Bipolar

1. BIPOLAR AFFECTIVE
DISORDER
RASHIED MUATH MAHMOUD SHIYYAB

2. DEFENITION
• Bipolar disorder (BD) is characterized by chronically occurring episodes of mania or hypomania alternating with depression and is often misdiagnosed initially.
• Bipolar and related disorders include bipolar I disorder (BD-I), bipolar II disorder (BD-II), cyclothymic disorder, other specified bipolar and related disorders, and
bipolar or related disorders, unspecified. The diagnostic label of "bipolar affective disorders" in the International Classification of Diseases 10th Revision (ICD-10)
was changed to “bipolar disorders” in the ICD-11. The section on bipolar disorders in the ICD-11 is labeled “bipolar and related disorders,” which is consistent with
the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).[1]
• A World Health Organization study showed “remarkably similar” international prevalence rates, severity, impact, and comorbidities of bipolar spectrum disorder,
defined as BD-I, BD-II, and subthreshold bipolar. The aggregate lifetime prevalence of the bipolar spectrum was 2.4%.[2]
• BD is often difficult to recognize because symptoms overlap with other psychiatric disorders, psychiatric and somatic comorbidity is common, and patients may
lack insight into their conditions, particularly hypomania. Treatment involves pharmacotherapy and psychosocial interventions, but mood relapse and incomplete
response occur, particularly with depression. Continual reevaluation and treatment modification are commonly required during the long-term care of these patients.
Management of comorbid psychiatric and chronic medical conditions may also be necessary. This activity provides an overview of the etiology, classification,
evaluation, and management of bipolar affective disorder

3. ETIOLOGY
• Currently, the etiology of BD is unknown but appears to be due to an interaction of genetic, epigenetic, neurochemical, and environmental
factors. Heritability is well established. Numerous genetic loci have been implicated as increasing the risk of BD; the first was noted in
1987 with "DNA markers" on the short arm of chromosome 11. Since then, an association has been made between at least 30 genes and an
increased risk of the condition.
• Although it is difficult to establish causation between life events and the development of BD, childhood maltreatment, particularly
emotional abuse or neglect, has been linked to the later development of the condition. Other stressful life events associated with
developing BD include childbirth, divorce, unemployment, disability, and early parental loss.In adulthood, more than 60% of patients with
BD report at least one "stressful life event" before a manic or depressive episode in the preceding 6 months.
• The etiology of BD is thought to involve imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine
and serotonin, and intracellular signaling systems that regulate mood. However, no singular dysfunction of these neurotransmitter systems
has been identified.
• In a recent neuroimaging review article, the ENIGMA Bipolar Disorder Working Group stated, "Overall, these studies point to a diffuse
pattern of brain alterations including smaller subcortical volumes, lower cortical thickness and altered white matter integrity in groups of
individuals with bipolar disorder compared to healthy controls.Neuroimaging studies have also shown evidence of changes in functional
connectivity

4. EPIDEMIOLOGY
• In the World Mental Health Survey Initiative, the use of mental health services for the bipolar spectrum
(BD-I, BD-II, and subthreshold BD) concluded, “Despite cross-site variation in the prevalence rates of
bipolar spectrum disorder, the severity, impact, and patterns of comorbidity were remarkably similar
internationally.” The aggregate lifetime prevalence of BD-I was 0.6%, BD-II 0.4%, subthreshold BD
1.4%, and bipolar spectrum 2.4%.
• There are two peaks in the age of onset: 15-24 years and 45-54 years, with more than 70% of individuals
manifesting clinical characteristics of the condition before 25 years of age. Bipolar disorder shows a
relatively equal distribution across sex, ethnicity, and urban compared to rural areas.
• Cyclothymia is associated with a lifetime prevalence of approximately 0.4-1% and a male-to-female ratio
of 1:1.

5. PATHOPHYSIOLOGY
• As with the etiology, the pathophysiology of BD is unknown and is thought to involve interactions between multiple genetic,
neurochemical, and environmental factors. A recent neurobiology review article discusses in detail the “genetic components,
signaling pathways, biochemical changes, and neuroimaging findings” in BD.
• Evidence supports a strong genetic component and an epigenetic contribution. Human studies have shown changes in brain-
derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in patients
with BD, indicating neurotrophic signaling is a molecular mechanism associated with decreased neuroplasticity. Other proposed
mechanisms include mitochondrial dysfunction, oxidative stress, immune-inflammatory imbalance, and compromised
hypothalamic-pituitary-adrenal axis. Additionally, neuroimaging studies have shown “evidence of change in regional activity,
functional connectivity, neuronal activity, and bioenergetics associated with BD,” and anatomic studies have revealed dendritic
spine loss in the dorsolateral prefrontal cortex in the post-mortem brain tissue of patients with BD.
• As mentioned, imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine and serotonin,
and intracellular signaling systems that regulate mood are thought to be involved. However, no singular dysfunction of these
neurotransmitter systems has been identified.

6. HISTORY AND PHYSICAL
• Because bipolar disorder is a clinical diagnosis, making the correct diagnosis requires a comprehensive clinical assessment, including the directed patient interview, preferably supplemented by interviews of their relatives and
the longitudinal course of their condition. Currently, there is no biomarker or neuroimaging study to aid in making the diagnosis.
• Most patients with bipolar disorder are not correctly diagnosed until approximately 6 to 10 years after first contact with a healthcare provider, despite the presence of clinical characteristics of the condition. Notably,
misdiagnosing BD after first contact differs from not recognizing the transition from major depressive disorder (MDD), the most common index presentation, to BD. Estimates of patients transitioning to BD within three years
of an MDD diagnosis range from 20-30%; therefore, clinicians must maintain an awareness of the potential for this transition when caring for patients with MDD who initially screened negative for BD.Also, subthreshold
hypomanic symptoms can occur in as many as 40% of patients with MDD.
• Although not highly sensitive and specific, self-report screening tools for BD may aid clinicians in making an accurate diagnosis. The most studied screening tools are the Mood Disorders Questionnaire (sensitivity 80%,
specificity 70%) and the Hypomania Checklist 32 (sensitivity 82%, specificity 57%). Positive results should motivate the clinician to conduct a thorough clinical assessment for bipolar disorder.
• A significant diagnostic challenge is distinguishing between unipolar and bipolar depression because episodes of unipolar major depression and bipolar depression have the same general diagnostic criteria. Clinicians must
inquire about past manic, hypomanic, and depressive episodes in patients presenting with symptoms of a depressive episode. Inquiry into past hypomanic or manic episodes is particularly important for patients with early onset
of their first depressive episode (ie, in patients younger than 25 years), a high number of lifetime depressive episodes (5 or more episodes), and a family history of bipolar disorder. These findings in the patient’s history have
been shown to increase the likelihood of a bipolar rather than a unipolar diagnosis.
• Other factors increasing the likelihood of a diagnostic change from MDD to BD include the presence of psychosis, unresponsiveness to antidepressants, the induction of manic or hypomanic symptoms by antidepressant drug
treatment, and polymorbidity, defined as 3 or more comorbid conditions.

7. DIAGNOSIS
• General DSM-5 Diagnostic Criteria for Bipolar and Related Disorders (American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders 5th edition (DSM-5). Arlington, VA: American
Psychiatric Publishing; 2013)
• BD-I: Criteria met for at least one manic episode, which might have been preceded or followed by a hypomanic episode or major depressive episode (hypomanic or major depressive episodes are not required for the
diagnosis).
• BD-II: Criteria met for at least one current or past hypomanic episode and a major depressive episode; no manic episodes.
• Cyclothymic disorder: Hypomanic symptoms that do not meet the criteria for hypomanic episodes and depressive symptoms that do not meet the criteria for major depressive episodes in numerousperiods (at least
half the time) for at least 2 years (1 year in those aged ≤18 years); criteria for major depressive, manic, or hypomanic episodes have never been met.
• Specified bipolar and related disorders: Bipolar-like phenomena that do not meet the criteria for BD-I, BD-II, or cyclothymic disorder due to insufficient duration or severity, ie, 1) short-duration hypomanic
episodes and major depressive disorder, 2) hypomanic episodes with insufficient symptoms and major depressive episode, 3) hypomanic episode without a prior major depressive episode, and 4) short-duration
cyclothymia.
• Unspecified bipolar and related disorders: Characteristic symptoms of bipolar and related disorders that cause clinically significant distress or impairment in social, occupational, or other important areas of
functioning but do not meet the full criteria for any category previously mentioned.
• The symptoms and episodes used to diagnose these disorders must not be related to the physiological effects of a substance or general medical condition.
• BD-I and BD-II can be further specified as rapid cycling or seasonal pattern and whether the episodes have psychotic features, catatonia, anxious distress, melancholic features, or peripartum onset. Rapid cycling
refers to 4 or more distinct mood episodes during a 12-month period.
• Mood-congruent delusions may be present in either a depressive or manic episode, including delusions of guilt or grandiose delusions of power and wealth. Psychotic features, by definition, are absent in hypomanic
episodes

8. DIAGNOSIS
• To better account for "mixed features," the current diagnostic criteria implements specifiers. Manic or hypomanic episodes with mixed features meet the full criteria for mania or hypomania and have at least 3 of the following
signs or symptoms: depressed mood, anhedonia, psychomotor retardation, fatigue, excessive guilt, or recurrent thoughts of death. Major depressive episodes with mixed features meet the full criteria for a major depressive
episode and have at least 3 of the following signs or symptoms: expansive mood, grandiosity, increased talkativeness, flight of ideas, increased goal-directed activity, indulgence in activities with a high potential for "painful
consequences," and decreased need for sleep. The mixed features must be present during "most days."
• DSM-5 Diagnostic Criteria for Bipolar I Disorder
• For a diagnosis of BD-I, it is necessary to meet the following criteria for a manic episode. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes (hypomanic or major
depressive episodes are not required for the diagnosis).
• A manic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 7 consecutive days or requiring hospitalization. The presence of 3 or more of the
following is required to qualify as a manic episode. If the mood is irritable, at least 4 of the following must be present:
• Inflated self-esteem or grandiosity
• Decreased need for sleep
• A compulsion to keep talking or being more talkative than usual
• Flight of ideas or racing thoughts
• High distractability
• Increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation (non-goal-directed activity)
• Excessive involvement in activities that have a high potential for painful consequences, such as engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments

9. DIAGNOSIS
• episode is not attributable to the physiological effects of a substance or general medical condition.
• The symptoms of a manic episode are markedly more severe than those of a hypomanic episode and result in impaired social or occupational functioning or require hospitalization.
• DSM-5 Diagnostic Criteria for Bipolar II Disorder
• For a diagnosis of BD-II, it is necessary to have met the criteria for at least one current or past hypomanic episode and a major depressive episode without a manic episode (see below for major depressive episode criteria).
• A hypomanic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 4 consecutive days. The presence of 3 or more of the following is required to
qualify as a hypomanic episode. If the mood is irritable, at least 4 of the following must be present:
• Inflated self-esteem or grandiosity
• Decreased need for sleep
• A compulsion to keep talking or being more talkative than usual
• Flight of ideas or racing thoughts
• High distractability
• Increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation (non-goal-directed activity)
• Excessive involvement in activities that have a high potential for painful consequences, such as engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments
• The episode is an unequivocal change in functioning, uncharacteristic of the person and observable by others. Also, the episode is not severe enough to cause marked impairment, is not due to the physiological effects of a
substance or general medical condition, and there is no psychosis (if present, this is mania by definition).

10. TREATMENT
• Although numerous clinical practice guidelines exist for the treatment and management of bipolar disorder, there is not enough consistency to generate a ‘meta-consensus’
model.Authors of a recent systematic review concluded, “The absence of a uniform language and recommendations in current guidelines may be an additional complicating factor
in the implementation of evidence-based treatments in BD.The following is an abbreviated synthesis of guidelines published by the National Institute for Health and Care
Excellence (NICE), British Association for Psychopharmacology, International College of Neuro-Psychopharmacology (CINP), Canadian Network for Mood and Anxiety
Treatments (CANMAT), International Society for Bipolar Disorders (ISBD), and Indian Psychiatric Society (IPS).
• Manic Episode
• Mania is considered a medical emergency and often requires psychiatric hospitalization. Initial treatment is aimed at stabilization of the potentially or acutely agitated patient to
help de-escalate distress, mitigate potentially dangerous behavior, and facilitate the patient assessment and evaluation. When possible, a calming environment with minimal stimuli
should be provided. Adjunctive benzodiazepines may be used concomitantly with mood stabilizers and antipsychotic drugs to reduce agitation and promote sleep.
• The patient’s current medications must be considered. For example, a second drug is recommended if the patient presents while the condition is already managed with lithium
monotherapy. Also, antidepressants are usually tapered and discontinued in a manic phase. First-line monotherapy includes a mood stabilizer, such as lithium or valproate, or an
antipsychotic, such as aripiprazole, asenapine, cariprazine, quetiapine, or risperidone.
• Add another medication if symptoms are inadequately controlled, or the mania is very severe. Combination treatments include lithium or valproate with either aripiprazole,
asenapine, olanzapine, quetiapine, or risperidone. Electroconvulsive therapy (ECT) may be considered as monotherapy or as part of combination therapy in patients whose mania is
particularly severe or treatment-resistant and in women with severe mania who are pregnant.
• Valproate should not be used for women of childbearing potential due to the unacceptable risk to the fetus of teratogenesis and impaired intellectual development