Bipolar Disorders: Comprehensive Notes
Mood disorder (affective disorder), continuum from unipolar depression to bipolar illness.
DSM-5 Classification:
Created a category for ‘Bipolar and Related Disorders’.
Not classified under either psychotic or affective disorders.
ICD-10 Classification:
Classified under mood disorders.
DSM-5 Subclassifications:
Bipolar I disorder.
Bipolar II disorder.
Cyclothymia.
Residual categories of atypical forms.
Subclassification based on the severity and duration of manic (or hypomanic) and depressive episodes.
Manic Episodes:
Hyperactivity.
Increased self-esteem.
Grandiosity.
Reduced need for sleep.
Expansive mood and behavior.
Psychotic symptoms.
Depressive Episodes:
Decreased energy.
Sadness.
Social withdrawal.
Hypersomnia.
Low self-esteem.
Psychosis:
Can occur during depressive episodes, more frequent during mania.
Hypomania:
Milder and shorter form of mania.
Individuals have relatively intact judgment.
Mixed Symptoms:
Acute episodes can include symptoms at both poles.
Remission and Latency:
Patients might achieve full remission and have symptom-free periods.
The disorder is assumed to be latent during these periods with optimal management.
Residual Symptoms:
Residual and subthreshold symptoms can persist, making functional recovery difficult, especially after multiple episodes.
Management:
Pharmacological and nonpharmacological treatments for acute phases.
Long-term therapy to prevent episode recurrence.
Epidemiology
Global Prevalence:
Affects >1% of the global population.
Lifetime prevalence:
Bipolar I disorder: 0.6%.
Bipolar II disorder: 0.4%.
Sub-threshold manifestations: 1.4%.
Broader bipolar spectrum: 2.4%.
Some studies report higher rates, e.g., a global 12-month prevalence of 1.5% and a lifetime prevalence of 2.1% for bipolar I disorder according to DSM-5 criteria.
Onset:
Independent of ethnicity, nationality, and socioeconomic status.
Prevalence of bipolar I disorder is similar in men and women.
Bipolar II disorder is more common in females.
Begins in youth, with a mean age of onset of ~20 years.
Earlier age of onset associated with greater comorbidity and onset beginning with depression.
Diagnosis and management usually commence in young adulthood.
5-year delay to diagnosis from the onset of symptoms has been shown in some studies, though variable data reported.
Longer time to diagnosis in patients with comorbidities and depressive onset polarity.
Duration of Untreated Illness (DUI):
Time between the first episode and adequate management.
Drives prognosis.
Longer DUI associated with increased suicide attempts and longer duration of illness.
Global Burden of Disease:
5 of the top 20 causes of disability are due to mental illnesses.
Bipolar disorders are the 17th leading cause of global burden of disease.
Mental illness accounted for 32.4% of years lived with disability and 13.0% of disability-adjusted life years.
Leads to functional impairment and reduced quality of life.
Burden extends to family members, with caregiver burden and depression being common.
High costs to society due to direct health-care costs and the costs of disability, which predominate.
Impact is greatest in younger individuals, disrupting developmental, relationship, educational, and occupational milestones.
Comorbidities
Psychiatric Comorbidities:
Anxiety disorders.
Substance use disorders.
Attention-deficit/hyperactivity disorder.
Personality disorders.
Make diagnosis and management more difficult; associated with poorer outcomes.
Nonpsychiatric Comorbidities:
Metabolic syndrome.
Diabetes mellitus.
Osteoporosis.
Fibromyalgia.
Other endocrine and cardiovascular disorders.
Metabolic syndrome is mainly driven by an unhealthy lifestyle and use of antipsychotic medications.
Premature Mortality:
Comorbid disorders associated with a greater risk of premature mortality in patients with bipolar disorders than in the general population.
Obesity:
Comorbid obesity is associated with poorer outcomes of bipolar disorders with lithium-based or quetiapine-based treatment.
Late-Onset Mania:
A later-in-life onset of mania might be suggestive of an underlying medical comorbidity.
Suicide
Rate:
Bipolar disorders have the highest suicide rate among the affective disorders.
Up to 20-times higher than the rate among the general population.
Approximately one-third to one-half of patients with bipolar disorders will attempt suicide at least once.
~15–20% of suicide attempts are lethal.
Risk Factors for Suicide Attempts:
A younger age at onset.
Female sex.
Depressive polarity.
Anxiety.
Substance abuse.
Personality disorder comorbidity.
Risk Factors for Completed Suicide:
A first-degree family history of suicide.
Male sex.
Treatment:
The risk of suicide is higher in untreated patients than those treated with antiepileptic drugs.
Mechanisms/Pathophysiology
Genetics
Complex Disorder:
multifactorial genesis: both genetic factors, such as common and rare variants, and environmental factors contribute.
Heritability:
Estimated to be up to 85%, one of the highest estimates for psychiatric disorders.
A multifactorial model of gene–environment interaction is believed to best fit this disorder.
GWAS Findings:
Significant genetic associations have been detected in 18 regions throughout the genome, many of which have been replicated.
Associated alleles have small effects (ORs <1.3), very large case–control samples are needed to validate these findings.
First pathway analyses have suggested major roles for calcium signal transmission, the glutamatergic system, hormone regulation, microRNAs and histone and immune pathways, although these data are preliminary.
Intracellular calcium signalling was suggested to have a role in the pathophysiology of bipolar disorders several decades ago.
Rare Variants:
Can also be relevant for disease development if they have a high penetrance and, therefore, convey an increased risk of the disease.
Classified according to their genomic size into single-nucleotide variants, smaller insertions and deletions and larger copy number variants (CNVs; deletions or duplications of large DNA sequences of 1kb to 3Mb that often affect several genes).
Most extensive results are available for CNV studies, compared with other neuropsychiatric conditions such as schizophrenia, autism spectrum disorder and intellectual disability, these studies in bipolar disorders have not produced robust results.
Some studies showed the accumulation of rare CNVs in patients with bipolar disorders, especially in those with early-onset disease; however, these findings could not always be reproduced.
One meta-analysis reported an association between three CNVs and bipolar disorders (duplications at 1q21.1 and 16p11.2 and deletions at 3q29) that had all previously been associated with schizophrenia.
Next-Generation Sequencing:
Expected to discover novel rare variants and corroborate previous findings.
Predictive Power:
Genetic variants that have been associated with bipolar disorders cannot be used to predict individual risk, the course of the disorders or the effects of medication.
The polygenic nature of these disorders makes it unlikely that a deterministic prediction will be possible in the future.
Future Prospects:
Speculate that ~100 loci will be identified from GWAS for bipolar disorders and major depressive disorder combined, which will narrow the gap between these conditions and schizophrenia, for which >100 loci have been identified.
Data from these studies should improve our understanding of the pathways and mechanisms underlying bipolar disorders and related traits and could potentially spur the development of novel pharmacological targets or lead to innovative drug repurposing trials.
Pharmacogenetics:
The influence of genetic variation on the pharmacokinetics and pharmacodynamics of pharmacological therapies and could, in principle, contribute to personalized medicine.
Studies in bipolar disorders have mainly encompassed candidate gene studies with small samples and have focused on lithium response.
No robustly replicated findings have been produced because of the small sample sizes of these studies and the different phenotypic definitions applied.
Largest GWAS for lithium response included 2,563 patients from >20 clinical centres in 4 continents, was performed by the Consortium on Lithium Genetics and reported a significant association with a locus on chromosome 21, which encodes the long, non-coding RNAs AL157359.3 and AL157359.4.
Poorer response to lithium in patients with bipolar disorders who have a higher genetic loading for schizophrenia has been reported by the Consortium on Lithium Genetics.
Further replication studies are necessary and causal associations between the associated markers and their expression need to be evaluated.
Environmental and Medical Risk Factors
Environmental Factors:
Perinatal risk factors such as caesarean section delivery, maternal influenza infection, maternal smoking during pregnancy and high paternal age have been implicated in increasing the risk of bipolar disorders.
Life events, particularly childhood adverse events, have classically been described as risk factors of bipolar disorders as well as predictors of a more-torpid course.
Drug misuse has the same role; consumption of cannabis or other drugs during adolescence might lead to the early onset of bipolar disorders and a more-severe course.
Treatment with antidepressants without mood stabilizers can induce hypomanic or manic episodes, unmasking bipolar disorders.
Other therapies associated with mood switches: corticosteroids, androgens, electroconvulsive therapy (ECT), isoniazid, and chloroquine.
Medical Conditions:
Associated with risk of bipolar disorders: multiple sclerosis, stroke, systemic lupus erythematosus, and endocrine disorders (such as Cushing syndrome and Addison disease).
Subthreshold hypothyroidism has been closely associated with rapid-cycling bipolar disorders.
Change of season and increased light exposure have also been described as triggers of bipolar disorders.
Pathophysiology
Monoamine Neurotransmitter Systems:
Historically, mood disorders were thought to result from an imbalance in the monoamine neurotransmitter systems, including the serotonergic, noradrenergic and — in particular — dopaminergic pathways.
No singular dysfunction in these systems has been identified.
Endocrine Functions:
Have been widely studied in mood disorders, including the analysis of hormone levels in the blood and urine and the evaluation of the neuroendocrine systems, particularly the hypothalamic–pituitary–thyroid axis and the hypothalamic–pituitary–adrenal axis.
The early rebound of cortisol in the dexamethasone suppression test has been generally reported in affective illness.
Synaptic and Neural Plasticity:
Current studies are more focused on the modulation of synaptic and neural plasticity in brain regions, such as the prefrontal cortex, hippocampus, amygdala and other regions of the limbic system, in bipolar disorder.
Dendritic spine loss has been reported in the prefrontal cortex in post-mortem tissue from patients with bipolar disorders.
Cellular and Molecular Alterations:
Can alter neuronal interconnectivity: mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation, oxidation, apoptosis, and epigenetic changes.
Whether dysfunction of these pathways contributes to the development of bipolar disorder is not known.
Other Fields of Research:
Induced pluripotent stem cells (iPSCs) derived from patients with bipolar disorders, used to examine hyperexcitability in iPSC-derived neurons.
Studies examining the possible role of the gut–brain axis; alterations in the gut microbiota composition or concentration might activate immuno-inflammatory processes, changes in neuronal membrane permeability, and oxidative stress.
Biphasic Energy Shift:
Corresponding monitoring of phasic dysregulation in mood, sleep, and behavior is attracting attention.
Neuroprogression:
Aligned with the notion of the progressive course of bipolar disorders, first described by Kraepelin and recently encompassed by the concept of neuroprogression. The shortening of the interepisode interval after each episode recurrence and the reduced probability of treatment response with progression in a subset of patients putatively result from neurobiological interrelated processes in the brain.
Kindling hypothesis: alterations in brain plasticity lead to a gradual sensitization to stressors, which increases vulnerability to episode recurrence.
Allostatic hypothesis: repeated neurobiological stress, such as during an episode, requires biological adjustments that can increase allostatic load, increasing the risk of further episodes and precipitating and accelerating progressive illness.
Encompasses the pathological ‘rewiring’ of the brain that occurs in parallel to the clinical and neurocognitive deterioration during the course of bipolar disorders.
Alterations implicated in neuroprogression: increased neurodegeneration, neuronal apoptosis, neurotoxic susceptibility, and altered neuroplasticity, which are driven by changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress, and neurogenesis.
Neuroimaging changes in bipolar disorders are progressive and include grey matter loss in the left pars opercularis, left fusiform gyrus, left rostral middle frontal cortex, and the hippcampus.
Staging models have been proposed according to the model of neuroprogression based on the number of relapses and functional impairment, although these are not currently used in clinical practice.
Diagnosis, Screening, and Prevention
Classification
Bipolar I Disorder:
Characterized by episodes of mania.
Diagnosis requires only a history of mania or the presence of mania; episodes of major depression are not required.
~5% of patients with bipolar I disorder experience only manic episodes (unipolar mania).
Hypomanic symptoms can occur.
Psychosis can also occur (up to 75% of patients with an acute manic episode).
Patients were found to be symptomatically ill in 47.3% of follow-up weeks, with depressive symptoms during 31.9% of follow-up weeks and manic or hypomanic symptoms for 8.9% of follow-up weeks. Subsyndromal symptoms were three-times more frequent than syndromal episodes.
Bipolar II Disorder:
Characterized by at least one hypomanic episode and one major depressive episode.
Symptoms must not be due to substance or medication use, or to other psychiatric or medical conditions.
The course of illness is usually characterized by substantial and often prolonged periods of depression and periodic hypomanic symptoms.
Degree of functional impairment and suicide risk is about the same for patients with bipolar II disorder as for those with bipolar I disorder.
Longitudinal studies have suggested that bipolar II disorder is a stable diagnosis that persists throughout the lifetime of an individual.
Psychotic symptoms can occur during bipolar II depressive episodes (up to 50% of patients).
Patients were symptomatically ill in 53.9% of follow-up weeks, with symptoms of depression in 50.3% of follow-up weeks and hypomania in 1.3% of follow-up weeks. Subsyndromal symptoms were three-times more frequent than major depressive symptoms.
Cyclothymia:
Mood instability for >2 years with both hypomanic and depressive symptoms that do not meet the criteria for hypomanic or depressive episodes.
≥30% of people diagnosed with cyclothymia develop a bipolar disorder, predominantly bipolar II disorder.
Other Specified Bipolar and Unspecified Bipolar and Related Disorders:
Replace the ‘not otherwise specified’ category in the DSM-IV.
Include short-duration hypomanic episodes (2–3 days) and major depressive episodes, hypomanic episodes with insufficient symptoms and major depressive episodes, hypomanic episodes without prior major depressive episode, and short-duration cyclothymia (<2 years).
The category ‘unspecified bipolar and related disorders’ is intended for temporary use.
Substance-Induced and Medication-Induced Bipolar and Related Disorders:
Includes symptoms of bipolar disorders such as mood instability and mania that are caused by any substance, medication or medical conditions.
When the causal element is removed, bipolar symptoms should not recur.
Specifiers:
Used to provide additional detail about the nature of the symptoms of an episode or throughout the course of the disorder.
New additions to the DSM-5 bipolar and related disorders category include the specifiers ‘with anxious distress’ and ‘with mixed features.’ Other specifiers were continued from the DSM-IV to DSM-5, such as ‘with rapid cycling’, ‘with melancholic features’ or ‘with atypical features’ during depressive episodes and ‘with psychotic features’.
Other specifiers include ‘with peripartum onset’ and ‘with seasonal pattern,’ which can be used for depressive and hypomanic or manic symptoms. Specifiers to be considered for inclusion in future updates to the DSM include predominant polarity (that is, either manic or depressive polarity), the presence of cognitive impairment, family history of bipolar disorders, and age at onset (for example, using 18 years of age as a cut-off to define early onset).
The ‘with mixed features’ specifier can, for the first time, be used for symptoms of major depressive disorder or bipolar disorders; individuals in a manic episode can simultaneously experience symptoms of depression or, conversely, that patients can experience hypomanic symptoms during a depressive episode.
Mixed symptoms are associated with a more torpid course of disease and a higher likelihood of suicide, defined by symptoms that occur only during hypomanic, manic, or depressive episodes.
Diagnostic Work-Up
Recognizing Symptoms:
Individuals are typically very conscious of and sensitive to their depressive symptoms but do not recognize their hypomanic or manic symptoms.
Ask patients whether they have periods of depressive symptoms in which they have excessive energy or periods of extreme irritability and high activity.
Identification of past or current hypomanic or manic symptoms in patients who present with depression is critically important.
Asking individuals about changes in activity and energy levels, not just mood, is also important.
Including family members or partners in the evaluation is crucial.
Screening:
Screening patients for suicide intent or plan is very important.
Screening instruments that may be of possible benefit include life charting, the Young Mania Rating Scale and the Hypomania/Mania Symptom Checklist (HCL-32).
Screening tools for bipolar disorders such as the Mood Disorders Questionnaire and HCL-32 are often used but have low sensitivity and specificity, especially in the community setting.
Major depressive episodes are similar in bipolar disorders and major depressive disorder, although mixed features are more common in patients with bipolar disorders than in those with major depression.
Evaluate depressive symptoms with self-report questionnaires (Patient Health Questionnaire-9 (PHQ-9) or the Inventory of Depressive Symptomatology (IDS) or clinician-driven forms (Hamilton Rating Scale for Depression and the clinician version of the IDS).
Prevention
Early Interventions:
Some studies have suggested that early interventions in high-risk children and adolescents alter the course and development of bipolar disorders.
Individuals at highest risk, such as children or adolescents with subsyndromal manic symptoms or children of patients with bipolar disorders, are providing important new information.
Environmental Factors:
Role of environmental factors (such as diet, physical activity and smoking, as well as stress, substance abuse or neurological insult) in the development of bipolar disorders is increasingly appreciated.
Biological Symptoms:
Some groups are trying to identify the earliest biological symptoms of bipolar disorders and interventions that could change the course of illness.
Management
Treatment Goals:
Effective treatment of acute depressive and hypomanic or manic symptoms and the prevention of relapses are essential.
Management Components:
Involves the acute treatment of manic or hypomanic episodes in addition to maintenance therapy to prevent relapses and further episodes.
Lithium was the first medication approved by the US FDA for the treatment of acute mania.
Approvals of most of these therapies were based on results from randomized, double-blind, placebo-controlled studies using DSM-IV diagnostic criteria.
Enhancing adherence is one of the cornerstones in the management of patients with bipolar disorders.
Balancing short-term and long-term effectiveness and safety for all drugs in patients with bipolar disorders is essential.
Treatment of Acute Mania
Pharmacological Therapy:
Cornerstone treatment for acute mania, although nonpharmacological treatments can be used in patients with treatment-resistant and severe mania.
Differences in the reported efficacy of the FDA-approved therapies for the treatment of mania in adults are small.
Adverse-effect profiles of therapies for mania is widely variable.
More-recent meta-analysis supports that when a patient does not respond after 1–2 weeks, a different medication should be considered; the combination of a mood stabilizer and an antipsychotic, especially for more-severe illness, may be a better choice than either medication alone.
Antipsychotic risperidone had a higher efficacy than lithium and divalproex sodium but was associated with more-severe metabolic adverse effects.
Other Therapies:
ECT can also be used for the treatment of acute mania, especially in patients with refractory mania or those with aggressive behaviour and/or psychosis.
Studies showed the efficacy of repetitive transcranial magnetic stimulation of the right prefrontal cortex for the treatment of acute mania in adults.
Blue light-blocking glasses (when used as an additive to standard pharmacological treatment) in reducing manic symptoms compared with standard treatment alone.
Cognitive–behavioural therapy (CBT) was suggested to improve the severity of manic symptoms in one meta-analysis.
Treatments for Acute Depression
Approved Medications:
Fewer studies focus on depression, and only three medications — all antipsychotics — have been approved by the FDA for bipolar depression.
Sensitivity to Treatment:
Patients with depression are more sensitive to, but less tolerant of, pharmacological treatments — especially antipsychotics — than they are during mania.
Lower starting dose and slower titration might be necessary for patients with depression.
Monitoring:
Antipsychotic-induced metabolic abnormalities have become a major concern, and monitoring weight changes and metabolic profiles at each health-care visit should be routine.
Off-Label and Combinatorial Therapy:
Given the limited number of approved medications for bipolar depression, off-label use of therapies, or combinatorial therapy, is common.
Treatments, including anticonvulsants (such as divalproex and lamotrigine), olanzapine monotherapy and combined lithium and lamotrigine therapy, were superior to placebo in reducing the severity of depressive symptoms in patients with bipolar disorders.
Quetiapine–lamotrigine combination therapy was superior to quetiapine alone; Lurasidone has shown compelling results in acute depression in trials in children and adolescents with bipolar disorders.
Anti-Inflammatory Agents:
Might also have antidepressant effects in bipolar depression when used adjunctive to conventional therapy.
Antidepressants:
The controversy surrounding the efficacy of antidepressants in acute bipolar depression and the risk of mood switching to hypomanic episodes, manic episodes or mixed states, particularly with monotherapy, remains unsettled.
Nonpharmacological Treatments:
Include ECT, repetitive transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, lifestyle interventions and psychotherapies; ECT is commonly used for treatment-refractory depression.
Psychotherapy, such as psychoeducation, CBT, family-focused therapy, dialectical behaviour therapy, mindfulness-based CBT and interpersonal and social rhythm therapy, might be useful primarily as adjunctive treatments for managing bipolar depression.
Maintenance Treatment
Preventive Strategy:
Considering the recurrent and chronic nature of bipolar disorders, optimal long-term management requires a preventive strategy that includes pharmacological treatments, psychological therapies and lifestyle approaches.
Pharmacotherapy and Psychosocial Interventions:
Can decrease the risk of relapse, improve treatment adherence and reduce the number and length of hospitalizations.
Lithium:
Remains one of the most effective drugs for the prevention of both manic and depressive episodes.
Lithium monotherapy and combined lithium–valproate therapy were found to be more likely to prevent relapses in patients with bipolar I disorder than valproate monotherapy, regardless of the severity of illness in the BALANCE study.
Adjunctive lithium to optimized personalized treatment had no additional benefit compared with optimized personalized treatment alone.
Associated with a decline in renal function and the development of hypothyroidism and hypercalcaemia following long-term use.
Quetiapine:
And combined quetiapine–lithium and quetiapine–divalproex therapy have also been suggested as suitable therapies for the maintenance treatment of patients with bipolar disorders; polarity index of drug nearly to 1 equal efficacy in preventing manicure and depressive episodes.
Alignment with Predominant Polarity:
Pharmacological maintenance treatment should be aligned with the patient’s predominant polarity, which is defined as the pole at which a patient has at least twice as many episodes as at the other pole.
Psychoeducation:
Has shown long-lasting prophylactic effects in individuals with bipolar disorders who attended group psychoeducation for 6 months; at 5-year follow-up, patients who received psychoeducation had a longer time to recurrence, had fewer recurrences, spent less time in an episode and had reduced duration of hospitalization.
Functional Remediation:
Recently, functional remediation (a restoring psychosocial therapy that uses ecological neurocognitive techniques) has improved functioning in patients with bipolar I disorder and patients with bipolar II disorder with psychosocial functional impairment; improvement in psychosocial functioning has been shown to remain after 1‑year follow-up.
Internet-Based Approaches:
Internet-based approaches and applications are gaining traction and are starting to be used in clinics.
Valproate and Carbamazepine:
Not recommended for the treatment of women of childbearing age as they increase the risks of spina bifida and low IQ in offspring.
Quality of Life
Reduced Quality of Life:
Associated with reduced quality of life that can be more severe than that which occurs in other mood or anxiety disorders; poor quality of life correlates with depressive symptoms more than manic or hypomanic symptoms. Associated with residual depressive symptoms that can occur during remission and the high comorbidity of bipolar disorders with anxiety disorders.
Factors Affecting Quality of Life:
Also comprises individuals’ perceptions of their position in life in the context of their culture, value system, personal goals, expectations, and standards.
Unemployment rate is 4–10 times higher and the divorce and separation rate is 2–3 times higher in patients with bipolar disorders than in the general population.
Cognitive Impairment:
Presence of persistent cognitive impairment, including impairments in memory and executive function.
Substantial cognitive impairment has been reported in 50–70% of patients during periods of remission.
Functional remediation is a recently developed psychological intervention that aims to restore psychosocial functioning in patients with several disorders.
Outlook
Evolving Concept:
Over the past 30 years, the traditional concept of ‘bipolar disorder’ has evolved into a range of interconnected conditions that vary in terms of severity, frequency and polarity of mood shifts; severe affective psychoses and milder syndromes, such as cyclothymia, are now recognized under the umbrella term of bipolarity and might share some common aspects of their pathophysiology and response to treatments.
Study Design and Experimental Techniques:
Need to widen our horizon and use new techniques and strategies; diagnostic criteria should still be studied, focusing on the biology underlying the course, outcome and recovery of these disorders; sample sizes of pharmacogenetics studies should be increased, and genomic approaches should be complemented using other techniques, such as epigenomics, proteomics, transcriptomics and metabolomics.
Staging and Stage-Specific Treatments:
Awareness of the importance of staging bipolar disorders is increasing, which will establish more tailored pharmacological and psychological treatments; interest in early intervention is also increasing .Early intervention needs to be minimally invasive and almost free of adverse effects, given the nonspecific prodromal symptoms and the high risk of false positives.
New Therapies and Personalized Treatment:
Improvements in our understanding of the pathophysiology of bipolar disorders are expected and should lead to more accurate diagnosis and improved treatments.
New treatments based on chemical, physical and psychological paradigms may be designed to tackle specific dimensions of the disease; of the drugs in the current pipeline, 50% are derived from currently available therapies that are based on traditional targets, such as dopamine and serotonin receptor antagonists or inhibition of monoamine transport, among others.