Table of Contents

Bipolar I Disorder

Primer

Bipolar I Disorder is a mental disorder characterized by episodes of highly elevated or irritable mood, known as mania. Individuals may also present with decreased sleep, grandiosity, talkativeness, racing thoughts, and indiscretion or risk-taking behaviours. In some presentations, one's mood can shift very quickly between mania, anger, irritability, and/or depression, indicating a “mixed features” presentation of bipolar disorder.

Epidemiology
Prognosis
Comorbidity
Risk Factors
  • Individuals with a diagnosis of bipolar disorder often have a history of anxiety disorder in childhood.
  • Bipolar disorder is one of the most heritable psychiatric disorders (between 79-93%) which is higher than diseases such as breast cancer.
  • Monozygotic (identical) twins have 40–45% concordance rates (i.e. - percent chance that the other twins will have bipolar disorder if one has it).[12]
  • Depressive episodes often precede manic episodes. Individuals with the following depression factors are at higher risk for having bipolar disorder: early age of illness onset (<age 25), highly recurrent depressive episodes, a family history of bipolar disorder, depression with psychotic features, atypical features such as hypersomnia and increased appetite, leaden paralysis, psychomotor agitation, postpartum depression or psychosis, and antidepressant induced irritability.[13]

Relative Risk Factors in Bipolar Disorder

Barnett, J. H et al. (2009). The genetics of bipolar disorder. Neuroscience, 164(1), 331-343.
Risk Factor Risk
Monozygotic twin affected 40-45%
1st degree relative affected 9%

DSM-5 Diagnostic Criteria

Criterion A

Criteria have been met for at least 1 manic episode (see Manic Episode Criteria below)

Criterion B

The occurrence of the manic and major depressive episode(s) is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder.

Manic Episode Criteria

Note: Criteria A to D constitute a manic episode. At least 1 lifetime manic episode is required for the diagnosis of bipolar I disorder. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes.
Criterion A
Criterion B

During the period of mood disturbance and increased energy and activity, at least 3 of the following symptoms have persisted (4 symptoms if the mood is only irritable), represent a noticeable change from usual behaviour, and have been present to a significant degree:

  1. Distractibility (i.e. - attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed.
  2. Indiscretion, characterized by excessive involvement in activities that have a high potential for painful consequences (e.g. - unrestrained buying sprees, sexual behaviours, or foolish business investments).
  3. Grandiosity or inflated self-esteem.
  4. Flight of ideas or subjective experience that thoughts are racing.
  5. Activity (goal-directed) increasing (e.g. - either socially, at work or school, or sexually) or psychomotor agitation.
  6. Sleep decreased (e.g. - feels rested after only 3 hours of sleep).
  7. Talkative (more than usual or pressure to keep talking)

Mnemonic

The mnemonic DIGFAST can be used to remember the criteria for bipolar I and II disorder.[14]

  • D - Distractibility
  • I - Indiscretion
  • G - Grandiosity
  • F - Flight of ideas
  • A - Activity increased
  • S - Sleep decreased
  • T - Talkativeness
Criterion C

The mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

Criterion D

The episode is not attributable to the physiological effects of a substance (e.g. - a drug of abuse, a medication, other treatment) or to another medical condition.

What If There Is A Medication-induced Mania?

Manic symptoms that are attributable to the physiological effects of a drug of abuse (e.g. - cocaine or amphetamines), medication or treatment side effect (e.g. - steroids, L-dopa, antidepressants, stimulants), or another medical condition do not count toward the diagnosis of bipolar I disorder. However, a fully syndromal manic episode that arises during treatment (e.g. - with an antidepressant, electroconvulsive therapy, or light therapy) or drug of abuse, and persists beyond the physiological effect of the inducing agent (i.e. - after a medication or substance is fully out of the individual’s system or the effects of electroconvulsive therapy would be expected to have dissipated completely) is sufficient evidence for a manic episode diagnosis, and therefore a bipolar I disorder diagnosis.

Specifiers

Episode Specifier

  • Current or most recent episode manic
  • Current or most recent episode hypomanic
  • Current or most recent episode depressed
  • Current or most recent episode unspecified

Severity Specifier

  • Mild: Few, if any, symptoms in excess of those required to make the diagnosis are present, the intensity of the symptoms is distressing but manageable, and the symptoms result in minor impairment in social or occupational functioning.
  • Moderate: The number of symptoms, intensity of symptoms, and/or functional impairment are between those specified for “mild” and “severe.”
  • Severe: The number of symptoms is substantially in excess of that required to make the diagnosis, the intensity of the symptoms is seriously distressing and unmanageable, and the symptoms markedly interfere with social and occupational functioning.

Remission Specifier

  • In partial remission: Symptoms of the immediately previous manic, hypomanic, or depressive episode are present, but full criteria are not met, or there is a period lasting less than 2 months without any significant symptoms of a manic, hypomanic, or major depressive episode following the end of such an episode.
  • In full remission: During the past 2 months, no significant signs or symptoms of the disturbance were present.

With anxious distress

  • At least 2 of the following symptoms during the majority of days of the current or most recent episode of mania, hypomania, or depression:
    • (1) Feeling keyed up or tense
    • (2) Feeling unusually restless
    • (3) Difficulty concentrating because of worry
    • (4) Fear that something awful may happen
    • (5) Feeling that the individual might lose control of himself or herself
  • Severity:
    • Mild: 2 symptoms
    • Moderate: 3 symptoms
    • Moderate-severe: 4 or 5 symptoms
    • Severe: 4 or 5 symptoms and with motor agitation
Note: Anxious distress has been noted as a prominent feature of both bipolar and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with higher suicide risk, longer duration of illness, and greater likelihood of treatment nonresponse. As a result, it is clinically useful to specify accurately the presence and severity levels of anxious distress for treatment planning and monitoring of response to treatment.

With mixed features

The mixed features specifier can apply to the current manic, hypomanic, or depressive episode in bipolar I or bipolar II disorder:

Manic or hypomanic episode, with mixed features:

  • A. Full criteria are met for a manic episode or hypomanic episode, and at least 3 of the following symptoms are present during the majority of days of the current or most recent episode of mania or hypomania:
    • (1) Prominent dysphoria or depressed mood as indicated by either subjective report (e.g. - feels sad or empty) or observation made by others (e.g. - appears tearful)
    • (2) Diminished interest or pleasure in all, or almost all, activities (as indicated by either subjective account or observation made by others)
    • (3) Psychomotor retardation nearly every day (observable by others and not merely subjective feelings of being slowed down)
    • (4) Fatigue or loss of energy
    • (5) Feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick)
    • (6) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
  • B. Mixed symptoms are observable by others and represent a change from the person’s usual behavior
  • C. For individuals whose symptoms meet full episode criteria for both mania and depression simultaneously, the diagnosis should be manic episode, with mixed features, due to the marked impairment and clinical severity of full mania
  • D. The mixed symptoms are not attributable to the physiological effects of a substance (e.g. - a drug of abuse, a medication, other treatment)

Depressive episode, with mixed features:

  • A. Full criteria are met for a major depressive episode, and at least 3 of the following manic/hypomanic symptoms are present during the majority of days of the current or most recent episode of depression:
    • (1) Elevated, expansive mood
    • (2) Inflated self-esteem or grandiosity
    • (3) More talkative than usual or pressure to keep talking
    • (4) Flight of ideas or subjective experience that thoughts are racing.
    • (5) Increase in energy or goal-directed activity (either socially, at work or school, or sexually)
    • (6) Increased or excessive involvement in activities that have a high potential for painful consequences (e.g. - engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
      • (7) Decreased need for sleep (feeling rested despite sleeping less than usual; to be contrasted with insomnia)
  • B. Mixed symptoms are observable by others and represent a change from the person’s usual behavior
  • C. For individuals whose symptoms meet full episode criteria for both mania and depression simultaneously, the diagnosis should be manic episode, with mixed features
  • D. The mixed symptoms are not attributable to the physiological effects of a substance (e.g. - a drug of abuse, a medication, or other treatment)
Note: Mixed features associated with a major depressive episode have been found to be a significant risk factor for the development of bipolar I or bipolar II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring of response to treatment.

With rapid cycling

This specifier (can be applied to bipolar I or bipolar II disorder). There is presence of at least 4 mood episodes in the previous 12 months that meet the criteria for manic, hypomanic, or major depressive episode.

Note: The essential feature of a rapid-cycling bipolar disorder is the occurrence of at least 4 mood episodes during the previous 12 months. These episodes can occur in any combination and order. The episodes must meet both the duration and symptom number criteria for a major depressive, manic, or hypomanic episode and must be demarcated by either a period of full remission or a switch to an episode of the opposite polarity. Manic and hypomanic episodes are counted as being on the same pole. Episodes are demarcated by either partial or full remissions of at least 2 months or a switch to an episode of the opposite polarity (e.g. - major depressive episode to manic episode). Except for the fact that they occur more frequently, the episodes that occur in a rapid-cycling pattern are no different from those that occur in a non-rapid cycling pattern. Mood episodes that count toward defining a rapid-cycling pattern exclude those episodes directly caused by a substance (e.g. - cocaine, corticosteroids) or another medical condition.
Hypothyroidism, antidepressant use, and substance use is associated with rapid cycling. So assessing thyroid function, stopping any offending antidepressants, stimulants, and other psychotropics that might contribute to cycling is critical!

With melancholic features

  • A. 1 of the following is present during the most severe period of the current episode:
    • (1) Loss of pleasure in all, or almost all, activities
    • (2) Lack of reactivity to usually pleasurable stimuli (does not feel much better, even temporarily, when something good happens)
  • B. 3 or more of the following:
    • (1) A distinct quality of depressed mood characterized by profound despondency, despair, and/or moroseness or by so-called empty mood,
    • (2) Depression that is regularly worse in the morning
    • (3) Early-morning awakening (i.e. - at least 2 hours before usual awakening)
    • (4) Marked psychomotor agitation or retardation
    • (5) Significant anorexia or weight loss
    • (6) Excessive or inappropriate guilt

With atypical features

This specifier can be applied when these features predominate during the majority of days of the current or most recent major depressive episode.

  • A. Mood reactivity (i.e. - mood brightens in response to actual or potential positive events)
  • B. 2 or more of the following:
    • (1) Significant weight gain or increase in appetite
    • (2) Hypersomnia
    • (3) Leaden paralysis (i.e. - heavy, leaden feelings in arms or legs)
    • (4) A long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) that results in significant social or occupational impairment
  • C. Criteria are not met for “with melancholic features” or “with catatonia” during the same episode

With psychotic features

Delusions or hallucinations are present at any time in the episode. If psychotic features are present, specify if mood-congruent or mood-incongruent:

  • With mood-congruent psychotic features:
    • The content of all delusions and hallucinations is consistent with the typical depressive themes of personal inadequacy, guilt, disease, death, nihilism, or deserved punishment
  • With mood-incongruent psychotic features:
    • The content of the delusions or hallucinations does not involve typical depressive themes of personal inadequacy, guilt, disease, death, nihilism, or deserved punishment, or the content is a mixture of mood-incongruent and mood-congruent themes

With catatonia

This specifier can apply to an episode of mania or depression if catatonic features are present during most of the episode.

With peripartum onset

This specifier can be applied to the current or, if the full criteria are not currently met for a mood episode, most recent episode of mania, hypomania, or major depression in bipolar I or bipolar II disorder if onset of mood symptoms occurs during pregnancy or in the 4 weeks following delivery.

With seasonal pattern

This specifier applies to the lifetime pattern of mood episodes. The essential feature is a regular seasonal pattern of at least 1 type of episode (i.e. - mania, hypomania, or depression). The other types of episodes may not follow this pattern. For example, an individual may have seasonal manias, but his or her depressions do not regularly occur at a specific time of year.

  • A. There has been a regular temporal relationship between the onset of manic, hypomanic, or major depressive episodes and a particular time of the year (e.g. - in the fall or winter) in bipolar I or bipolar II disorder. Do not include cases in which there is an obvious effect of seasonally related psychosocial stressors (e.g. - regularly being unemployed every winter).
  • B. Full remissions (or a change from major depression to mania or hypomania or vice versa) also occur at a characteristic time of the year (e.g. - depression disappears in the spring)
  • C. In the last 2 years, the individual’s manic, hypomanic, or major depressive episodes have demonstrated a temporal seasonal relationship, as defined above, and no non-seasonal episodes of that polarity have occurred during that 2-year period.
  • D. Seasonal manias, hypomanias, or depressions (as described above) substantially outnumber any nonseasonal manias, hypomanias, or depressions that may have occurred over the individual’s lifetime.

Pediatric Bipolar

Screening and Rating Scales

Psychometric Scales for Bipolar Disorder

Name Rater Description Download
Young Mania Rating Scale (YMRS) Clinician Most frequently utilized to assess manic symptoms. 11 items on the patient’s subjective report over the last 48 hours plus clinical observations.[17] Takes 15–30 minutes to complete. YMRS Download
Mood Disorder Questionnaire (MDQ) Patient The MDQ screens for bipolar spectrum disorder, (which includes Bipolar I, Bipolar II and unspecified bipolar disorder). There are 13 self-rated questions. Although the original study claimed a 90% specificity and 70% sensitivity for an eventual diagnosis of bipolar disorder, more recent studies show that the MDQ risks falsely identifying individuals with bipolar disorder.[18][19][20] For example, borderline personality disorder, PTSD, substance use disorder, and childhood abuse are associated with false positives on the MDQ. More recent studies have shown that the positive predictive value of the MDQ is only around 55%.[21] MDQ Download

Pathophysiology

Genetics

Genome Wide Association Studies (GWAS) suggest that the ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) genes may be involved in the pathogenesis of bipolar disorder. Both of these genes for for ion channels, and suggest that channelopathies may play a role in the development of bipolar disorder.[22] Other candidate genes for bipolar disorder include:

Neuroimaging

Differential Diagnosis

It is important to keep your differential diagnosis broad to avoid overdiagnosis and misdiagnosis of bipolar disorder. Common comorbidities such as substance use disorders, impulse control disorders, anxiety disorders, and personality disorders such as borderline personality disorder have a significant symptom overlap with bipolar disorder.

  • Major depressive disorder or persistent depressive disorder
    • Major depressive disorder may also be accompanied by hypomanic or manic symptoms (but have fewer symptoms or for a shorter duration than required for mania or hypomania criteria). When the individual presents in an episode of major depression, one must depend on corroborating history regarding past episodes of mania or hypomania. Symptoms of irritability may be associated with either major depressive disorder or bipolar disorder, adding to diagnostic complexity.
  • Other bipolar disorders (e.g. - bipolar II)
    • Diagnosis of bipolar I disorder is differentiated from bipolar II disorder by determining whether there have been any past episodes of mania. Other specified and unspecified bipolar and related disorders should be differentiated from bipolar I and II disorders by considering whether either the episodes involving manic or hypomanic symptoms or the episodes of depressive symptoms fail to meet the full criteria for those conditions. Bipolar disorder due to another medical condition may be distinguished from bipolar I and II disorders by identifying, based on best clinical evidence, a causally related medical condition.
  • Bipolar or related disorder due to another medical condition
  • Substance‐ or medication‐induced mood disorder
    • Mood episodes are determined to be a consequence of a substance such as an illicit/recreational drug, or a medication (stimulants, steroids, L‐dopa or antidepressants) or toxin exposure. Episodes may also be related to intoxication or withdrawal. Substance use disorders may manifest with substance/medication-induced manic symptoms that should be distinguished from bipolar I disorder; response to mood stabilizers during a substance/medication-induced mania may not necessarily be diagnostic for bipolar disorder. There may be substantial overlap since individuals with bipolar I disorder may overuse substances during an episode. A primary diagnosis of bipolar disorder must be established based on symptoms that remain once substances are no longer being used.
  • Cyclothymic disorder
    • Hypomanic symptoms do not meet the full criteria for a hypomanic episode, and depressive symptoms do not meet the criteria for a major depressive episode.
  • Disruptive mood dysregulation disorder (DMDD)
    • In individuals with severe irritability, particularly children and adolescents, care must be taken to apply the diagnosis of bipolar disorder only to those who have a clear episode of mania or hypomania. This means a distinct time period and duration, in which the irritability was clearly different from the individual's baseline and also accompanied by the onset of Criterion B symptoms. When a child's irritability is persistent and severe, the diagnosis of disruptive mood dysregulation disorder would be more appropriate. When any child is being assessed for mania, it is essential that the symptoms represent a clear change from the child's typical behavior.
  • Psychotic disorders
    • Periods of psychotic symptoms in the absence of prominent mood symptoms. Consider onset, accompanying symptoms, pervious course and family history.
  • Generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or other anxiety disorders
    • Anxiety disorders need to be considered as either the primary disorder or a comorbid disorder. A careful history and psychiatric interview is needed to differentiate generalized anxiety disorder from bipolar disorder, since anxious ruminations may be mistaken for racing thoughts. Similarly, efforts to minimize anxious feelings may be misinterpreted by the clinician as impulsive behavior. Similarly, symptoms of posttraumatic stress disorder (PTSD) must be differentiated from bipolar disorder. It is helpful to assess the episodic nature of the symptoms described, as well as to consider symptom triggers to help differentiate between the disorders.
  • Attention-deficit/hyperactivity disorder (ADHD)
    • ADHD may be misdiagnosed as bipolar disorder, especially in adolescents and children. Many symptoms overlap with the symptoms of mania, such as rapid speech, racing thoughts, distractibility, and decreased need for sleep. One can avoid “double counting” symptoms toward both ADHD and bipolar disorder if the clinician clarifies whether the symptom(s) represents a distinct episode as opposed to the child's baseline personality/symptoms.
  • Personality disorders (can still co-occur with bipolar disorder)
    • A diagnosis of a personality disorder should not be made during an untreated mood episode. Symptoms must represent a distinct episode, and the noticeable increase over baseline required for the diagnosis of bipolar disorder must be present.
    • Borderline personality disorder
      • Instability of interpersonal relationships, self‐image and mood, with marked impulsivity and a central theme of intense abandonment fears. Borderline personality disorder has an early onset and long‐standing course. True euphoria and prolonged well‐functioning intervals are extremely rare.
      • Individuals with bipolar disorder are more likely to have a family history of bipolar illness, whereas self-harm and past sexual abuse are more likely in borderline personality disorder.[24]
    • Narcissistic personality disorder
      • Grandiosity, need for admiration and lack of empathy of early onset. Grandiosity not associated with mood changes or functional impairments.
    • Antisocial personality disorder
      • Early onset of disregard for, and violation of, the rights of others, which does not occur only in the context of a manic episode.
  • Obstructive sleep apnea
  • Vitamin B12 deficiency
  • Endocrine dysfunction
    • Hypo or hyperthyroidism
    • Hypercortisolemia
  • Infectious etiologies

Bipolar I vs. Bipolar II

There are key differences in the diagnostic criteria between bipolar I and bipolar II disorder. The table below outlines these differences.

Comparison of Bipolar I vs. Bipolar II

Bipolar I Bipolar II
Diagnostic Criteria manic episode only hypomanic episode + depressive episode
Length > 7 days > 4 days
Impairment Severe Minor to none
Hospitalization Possible No
Psychosis Possible No

Mixed Features: Mania and Hypomania Symptoms Can Also Occur During Depressive Episodes!

Bipolar vs. Depression

Since bipolar disorder often presents first with a depressive episode, individuals may be misdiagnosed with major depressive disorder instead of bipolar disorder. Patients often fail (unintentionally) to report hypomanic/manic episodes as well. A missed diagnosis of bipolar disorder can result in the worse prognosis and inadequate treatment.[26][27]

Features of Depression that May Increase Suspicion of a Bipolar vs Unipolar Illness

Adapted from: Mitchell, P. B. et al (2008). Diagnostic guidelines for bipolar depression: a probabilistic approach. Bipolar disorders, 10(1p2), 144-152.
Feature Suggests Bipolar Suggests Unipolar Depression
Symptomatology and Mental State Signs • Hypersomnia and/or increased daytime napping
• Hyperphagia and/or increased weight
• Other “atypical” depressive symptoms such as leaden paralysis
• Psychomotor retardation
• Psychotic features and/or pathological guilt
• Lability of mood, irritability, psychomotor agitation, racing thoughts 		• Initial insomnia/reduced sleep
• Appetite and/or weight loss
• Normal activity levels
• Somatic complaints
Course of Illness • Early onset of first depression (<25 years)
• Multiple prior episodes (≥5 episodes) 		• Late onset of first depression (>25 years)
• Long duration of current episode (>6 months)
Family History • Positive family history of bipolar disorder • Negative family history of bipolar disorder

Late-Life Bipolar Disorder

Investigations

Neuroimaging

Treatment

Medication

Mood Stabilizers and Predictors of Outcomes

Adapted from: Yatham, L. et al. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97–170.
Medication Use If Possible Adverse Events
Lithium • Classical euphoric grandiose mania (elated mood in the absence of depressive symptoms)
• Classical mania‐depression‐euthymia course
• Fewer prior episodes of illness
• Family history of bipolar and/or lithium response 		Renal impairment, thyroid dysfunction, worsening of psoriasis
Valproate • Both classical and dysphoric mania (mixed features)
• Predominant irritable or dysphoric mood
• Comorbid substance use
• History of traumatic brain injury 		Teratogen, and PCOS
Carbamazepine • History of traumatic brain injury
• Comorbid anxiety and substance use
• Schizoaffective disorder with mood-incongruent delusions
• Negative family history of bipolar disorder 		Teratogen, hepatic CYP enzyme autoinduction, risk of SJS/TEN as well
Lamotrigine • Predominant depressive symptoms (remember that lamotrigine does not treat mania!)
• Comorbid anxiety 		Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

For Women of Childbearing Age...

Contraceptive counselling and medication risks must be included as part of the comprehensive treatment plan for bipolar disorder. This is for two reasons:
  • Contraception efficacy: many of the treatments used in bipolar disorder, especially anticonvulsants (such as carbamazepine, topiramate, and lamotrigine) can significantly reduce the effectiveness of oral contraceptives (OCPs), and increase the risk for unintended pregnancy. On the flipside, OCPs can also reduce the efficacy of medications like lamotrigine.
  • Teratogenicity: valproate products (valproic acid, divalproex) have high teratogenic potential and also increase the risk for developmental disorders in infants exposed to valproate in utero. Thus, women on valproate products should be on contraception, and informed about the risks of using valproate during pregnancy. Additionally, individuals wishing to become pregnant should work with their clinician to switch off from valproate.
Acute Mania

Pharmacological Treatments for Acute Mania in Bipolar I

Adapted from: Yatham, L. et al. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97–170.
1st line Monotherapy: lithium, quetiapine (dose range 400 to 800 mg)[37], divalproex, asenapine, aripiprazole, paliperidone (>6mg), risperidone, cariprazine
Combination therapy: quetiapine + Li/DVP, aripiprazole + Li/DVP, risperidone + Li/DVP, asenapine + Li/DVP
2nd line Monotherapy: olanzapine, carbamazepine, ziprasidone, haloperidol, ECT
Combination therapy: olanzapine + Li/DVP, lithium + DVP
3rd line Monotherapy: chlorpromazine, clonazepam, clozapine
Combination therapy: Carbamazepine/oxcarbazepine + Li/DVP, haloperidol + Li/DVP, rTMS, tamoxifen, tamoxifen + Li/DVP
Not recommended Allopurinol, eslicarbazepine/licarbazepine, gabapentin, lamotrigine, Omega-3 fatty acids, topiramate, valnoctamide, zonisamide
Li = lithium, DVP = divalproex
Maintenance

Pharmacological Treatments for Maintenance Therapy in Bipolar I Disorder

Adapted from: Yatham, L. et al. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97–170.
1st line Monotherapy: lithium, quetiapine, divalproex, lamotrigine (limited efficacy in preventing mania), asenapine, aripiprazole, aripiprazole OM (once monthly)
Combination therapy: quetiapine + Li/DVP, aripiprazole + Li/DVP
2nd line Monotherapy: olanzapine, risperidone LAI, carbamazepine, paliperidone (>6 mg)
Adjunctive therapy: risperidone LAI
Combination therapy: lurasidone + Li/DVP, ziprasidone + Li/DVP
3rd line Combination therapy: aripiprazole + lamotrigine, olanzapine + fluoxetine
Adjunctive therapy: clozapine, gabapentin
Not recommended Monotherapy: perphenazine, tricyclic antidepressants
Li = lithium, DVP = divalproex
Depression

Mnemonic for Bipolar Depression Medications

Remember the 3 “L's” for bipolar depression: Lithium, Lurasidone, Lamotrigine.

Pharmacological Treatments for Acute Bipolar I Depression

Adapted from: Yatham, L. et al. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97–170.
1st line Monotherapy: quetiapine (target dose: 300 mg/day), lithium (target level: 0.8-1.2 meq/L), lamotrigine (minimum dose: 200 mg), lurasidone
Combination therapy: lurasidone + Li/DVP
Adjunctive therapy: lamotrigine
2nd line Monotherapy: divalproex, ECT, cariprazine
Combination therapy: olanzapine-fluoxetine (combination pill)
Adjunctive therapy: SSRIs/bupropion
3rd line Monotherapy: carbamazepine, olanzapine
Adjunctive therapy: aripiprazole, armodafinil, asenapine, eicosapentaenoic acid (EPA), ketamine (IV), light therapy ± total sleep deprivation, levothyroxine, modafinil, N‐acetylcysteine, pramipexole, repetitive transmagnetic stimulation (rTMS), SNRI/MAOI
Not recommended Monotherapy: antidepressant, aripiprazole
Combination therapy: lamotrigine + folic acid
Adjunctive therapy: mifepristone
Li = lithium, DVP = divalproex

Should Antidepressants Be Used in Bipolar I Depression?

  • Antidepressants should never be used as a single monotherapy treatment for bipolar I depression
  • Antidepressants should also never be used to treat a current mixed episode or in patients with a history of rapid cycling, even if the patient is on a mood stabilizer.
  • In general, there is very weak evidence for the use of antidepressants and bipolar I depression.
    • For certain patients, antidepressants could be used in conjunction with a mood stabilizer for acute short term treatment of bipolar depression, with the goal of tapering and discontinuing the antidepressant 6 to 8 weeks after full remission of depressive symptoms.

For a deeper dive into the literature, the STEP-BD trial showed that adjunctive treatment with antidepressants does not improve clinical outcomes in people with bipolar disorder taking a mood stabilizer.[41] Recent randomized clinical trials have shown that antidepressants may worsen outcomes in maintenance treatment of bipolar disorder as well.[42]

Summary

Pharmacological Treatments for Various Phases of Bipolar Disorder

Adapted from: Yatham, L. et al. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97–170.
Acute Mania Acute Depression Mania Prevention Depression Prevention Prevention of Any Mood Episode
Lithium Yes1 Yes2 Yes1 Yes1 Yes1
Quetiapine Yes1 Yes1 Yes1 Yes1 Yes1
Divalproex Yes1 Yes1 Yes3 Yes1 Yes1
Lamotrigine No! Yes1 Yes2 Yes1 Yes1
Asenapine Yes1 No data Yes2 Yes2 Yes2
Aripiprazole Yes1 Not recommended! Yes2 No Yes2
Paliperidone Yes1 No Yes2 No data Yes2
Olanzapine* Yes1 Yes1 Yes1 Yes1 Yes1
* = Olanzapine is generally no longer first-line given significant metabolic side effects. 1 = Level 1 evidence, 2 = Level 2 evidence, 3 = Level 3 evidence

Psychotherapy

Adjunctive Psychological Treatments in Bipolar Disorder

Adapted from: Yatham, L. et al (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
Mania Maintenance Bipolar Depression
1st line None • Psychoeducation (PE) None
2nd line None • Cognitive behavioural therapy (CBT)
• Family-focused therapy (FFT) 		• Cognitive behavioural therapy (CBT)
• Family-focused therapy (FFT)
3rd line None • Interpersonal and social rhythm therapy (IPSRT)
• Peer support 		• Interpersonal and social rhythm therapy (IPSRT)
Insufficient evidence None Cognitive and functional remediation, dialectical behavioural therapy (DBT), family/caregiver interventions, mindfulness‐based cognitive therapy (MBCT), online interventions Psychoeducation, cognitive and functional remediation, dialectical behavioural therapy (DBT), family/caregiver interventions, mindfulness‐based cognitive therapy (MBCT), online interventions

ECT

Electroconvulsive therapy is a second line treatment for bipolar mania and bipolar (I and II) depression. It is well-tolerated and safe, and may be useful in cases where rapid resolution of symptoms is required, such as in pregnancy where there is concern about maternal/fetal well-being.

Nutrition

Coenzyme Q10, likely due to its antioxidant and anti-inflammatory properties, has been found to improve symptoms of bipolar depression.[45]

Guidelines

Bipolar Disorder Guidelines

Guideline Location Year PDF Website
Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) Canada, International 2018 PDF Link
American Psychiatric Association (APA) USA 2002 PDF • Guideline (2002)
• Guideline Watch (2005)
• Quick Reference
National Institute for Health and Care Excellence (NICE) UK 2014 PDF Link
British Association for Psychopharmacology (BAP) UK 2016 PDF Link
Royal Australian and New Zealand College of Psychiatrists (RANZCP) AUS, NZ 2020 PDF Link

Resources

For Patients
For Providers
Articles
Research

References

1) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
2) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
3) Bellivier, F., Golmard, J. L., Rietschel, M., Schulze, T. G., Malafosse, A., Preisig, M., ... & Leboyer, M. (2003). Age at onset in bipolar I affective disorder: further evidence for three subgroups. American Journal of Psychiatry, 160(5), 999-1001.
4) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
5) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
6) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
7) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
8) Chen, C. K., Lee, C. Y., Lee, Y., Hung, C. F., Huang, Y. C., Lee, S. Y., ... & Wang, L. J. (2018). Could schizoaffective disorder, schizophrenia and bipolar I disorder be distinguishable using cognitive profiles?. Psychiatry research, 266, 79-84.
9) Huang, Y. C., Lee, Y., Lee, C. Y., Lin, P. Y., Hung, C. F., Lee, S. Y., & Wang, L. J. (2020). Defining cognitive and functional profiles in schizophrenia and affective disorders. BMC psychiatry, 20(1), 39.
10) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
11) McElroy, S. L. (2004). Diagnosing and treating comorbid (complicated) bipolar disorder. The Journal of clinical psychiatry, 65, 35-44.
12) Barnett, J. H., & Smoller, J. W. (2009). The genetics of bipolar disorder. Neuroscience, 164(1), 331-343.
13) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
14) Mnemonics in a mnutshell: 32 aids to psychiatric diagnosis. Current Psychiatry. 2008 October;7(10):27-33
15) Parry, P. I., & Levin, E. C. (2012). Pediatric bipolar disorder in an era of “mindless psychiatry”. Journal of Trauma & Dissociation, 13(1), 51-68.
16) Blader, J. C., & Carlson, G. A. (2007). Increased rates of bipolar disorder diagnoses among US child, adolescent, and adult inpatients, 1996–2004. Biological psychiatry, 62(2), 107-114.
17) Young, R. C., Biggs, J. T., Ziegler, V. E., & Meyer, D. A. (1978). A rating scale for mania: reliability, validity and sensitivity. The British Journal of Psychiatry, 133(5), 429-435.
18) Paterniti, S., & Bisserbe, J. C. (2018). Factors associated with false positives in MDQ screening for bipolar disorder: Insight into the construct validity of the scale. Journal of affective disorders, 238, 79-86.
19) Hirschfeld, R. M., Holzer, C., Calabrese, J. R., Weissman, M., Reed, M., Davies, M., ... & Tierce, J. (2003). Validity of the mood disorder questionnaire: a general population study. American Journal of Psychiatry, 160(1), 178-180.
20) Hirschfeld, R. M., Williams, J. B., Spitzer, R. L., Calabrese, J. R., Flynn, L., Keck Jr, P. E., ... & Zajecka, J. (2000). Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. American journal of psychiatry, 157(11), 1873-1875.
21) Paterniti, S., & Bisserbe, J. C. (2018). Factors associated with false positives in MDQ screening for bipolar disorder: Insight into the construct validity of the scale. Journal of affective disorders, 238, 79-86.
22) Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M, Morris DW, Elkin A, Muir WJ, McGhee KA, Williamson R, MacIntyre DJ, MacLean AW, St CD, Robinson M, Van Beck M, Pereira AC, Kandaswamy R, McQuillin A, Collier DA, Bass NJ, Young AH, Lawrence J, Ferrier IN, Anjorin A, Farmer A, Curtis D, Scolnick EM, McGuffin P, Daly MJ, Corvin AP, Holmans PA, Blackwood DH, Gurling HM, Owen MJ, Purcell SM, Sklar P, Craddock N; Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008 Sep;40(9):1056-8
23) Guzman, F. Lithium’s Mechanism of Action: An Illustrated Review
24) Ghaemi, S. N., Dalley, S., Catania, C., & Barroilhet, S. (2014). Bipolar or borderline: a clinical overview. Acta Psychiatrica Scandinavica, 130(2), 99-108.
25) Goldberg, J. F., Perlis, R. H., Bowden, C. L., Thase, M. E., Miklowitz, D. J., Marangell, L. B., Calabrese, J. R., Nierenberg, A. A., & Sachs, G. S. (2009). Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. The American journal of psychiatry, 166(2), 173–181.
26) Lish, J. D., Dime-Meenan, S., Whybrow, P. C., Price, R. A., & Hirschfeld, R. M. (1994). The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. Journal of affective disorders, 31(4), 281-294.
27) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
28) Prabhakar, D., & Balon, R. (2010). Late-onset bipolar disorder: a case for careful appraisal. Psychiatry (Edgmont), 7(1), 34.
29) Carlino, A. R., Stinnett, J. L., & Kim, D. R. (2013). New onset of bipolar disorder in late life. Psychosomatics, 54(1), 94-97.
30) Sajatovic, M., & Chen, P. (2011). Geriatric bipolar disorder. Psychiatric Clinics, 34(2), 319-333.
31) Balance Investigators. (2010). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. The Lancet, 375(9712), 385-395.
32) Smith, E. G., Austin, K. L., Kim, H. M., Eisen, S. V., Kilbourne, A. M., Miller, D. R., ... & Valenstein, M. (2015). Mortality associated with lithium and valproate treatment of US Veterans Health Administration patients with mental disorders. The British Journal of Psychiatry, 207(1), 55-63.
33) Yatham, Lakshmi N., et al. "Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013." Bipolar disorders 15.1 (2013): 1-44.
34) Lähteenvuo, M., Tanskanen, A., Taipale, H., Hoti, F., Vattulainen, P., Vieta, E., & Tiihonen, J. (2018). Real-world effectiveness of pharmacologic treatments for the prevention of rehospitalization in a Finnish nationwide cohort of patients with bipolar disorder. JAMA psychiatry.
35) Woods, S. W. (2000). The economic burden of bipolar disease. The Journal of clinical psychiatry.
36) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
37) Muneer, A. (2015). Pharmacotherapy of bipolar disorder with quetiapine: a recent literature review and an update. Clinical Psychopharmacology and Neuroscience, 13(1), 25.
38) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
39) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
40) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
41) Sachs, G. S., Nierenberg, A. A., Calabrese, J. R., Marangell, L. B., Wisniewski, S. R., Gyulai, L., ... & Ketter, T. A. (2007). Effectiveness of adjunctive antidepressant treatment for bipolar depression. New England Journal of Medicine, 356(17), 1711-1722.
42) Ghaemi, S. N., Whitham, E. A., Vohringer, P. A., Barroilhet, S. A., Amerio, A., Sverdlov, O., & Patkar, A. A. (2021). Citalopram for Acute and Preventive Efficacy in Bipolar Depression (CAPE-BD): a randomized, double-blind, placebo-controlled trial. The Journal of Clinical Psychiatry, 82(1), 0-0.
43) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
44) Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
45) Mehrpooya, M., Yasrebifar, F., Haghighi, M., Mohammadi, Y., & Jahangard, L. (2018). Evaluating the Effect of Coenzyme Q10 Augmentation on Treatment of Bipolar Depression: A Double-Blind Controlled Clinical Trial. Journal of clinical psychopharmacology, 38(5), 460-466.