other side effects. Higher doses equal more side effects, but lower doses (within the therapeutic window) have little to no side effects.

Anticonvulsant medications commonly cause sedation, weight gain, electrolyte disturbances, or other side effects. If one cannot tolerate one of the anticonvulsants, it’s advisable to try another anticonvulsant. Two or more anticonvulsants in combination can often result in a lower effective dose of each and lower side effects.

The side effect profile of the atypical antipsychotics vary widely between agents. Generally speaking, the most common side effects of the atypicals are sedation and metabolic disturbances (i.e. weight gain, dyslipidemia, hyperglycemia). Atypical antipsychotics may also cause extrapyramidal side effects and restlessness. Atypical antipsychotics also carry a risk of causing tardive dyskinesia; however, the risk with the newer atypical agents is much less than the risk associated with older antipsychotics (e.g. haloperidol). The risk of TD is thought to be proportionate to the duration of neuroleptic/antipsychotic use (roughly 5% per year in non-elderly patients treated with older antipsychotics). Patients and physicians need to be careful to watch for symptoms of this side effect carefully so that an antipsychotic can be reduced in dosage, or changed to another medication, before the condition progresses. The physician should, of course, be consulted about any change in dosage.

A recent large-scale study ^[1] found that severe depression in patients with bipolar disorder responds no better to a combination of antidepressant medications and mood stabilizers than it does to mood stabilizers alone. Furthermore, this federally funded study found that antidepressant use does not hasten the emergence of manic symptoms in patients with bipolar disorder.

Medications work differently in each person, and it takes considerable time to determine in any particular case whether a given drug is effective at all, since bipolar disorder is by nature episodic, and patients may experience remissions whether or not they receive treatment. For this reason, neither patients nor their doctors should expect immediate relief, although psychosis with mania can respond quickly to anti psychotics, and bipolar depression can be alleviated quickly with electroconvulsive therapy (ECT). Many doctors emphasize that patients should not expect full stabilization for at least 3-4 weeks (some antidepressants, for example, take 4-6 weeks to take effect), and should not give up on a medication prematurely,^[2] nor should they discontinue medication with the disappearance of symptoms as the depression may return.

Compliance with medications can be a major problem, because some people as they become manic lose the awareness of having an illness, and they therefore discontinue medications. Patients also often quit taking medication when symptoms disappear, erroneously thinking themselves “cured”, and some people enjoy the effects of unmedicated hypomania.

Depression does not respond instantaneously to resumed medication, typically taking up to 6 weeks to respond. Mania may disappear slowly, or it may become depression.

Other reasons cited by individuals for discontinuing medication are side effects, expense, and the stigma of having a psychiatric disorder. In a relatively small number of cases stipulated by law (varying by locality but typically, according to the law, only when a patient poses a threat to himself or others), patients who do not agree with their psychiatric diagnosis and treatment can legally be required to have treatment without their consent. Throughout North America and the United Kingdom, involuntary treatment or detention laws exist for severe cases of bipolar disorder and other mental illnesses where there is a potential for harm to oneself or others.

The use of lithium salts as a treatment of bipolar disorder was first discovered by Dr. John Cade, an Australian psychiatrist who published a paper on the use of lithium in 1949.

Lithium salts had long been used as a first-line treatment for bipolar disorder. In ancient times, doctors would send their mentally ill patients to drink from “alkali springs” as a treatment. They did not know it, but they were really prescribing lithium, which was present in high concentration in the waters. The therapeutic effect of lithium salts appears to be entirely due to the lithium ion, Li⁺.

The two lithium salts used for bipolar therapy are lithium carbonate (mostly) and lithium citrate (sometimes). Approved for the treatment of acute mania in 1970 by the Food and Drug Administration (FDA), lithium has been an effective mood-stabilizing medication for many people with bipolar disorder. Lithium is also noted for reducing the risk of suicide.^[3] Although lithium is among the most effective mood stabilizers, persons taking it may experience side effects similar to the effects of ingesting too much table salt, such as high blood pressure, water retention, and constipation. Regular blood testing is required when taking lithium to determine the correct lithium levels since the therapeutic dose is close to the toxic dose.

The mechanism of lithium salt treatment is believed to work as follows: some symptoms of bipolar disorder appear to be caused by the enzyme inositol monophosphatase (IMPase), an enzyme that splits inositol monophosphate into free inositol and phosphate. It is involved in signal transduction and is believed to create an imbalance in neurotransmitters in bipolar patients. The lithium ion is believed to produce a mood stabilizing effect by inhibiting IMPase by substituting for one of two magnesium ions in IMPase’s active site, slowing down this enzyme.

Lithium orotate is used as an alternative treatment to lithium carbonate by some individuals with bipolar disorder, mainly because it is available without a doctor’s prescription. It is sometimes sold as “organic lithium” by nutritionists, as well as under a wide variety of brand names. There seems to be little evidence for its use in clinical treatment in preference to lithium carbonate. Individuals with bipolar disorder have complained that it is much weaker than lithium carbonate and, therefore, less effective.

Lithium has problems with its side effects, including hand trembling and intolerance of hot weather. Cogentin is sometimes used to control the trembling, but itself causes sedation. Lithium has a very narrow window of effectiveness. Below that level it has no effect, and above it is toxic. For that reason blood must be sampled frequently to determine if the proper blood level is currently present.

Anticonvulsant medications, particularly valproate and carbamazepine, have been used as alternatives or adjuncts to lithium in many cases. Valproate (Depakote, Epival) was FDA approved for the treatment of acute mania in 1995, and is now considered by some doctors to be the first line of therapy for bipolar disorder. A similar medication, valproic acid (Depakene) is also used. For some, it is preferable to lithium because its side effect profile seems to be less severe, compliance with the medication is better, and fewer breakthrough manic episodes occur. However, valproate is not as effective as lithium in preventing or managing depressive episodes, so patients taking valproate may also need an antidepressant as an adjunct medicinal therapy.

New research suggests that different combinations of lithium and anticonvulsants may be helpful. Anticonvulsants are also used in combination with antipsychotics. Newer anticonvulsant medications, including lamotrigine and oxcarbazepine, are also effective as mood stabilizers in bipolar disorder. Lamotrigine is particularly promising, as it alleviates bipolar depression and prevents recurrence at higher rates.^[4],[5]

Zonisamide (trade name Zonegran), another anticonvulsant, also may show promise in treating bipolar depression according to Frederick K. Goodwin M.D. on a recent Medscape webcast titled “The Accurate Diagnosis and Long-Term Treatment of Bipolar Depression” to view the webcast click here. (free reg required).

Topiramate has not done well in clinical trials; it seems to help a few patients very much but most not at all. It appears to be useful in some treatment resistant cases and for anxiety issues when clonazepam cannot be prescribed. Gabapentin has failed to distinguish itself from placebo as a mood stabilizer.

According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician. However, the therapeutic dose for a patient taking valproate for epilepsy is much higher than the therapeutic dose of valproate for an individual with bipolar disorder.

Other anticonvulsants effective in some cases and being studied closer include phenytoin, levetiracetam, pregabalin and valnoctamide.^[6] .

The newer atypical antipsychotic drugs such as risperidone, quetiapine, and olanzapine are often used in acutely manic patients, because these medications have a rapid onset of psychomotor inhibition, which may be lifesaving in the case of a violent or psychotic patient. Parenteral and orally disintegrating (in particular, Zydis wafers) forms are favoured in emergency room settings.^[7] These drugs can also be used as adjunctives to lithium or anticonvulsants in refractory bipolar disorder and in prevention of mania recurrence. They also have fewer side effects, and are often used in place of lithium, in combination with an antidepressant, an anticonvulsant, or both.

In light of recent evidence, olanzapine (Zyprexa) has been FDA approved as an effective monotherapy for the maintenance of bipolar disorder.^[8] A head-to-head randomized control trial in 2005 has also shown olanzapine monotherapy to be just as effective and safe as lithium in prophylaxis.^[9] Eli Lilly and Company also offers Symbyax, a combination of olanzapine and fluoxetine.^[10]

Ziprasidone (Geodon) and aripriprazole (Abilify) also show promise according to Gary Sachs M.D. of Harvard’s Massachusetts General Hospital Bipolar Clinic and Research Program. (View the webcast above at the Bipolar Clinic and Research Program link).

The atypical antipsychotics have some potential for causing weight gain and diabetes, and in larger doses over long periods may simetimes create tardive dyskinesia, though with much lesser probability than with the typical antipsychotics, such as Thorazine, Stelazine, or Haliperidol (Haldol.)

Modafinil (Provigil) and Pramipexole (Mirapex) show promise in treating the cognitive deterioration related to bipolar depression. In addition Riluzole, an ALS treatment, has been shown to be effective treatment. The breast cancer medicine tamoxifen has shown quick response to manic phases.^[11]

Certain types of psychotherapy, used in combination with medication, may provide some benefit in the treatment of bipolar disorders. Psychoeducation has been shown to be effective in improving patients’ compliance with their lithium treatment.^[12] Several studies of family therapy report it can improve family communication, social functioning and lithium compliance, though it appears to be effective mainly on females.^[13] Evidence for the efficancy of other psychotherapies is absent or weak,^[13] often not being performed under randomized and controlled conditions.^[14] Well-designed^[14] studies have found interpersonal and social rhythm therapy to be ineffective.^[15]

Although medication and psychotherapy cannot cure the illness, therapy can often be valuable in helping to address the effects of disruptive manic or depressive episodes that have hurt a patient’s career, relationships or self-esteem. Therapy is available not only from psychiatrists but from social workers, psychologists and other licensed counselors.

Electroconvulsive therapy (ECT) is sometimes used to treat severe bipolar depression in cases where other treatments have failed and is 60 to 70 percent effective. Although it has proved to be a highly effective treatment, doctors are reluctant to use it except as a treatment of last resort because of the side-effects and possible temporary memory loss complications of ECT, particularly when repeated treatments (“maintenance ECT”) are needed.

Omega-3 fatty acids may also be used as a treatment for bipolar disorder, particularly as a supplement to medication. An initial clinical trial by Stoll et al. produced positive results ^[16]. However, since 1999 attempts to confirm this finding of beneficial effects of omega-3 fatty acids in several larger double-blind clinical trials have produced inconclusive results. It was hypothesized that the therapeutic ingredient in omega-3 fatty acid preparations is eicosapentaenoic acid (EPA) and that supplements should be high in this compound to be beneficial.^[17] Omega-3 fatty acids may be found in fish, fish oils, algae, and to a lesser degree in other foods such as flaxseed, flaxseed oil and walnuts. Some researchers have found that only omega-3 fatty acids derived from fish products shows efficacy, whereas omega-3 fatty acids derived flaxseed oil or supplements are ineffective.

Complementary and/or non-Western treatments, such as acupuncture, meditation, yoga and orthomolecular therapy, are used by some people with bipolar disorder, and some research shows one, particularly yoga in mild bipolar depression, may have some scientific merit. However, further studies are needed to indicate which complementary therapies are effective and for what illness type and for whom.

Understanding the symptoms, when they occur and ways to better control them has given many people diagnosed with bipolar a chance. A helpful hint is to remember that this is not a major illness, rather a benefit in most controlled cases.

A ketogenic diet similar to the diet used for pediaric epilepsy was thought to have mood stabilizing and antidepressant effects. Stanford University Medical School attempted a study using a ketogenic diet protocol on bipolar patients. However due to the lack of ability to attract subjects the trial was never started. Studies have shown it to have anti-depressant properties in rats.

Some people claim that medical marijuana can help control the mood swings in some forms of bipolar disorder (2). Views on this issue are divided.

Some claim that THC can relieve depressive phases through its euphoriant action, while the tranquilizing effects of THC can alleviate manic phases. Others note that marijuana may increase anxiety and depression, consequently lowering one’s threshold for future mood episodes.

One recent online survey questioned the notion that marijuana smoking increases a user’s risk for depression. ^[18] The authors of the study show that marijuana users reported fewer somatic symptoms and daily users reported less depressed mood and more positive affect than non-users. These self-report data suggest that adults apparently do not increase their risk for depression by using marijuana. Many find that the calming sedation associated with the use of cannabis helps to alleviate depression.

Current medical marijuana pharmaceuticals (such as dronabinol, marketed as Marinol) exist in the U.S. while Sativex, a whole-plant cannabis extract, is currently being marketed in Canada, the UK and Spain. Sativex is used for various illnesses, such as MS, cancer, and depression . Individuals who want to access pharmaceutical cannabis, however, may not be able to receive it due to drug laws against marijuana. Although illegal in many places around the world, cannabis remains easy to grow and purchase. See legal issues of cannabis for more information.

On the other hand cannabis may not be a very suitable medicine for people with bipolar disorder, as scientists have shown cannabis may trigger psychosis, hallucinations or psychotic illnesses in individuals who have an existing predisposition to mental illness or are already suffering from it. [2]

Summing up, while there may be an application for cannabis in some cases of bipolar illness, this view is currently the subject of much controversy and in need of more research.

There is increasing evidence that certain antidepressants are contraindicated in bipolar disorder. Fredrick K. Goodwin M.D.(1), coauthor of Manic Depressive Illness with Kay Redfield Jamison PhD and the NIMH’s Robert M. Post (2) gleaned evidence by comparing the life charts of individuals with BP I and BP II who were medicated with certain mood stabilizers only versus any combination of those mood stabilizers plus certain antidepressants. The life chart trends indicated that use of certain antidepressants (over months to years) caused a long-term worsening of the illness over the life course compared to certain mood stabilizers alone in both bipolar I and bipolar II disorders. Specifically, they observed increased cycle frequency, increased mood episode severity, the emergence of mixed states and more treatment-resistant (difficult to treat) bipolar disorder.

Obvious forms of stress include having too much to do, too much complexity, conflicting demands, etc. There are also stresses that come from the absence of elements such as human contact, a sense of achievement, constructive creative outlets, and occasions or circumstances that will naturally elicit positive emotions. Stress reduction will involve reducing things that cause anxiety and increasing those that generate happiness. It is not enough to just reduce the anxiety.