Continuing Education Activity

Bipolar affective disorder is a chronic and complex disorder of mood that is characterized by a combination of manic (bipolar mania), hypomanic and depressive (bipolar depression) episodes, with substantial subsyndromal symptoms that commonly present between major mood episodes. It is one of the top causes of worldwide disability. Bipolar 1 disorder has been frequently associated with serious medical and psychiatric comorbidity, early mortality, high levels of functional disability, and compromised quality of life. The necessary feature of bipolar 1 disorder involves the occurrence of at least one lifetime manic episode, although depressive episodes are common. Bipolar 2 disorder needs the occurrence of at least one hypomanic episode and one major depressive episode. This activity reviews the etiology, pathophysiology, evaluation, and management of bipolar affective disorder and highlights the role of the interprofessional team in managing and improving care for patients with this condition. This activity also addresses the prognosis of bipolar affective disorder.

Objectives:

• Describe the etiology of bipolar affective disorder.
• Review screening and mental status exam findings associated with all subtypes of bipolar affective disorder.
• Outline the management options available for bipolar affective disorder with the most recent evidence-based data.
• Discuss interprofessional team strategies for improving care coordination and communication to advance the treatment of bipolar affective disorder and improve outcomes.

Introduction

"Mood" is defined as a ubiquitous and sustained feeling or emotion that dominates a person’s behavior and affects his perception. Mood disorders also known as affective disorders include unipolar and bipolar disorders. 

Hippocrates was the first to distinguish between different dispositions or humors--melancholic, choleric, phlegmatic, sanguine--but it was Jules Farley in 1854, who first described folie circulaire or the alternating cycle of euphoria and melancholia. In 1899, Emil Kraepelin then further elaborated upon this burgeoning nosological distinction as he distinguished the psychosis observed in manic-depressive disorders from that of dementia praecox (i.e. schizophrenia).    

Manic-depressive disorder--more contemporarily identified as bipolar disorder (BD)--is a chronic and complex disorder of mood that is characterized by a combination of manic, hypomanic, and depressive episodes, with subsyndromal symptoms extant in between the mood episodes.[1] It is one of the leading causes of worldwide disability and morbidity.[2] BD has been frequently associated with serious medical and psychiatric comorbidity, early mortality, high levels of functional disability, and compromised quality of life.[3] BD can be further subdivided into bipolar disorder I (BD I) and bipolar disorder II (BD II). The quintessential feature of BD I is the manifestation of at least one manic episode--although depressive episodes are common, only one manic episode in a lifetime is enough to label one with BD I. To be diagnosed with BD II, one must experience at least one hypomanic episode, without any history of any manic episodes. Both of these aforementioned manifestations must precipitate in the absence of any substance, iatrogenic agent, or organicity as such extant associations would be indicative of the diagnoses of 'substance/medication-induced bipolar and related disorder' and 'bipolar and related disorder due to another medical condition', respectively. Additionally, a less elucidated derivative of the bipolar spectrum is 'cyclothymic disorder' which is more analogous to a personality disorder in its chronicity and pervasiveness.

Etiology

Bipolar affective disorder can be caused by a variety of factors.[4] Some of those are listed below:

Biological Factors

1. Genetic Factors: The risk of bipolar disorder is 10-25% when one parent has a mood disorder. Twin studies have shown 70-90% concordance rates in monozygotic twins. Chromosomes 18q and 22q have the strongest evidence for linkage to bipolar disorder. Bipolar 1 disorder has the highest genetic link of all psychiatric disorders.[5]

2. Neuroanatomy: The prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala are important areas for emotion regulation, conditioning of responses, and behavior response to stimuli.

3. Structural and Functional Imaging: Abnormal hyperintensities in the subcortical regions, especially the thalamus, basal ganglia, and the periventricular area in bipolar disorder, indicated recurrent episodes and show neurodegeneration. Patients with severe depression or a family history of mood disorder show increased glucose metabolism in the limbic region with decreased metabolism of the anterior cerebral cortex.[6]

4. Biogenic Amines: Dysregulation of neurotransmitters that have been implicated in this disorder include dopamine, serotonin, and norepinephrine, however, the data have yet to converge to unveil a valid association.[4]

5. Second Messengers: G proteins or guanine binding nucleoproteins are targets for mood stabilizers. They interact with membrane receptors and form second messengers like cyclic adenosine monophosphate (cAMP ) and cyclic guanosine monophosphate (cGMP). Second messengers regulate neuronal membrane channels.[7]

6. Hormone Regulation Imbalance: Adrenocortical hyperactivity is observed in mania. Chronic stress decreases neurokinin brain-derived neurotrophic factor (BDNF), which impairs neurogenesis and neuroplasticity. The growth hormone is released after stimulation from dopamine and norepinephrine and its release inhibited by somatostatin. Increased CSF somatostatin levels are observed in mania.[4][7]

7. Immunological Factors: Chronic elevation of cytokines and interleukins associated with clinical severity.[7]

Psychosocial Factors

1. A significant life stressor can lead to neuronal changes such as neurotransmitter levels, synaptic signaling alterations, as well as neuronal loss. This is implicated in the first episode of the mood disorder, as well as the recurrence of subsequent episodes.

2. Those with coexistent histrionic, obsessive-compulsive, or borderline personality traits in the setting of BD are more prone to the precipitation of depressive episodes.[4]

Epidemiology

In the general population, the lifetime prevalence of BD is around 1% for BD I.[8][9] A large cross-sectional survey of 11 countries noted that the overall lifetime prevalence of bipolar spectrum disorders was 2-3%, with a prevalence of 0.4% for BD II.[10] Because of the ambiguity of its phenomenology, epidemiologic data on cyclothymia is equivocal, suggestive of a range of 0.5 to 6.3%.

Most studies suggest that BD I has an equal prevalence in both men and women, while others have recognized a higher prevalence of manic episodes--and thus bipolar type 1--in males and higher rates of bipolar type 2 in females.[10][11] Overall, the evidence is suggestive of an equal distribution between genders and ethnicity.

The mean age of onset of bipolar disorder is in early adulthood--18 to 20 years of age--although some findings are indicative of a later onset (>25 years of age).[9] A bimodal distribution has also been suggested, as noted by a large population-based cohort study, which found peaks in the age of onset at 15 to 24 years and at 45 to 54 years.[12][13] Of note, the precise distinction of the age of onset of BD is difficult to decipher as it can precipitate with subsyndromal manifestations or even be misattributed to another affective disorder.

Patients with mood disorders are at an increased risk of death by suicide. The incidence of death by suicide among patients with a diagnosis of bipolar affective disorder has been reported to be as high as 20 times more than the general population-- most notably when bipolar disorder is untreated.[14][15][16][17] About one in three to one in two patients with bipolar disorder attempt suicide at least once in the course of their lifetime, and approximately 15–20% of attempts are successful.[18]

Pathophysiology

Bipolar affective disorder is considered one of the most heritable psychiatric disorders; however, a multifactorial model, in which genes and the environment, in parallel with psychosocial stressors, dynamically interact to precipitate this phenomenon, is presently thought to be responsible.[19] Many alleles of small effect, which somewhat overlap with schizophrenia (e.g., CACNA1C, TENM4, and NCAN) and are described in genome-wide association studies, add to the polygenic risk of bipolar disorder.[19] 

Neurotrophic molecules, such as brain-derived neurotrophic factor (BDNF), have an important role in signaling pathways of dendritic sprouting and neural plasticity.[20] Dendritic spine loss has been observed in the post-mortem brain tissue of patients with bipolar affective disorder.[21] Other pathways that can affect neuronal interconnectivity are also being studied, which include dysfunction of mitochondria and endoplasmic reticulum stress, neuroinflammation, apoptosis, oxidation, and epigenetic changes, particularly histone and DNA methylation.[22]

History and Physical

The presentations of mania and depression will now be elucidated, however, patients can present in a mixed state which includes features from both 'poles' of BD.

General Appearance

A patient with mania is often hyperkinetic, unpredictable, and erratic. They often are garishly dressed, display negligence of social propriety--demonstrable via excessive friendliness, boundary violations, agitation,  or other improprieties--and appear to be unnaturally "happy" or euphoric, however, irritability is also observed, dispositionally. 

Mood and Affect

As previously stated, the mood is often elevated or euphoric, in mania. Affect is often heightened, intense, and extremely lability. Implicit with the affective lability of mania are hyperactivity and severe mobility. When presenting in a depressive state, the patient will report a sad or elegiac mood, while expressing a congruent affect (often tearful).

Speech

A manic patient will demonstrate pressured speech, which implies a rapid and continuous production of speech that is difficult to interrupt. Reciprocally, speech is slow and soft, in depression.

Perception

Mood congruent delusions may be present in either the depressed or manic phase (e.g. delusions of guilt during depressed phases or grandiose delusions of power and wealth during manic phases) A manic patient can also have mood-incongruent delusions.

Thought Process and Content

Patients with mania demonstrate easy distractibility, lack of concentration, illogical condensations, delusions of grandiosity, and flight of ideas. A depressed patient usually has negative thoughts and negative ruminations.

Sensorium and Cognition

Usually oriented to person, place, and time. Depressed patients may have some impairment in cognition and memory. Manic patients may have a grossly intact memory. Sometimes orientation is impaired and is called manic delirium.

Impulse Control

Extremely depressed patients demonstrate avolition and abulia--lack of willpower. It has been postulated that suicidal ideation originates during the depressive phases and is made manifest upon the transition to baseline or a subsequent manic state. Manic patients are threatening and assaultive.

Judgment and Insight

Impaired judgment is the distinctive feature of mania along with limited insight. Depressed patients often overemphasize their symptoms.

Reliability

Manic patients are usually unreliable in the information they provide. Depressed patients overemphasize negative symptoms and treatment failure.

Evaluation

The correct diagnosis of bipolar affective disorder is facilitated, to a large degree, by a general clinical psychiatric assessment with the patient and their relatives, to recognize the longitudinal course of the disorder.

Organicity, along with substance and iatrogenic causes, must first be ruled out, entailing a comprehensive medical examination (e.g. urine drug screen, serum alcohol levels, urinalysis, thyroid panel, medication profile, etc). Most laboratory results in BD are within normal limits. 

If the patient has already been diagnosed with bipolar affective disorder and has been on mood stabilizers for treatment, consider serum lithium, serum valproic acid levels, serum lamotrigine levels, or serum carbamazepine levels to determine therapeutic levels in order to titrate medication.

According to DSM-V

Mania, which is a feature of BD I, is diagnosable when:

• A distinct period of persistent and abnormally elevated, expansive, or irritable mood with the abnormal, persistent, increased goal-directed activity which lasts more than one week and is present most of the day almost every day.

• The mood disturbance causes social, occupational, and functional impairment with or without psychosis. There can also be a perceivable threat to self or others.

• Mood symptoms are not related to medication, illicit substances, or other medical conditions.

• The presence of three or more of the following symptoms during the episode, which is not usual behavior:

1. Grandiosity or elevated self-worth eg., unrealistic belief that one is powerful or influential

2. Decreased need for sleep

3. Pressured speech, talkative, fast speech

4. Flight of ideas or complain of racing thoughts

5. Distractibility and inability to focus easily jumps from one topic to another

6. Increased goal-directed activity or psychomotor agitation, appears restless, constant moving or tapping of feet

7. Engagement in activities that will have undesirable consequences, engaging in high-risk behavior

Hypomania, which can be a feature of BD I, BD II, or cyclothymia, is diagnosable when:

• A distinct period of persistent and abnormally elevated, expansive, or irritable mood with an abnormal, persistent, increased goal-directed activity that lasts at least four days and is present most of the day almost every day.

• Three or more symptoms of mania present.

• Mood symptoms are perceivable by others.

• No significant occupation or social functioning impairment and no psychosis.

• Hypomanic symptoms are independent of the action of medication, illicit substance, or another medical condition. Hypomania can be seen after antidepressant therapy initiation as well as after electroconvulsive therapy but when hypomania is related to bipolar disorder, the symptoms are present for a longer time and are more pronounced.

Major depressive episodes are present in BD I, BD II,  but not required for diagnosis. Five or more symptoms listed below present for more than two weeks which cause impairment in social and occupational functioning:

• A subjective or objective depressed mood eg., feeling empty, hopeless, sad, low, or observation by others that one is tearful

• Anhedonia or loss of interest in pleasurable activities

• Change in weight, loss, or gain, of 5% body weight within one month

• Change in sleep, insomnia, or hypersomnolence

• Psychomotor agitation or retardation (mostly objective)

• Guilt or worthlessness

• Decreased concentration, inability to focus

• Suicidal ideation with or without plan or thoughts of dying

The symptoms are not secondary to medication, illicit drugs, or other medical conditions.

The patient can also present with 'mixed features' signaling episodes of mania, depression, or hypomania accompanied by features of the opposite polarity. Manic or hypomanic episodes are signified with the distinction 'mixed features' when either full criteria for mania or hypomania is met along with at least 3 of the following symptoms: depressed mood, psychomotor retardation, asthenia, guilt, suicidal ideation, or anhedonia. Major depressive episodes are distinguished as mixed when the full criteria for major depression are met along with at least 3 of the following symptoms: elevated mood, grandiosity, verbose, flight of ideas, hyperkinesis, impulsivity, or insomnia.

When diagnosing bipolar disorder, it must be specified if the disorder is: 

1. Rapid cycling--at least four distinct mood episodes within the same twelve-month period.
2. With psychotic features--the presence of delusions, phobias or paranoid thoughts, auditory, visual or other hallucinations.
3. With mixed features--see above.
4. With atypical features--when a depressive episode has increased appetite, increased sleep, sensitivity to personal rejection.
5. With anxious distress--when the patient is uptight, tense, restless, and has feelings of loss of control and anxiety.
6. Has peripartum onset--which can be during pregnancy or within four weeks of delivery. A patient with a history of manic episodes postpartum has a high risk of relapse with future pregnancies.
7. The seasonal pattern--when a relationship can be observed with mania and a particular time of the year.

Treatment / Management

The primary step in the management of bipolar affective disorder is to confirm the diagnosis of mania or hypomania and define the patient’s mood state as the treatment approach differs significantly for hypomania, mania, depression, and euthymia. Various factors can affect pharmacological and psychological approaches; these comprise medical and psychiatric comorbidities, past or current treatments, treatment response or adverse effects in patients and relatives, and the patient’s inclination to be treated.

In acute management, the primary goals are to ensure the safety of patients and nearby people, achieve clinical and functional stabilization with the least possible adverse effects. Additionally, engagement in treatment and development of a therapeutic alliance is important in any chronic disorder that requires long-term adherence, and this collaboration is especially true during the first episode.[23]

Mood stabilizers and antipsychotics are the foundation of acute management of bipolar mania and depression.[24] Mood stabilizers are the main pharmacological agents for the treatment of bipolar affective disorder, particularly in the maintenance phase of mania. Lithium is the gold standard for the treatment of bipolar disorder as long-term use has demonstrated a reduction in suicide risk. 50%-70% of patients treated with lithium show a reduction in mania. However, lithium has a narrow therapeutic index, and serum lithium levels should be monitored. Carbamazepine and valproic acid are anticonvulsants that have a mood-stabilizing effect and are also utilized in many cases for acute manic episodes. Second generation or atypical antipsychotics like olanzapine, quetiapine, risperidone, ziprasidone are indicated as monotherapy or in combination with a mood stabilizer. Combination therapy using a mood stabilizer and an antipsychotic has shown a greater response than treatment with either single agent.[25][26] Of note, lurasidone is considered highly effective for depressive symptoms in bipolar affective disorder.[27] The FDA has approved 4 psychotropics in the setting of acute bipolar depression: lurasidone, cariprazine, quetiapine, and the olanzapine-fluoxetine combination.

Notably, evidence for the use of antidepressants to treat depression is not well understood, and these drugs should never be used as monotherapy in BD.[28] It has also been postulated that antidepressants can trigger a manic episode in patients with bipolar affective disorder, which is defined as a 'treatment emergent switch' or TEA.

Electroconvulsive therapy is extremely effective for treatment-resistant acute mood episodes like refractory depression or acute life-threatening mania, predominantly in patients with psychotic or catatonic features, and it is the best treatment for mania in a pregnant female.[29]

In long-term management, the main objectives are to prevent relapse of episodes and ensure functionality while optimizing treatment. Pharmacotherapy, usually consisting of a mood stabilizer alone or in combination with antipsychotic or antidepressant plus customized psychosocial interventions in euthymia, can reduce the chance of relapse, enhance treatment adherence, and decrease the number and duration of hospital admissions.[30][31] Psychoeducation has been shown to have significant prophylactic effects in individuals with bipolar disorder.[32][33] Other valuable treatments for patients include cognitive behavioral therapy, interpersonal and social rhythm therapy, and family-focused therapy.[34][35][36] Functional remediation has also shown efficacy in enhancing functioning ability in patients with bipolar 1 and bipolar 2 disorder with psychosocial functional deficits.[37][38]

Bipolar depression often persists longer, and it is very challenging to treat, needing a different approach from that used in unipolar depression. The broad consensus is that quetiapine, olanzapine, lamotrigine, lurasidone, and antidepressants have some efficacy but show varying tolerability.

Differential Diagnosis

• Major Depressive Disorder: The depressive episodes observed in MDD and BD can be indistinguishable, and thus a longitudinal history is paramount. Those with BD will report either a manic or hypomanic episode, which excludes the diagnosis of MDD. 

• Schizophrenia: Thought disorders can have mood features that can look like bipolar affective disorder, however, the mood symptomatology only manifests in the setting of the thought disorder, and not often.

• Substance-induced Bipolar Disorder: Mania and depression can both precipitate in the setting of substance use. A thorough laboratory evaluation should rule out the possibility of substance use to narrow the differential.

• Personality Disorders: Particularly borderline personality disorder and histrionic personality disorder, personality disorders have overlapping features with mania, hypomania, and depression.

• Attention-deficit/hyperactivity disorder (ADHD): ADHD can present with similar symptoms as mania in children and adolescents, however, there is a less episodic and undulant presentation than that witnessed in BD.

Toxicity and Side Effect Management

Medical comorbidities are quite prevalent in patients with bipolar disorder because of the adverse effects of treatment with mood stabilizers, anticonvulsants, antipsychotics, genetic vulnerability, and lifestyle factors (poor diet, lack of exercise, alcohol use, smoking). Keeping in mind the burden of these comorbidities and adverse effects of pharmacotherapy, regular monitoring of weight, glycemia, dyslipidemia, blood pressure, and liver function is necessary for patients with bipolar affective disorder.[39]

Blood concentrations of lithium and valproate, when taken by the patient, should be regularly monitored to ensure they are within the therapeutic range. In addition, renal and thyroid function testing is necessary because treatment with lithium is known to be associated with tubulointerstitial nephropathy, hypothyroidism, and nephrogenic diabetes insipidus.[39] For patients receiving valproate, the hepatic function should be monitored, and, in women, cases of polycystic ovary disease are known with valproate therapy.

Prognosis

Bipolar 1 disorder usually has a poor prognosis. 50% of patients experience a second episode within two years of the first episode.

Poor prognosis is associated with:

• Substance dependency
• Psychotic features
• Depression symptoms
• Interepisode depression
• Male gender

Lithium prophylaxis improves prognosis in about 50% of patients. About 45% of patients have a chronic disorder. The mean number of episodes of mania is 9, and the range is 2-30. More episodes indicate a poorer prognosis.

As discussed above, patients with bipolar affective disorder are at higher risk for suicidal ideation and attempts, which lead to a poorer prognosis.

Complications

The bipolar affective disorder has a progressive course and has implications on the patient’s cognitive and functional domains, in addition to affecting their physical health. Although patients with bipolar disorder may have normal or even higher cognition before diagnosis in many cognitive and neuroimaging studies, bipolar disorder has been related to significant neurocognitive deficits through all mood states, including periods of remission.[40][41][42] In addition to cognition and functioning, physical health is also affected profoundly in patients with bipolar disorder[43] Incidence of obesity, cardiovascular disorders, and diabetes is higher and arise earlier in the life course compared with the general population.[44] There are reports of increased mortality as well, with findings of one study which followed patients over a 30-year period showing that circulatory disorders and suicide are the main causes of death.[45]

Deterrence and Patient Education

It is important to educate patients and families on the importance of medication compliance, signs of hypomania, and mania. One of the greatest challenges includes ongoing engagement with treatment as most patients experience multiple manic, hypomanic, or depressive episodes in their life, and this is often secondary to medication non-compliance. Patients are asked to engage with both therapists and psychopharmacologists regularly and even support groups. Often patients may relapse even when they are adherent to medications. Support and ongoing psychoeducation of both patients and families are crucial in ongoing treatment.

Enhancing Healthcare Team Outcomes

Bipolar affective disorder is a serious mental disorder that results in impairments in the functionality of daily life, leading to increased costs for both patients and society. It is a multifaceted disease, and a comprehensive biological, social, and psychological approach should be employed in its management. The diagnosis of bipolar affective disorder frequently poses a diagnostic challenge. These patients may exhibit a variety of signs and symptoms such as depression, hypomania, mania, irritability, insomnia resulting in psychological distress over a long period of time. It is not always easy to obtain the exact timeline and chronology of symptoms, which frequently results in misdiagnosis. While the mental status exam of the patient may point towards the diagnosis of bipolar affective disorder, it is usually difficult to obtain a proper history of the patient's symptoms in one clinical visit. It is important to engage the patient in an empathic way and develop a therapeutic alliance to facilitate better treatment results.

While a psychiatrist or nurse practitioner is almost always involved in the care of patients with bipolar affective disorder, it is important to obtain input about the patient's behavior and symptoms from the interdisciplinary psychologists, activity therapists, nurses, nurse practitioners, physician assistants, pharmacists, behavioral health associates, and social workers especially in the inpatient unit and emergency services while taking care of the patient in these settings. Nurses are vital members of the interprofessional group as they monitor the patient's behavior, medication compliance, vital signs, and assist with psychoeducation of the patient and family. Psychopharmacologists are specialized in the field of psychotropic medications and called upon for complex medication management and education. To improve outcomes, an interdisciplinary approach is a mainstay in the treatment of patients with bipolar disorder. An interprofessional team that provides a holistic and integrated approach to patient care can help achieve the best possible outcomes. Once the patient is discharged to home, shelter, or supportive housing, consultation should be made with a social worker and community nurses who can monitor the patient and make referrals as needed.