Abstract
The Indian Psychiatric Society has previously published guidelines for the management of bipolar disorder (BD) in adults (2017) and children and adolescents (2019). The present guideline summarizes the major advancements in the management of BD since these publications. To make the guideline handier for the clinical practitioner, we have made several structural changes compared to the 2017 guideline. First: we have adopted a phase-specific approach with different sections and management algorithms for each major phase of BD (mania, depression, and mixed episodes in bipolar type I disorder [BD-I] and depression in bipolar type II disorder [BD-II]). Second: for better clarity and ease of adoption, we have structured our suggestions into first, second, and third-line treatments; these rankings are based on the composite of evidence, experience, and consensus ratings of efficacy, tolerability, availability, and affordability. Third: a separate section for BD-II disorder has been added, given its relatively high prevalence in the Indian setting. Fourth: we have added a detailed section on special treatment considerations, where practical issues such as the management of comorbidities, treatment adherence, the role of polypharmacy, clozapine, emerging treatments, and long-acting injectables, as well as the reproductive safety of medications in BD, are discussed. Finally, we have added an expert consensus section where we present our consensus opinions on common dilemmas in the management of BD. We liberally use tables and flowcharts to enhance understanding and uptake of the suggestions offered. We hope these guidelines promote evidence-informed decision-making in the management of BD.
Keywords: Antidepressants, antipsychotics, bipolar disorder, clinical practice guidelines, lithium, mood stabilizers
INTRODUCTION
This is the third clinical practice guideline document from the Indian Psychiatric Society on bipolar disorders (BD). The first general guideline, published in 2017, comprehensively outlined the assessment and management principles for BD among adults.[1] The second guideline, published in 2019, pertained exclusively to children and adolescents.[2] In recent years, several empirical insights have enhanced our understanding of the burden of BD and its management. For instance, data from the National Mental Health Survey (NMHS) 2016, published in 2023, showed a weighted current prevalence of 0.3% and a lifetime prevalence of 0.5% with moderate to severe disability, and a treatment gap of 70.4%.[3] The ongoing NMHS 2 reveals a lifetime prevalence of 0.7% after 30% of data collection (unpublished data); the most striking finding is the consistent treatment gap of 70% for BD in India.
BD, by its inherent description, is an episodic disorder; the long-term course in most patients follow a highly varying pattern, in terms of the duration, number, and frequency of episodes. It is practically impossible to predict the type and timing of the next episode. Extended periods of euthymia lasting, on occasions, for several years without any intervention are also a natural reality of the course of BD that should always be kept in mind, while interpreting the prophylactic efficacy (mood stabilization) of medications.
Accumulated knowledge and research evidence have challenged conventional beliefs that have dominated our practice for decades. For example, antipsychotic maintenance therapy is increasingly favored over traditional mood stabilizers (lithium, valproate, and carbamazepine/oxcarbazepine) in a subset of patients with BD.[4] In the present guidelines, we have attempted to cover these and other nuances in the management of BD. Our approach to formulating these guidelines was to ground evidence-based information from India and the West within local contextual and practical challenges, to offer suggestions for management that are as evidence-based as possible, while being user-friendly for everyday clinical practice.
Though primarily written for secondary and tertiary care settings, primary care practitioners may also find these guidelines helpful. Every major section in this document has a management algorithm summarizing the suggested pharmacological strategies, ordered hierarchically to enhance the utility of the guideline. The hierarchical sequencing of treatment options in this guideline document was informed by a synthesis of global evidence and pragmatic considerations relevant to the Indian context, including treatment availability, cost, and Indian evidence. We add that a formal analysis of costs and related issues was not conducted when preparing this document; therefore, practitioners must exercise their judgment when selecting pharmacological agents from those suggested.
This iteration of the BD management guideline differs from the previous version in several structural aspects. First, and most importantly, we have chosen a phase-specific approach to formulate management suggestions in BD. This was to make it handier for the clinical practitioner, who commonly refers to practice guidelines to know the next treatment options when faced with a difficult-to-treat mania or depression, rather than for general reading. Second, we have incorporated indicative Indian data into every major section to better contextualize and support the management suggestions offered. We have also included relevant data on the management of bipolar type II disorder (BD-II) and special considerations in the treatment of BD, with a particular focus on the pragmatic aspects of management. Finally, we have included an expert consensus section where we offer our consensus opinions on common clinical dilemmas in the management of BD. This section is expected to provide practical guidance to professionals.
These clinical practice guidelines are not a substitute for domain knowledge, clinical competence, and professional judgment. Practitioners must apply their judgment and discretion when using these guidelines and tailor the management plan to fit the individual patient and family’s unique treatment needs and circumstances, treatment setting, and available resources.
ASSESSMENT
Assessment of suspected bipolar disorder
BD typically presents in late adolescence or early adulthood. Interviewing the patient and caregiver is essential to elicit a comprehensive history in individuals presenting with mood symptoms. Specific symptoms, such as overtalkativeness manifesting as flight of ideas, are more distinctive of mania, and guilt is more unique to depression. Some symptoms, such as irritability, can be present in both mania, and depression.
It is vital to understand the initial presentation, including age of onset, duration of episodes, predominant polarity, polarity sequence, nature and extent of inter-episodic symptoms, and functioning, in addition to the nature of any psychosocial stressor(s). For a complete list of domains to assess, readers are referred to Table 1. Delineating specific illness presentations such as peripartum onset, seasonal pattern, catatonic or psychotic or mixed features, melancholic symptoms, rapid cycling, mood-congruent, and mood-incongruent psychotic features is also essential to plan management. Validated screening instruments such as the Mood Disorder Questionnaire (MDQ)[5] and the Bipolar Spectrum Diagnostic Scale (BSDS)[6] may be used to screen patients for latent bipolarity, particularly in those with recurrent depression, and identify those who need a more detailed evaluation.
Table 1.
Assessment of bipolar disorder
|
• Socio-demographics
• Onset of illness
• Course
• Current episode
• Associated clinical features
• Precipitating factors
• Psychosocial stressors (such as discrete life events or chronic stressors) • Comorbid psychiatric and substance use disorder • Comorbid physical illness • Treatment history
• Family history
• Psychosocial aspects of caregiving
|
Differential diagnoses
Proper attention must be paid to collecting history and conducting mental state examination, especially during the initial part of the illness, where it may be challenging to distinguish symptoms of mania from other psychiatric diagnoses such as acute transient psychotic disorder, schizoaffective disorder, major depressive disorder, and personality disorders [Table 2]. A possibility of substance-induced mood disorder should be considered if there is a temporal association of mood symptoms with the use of implicating substances, such as alcohol, cannabis, or opioids. This issue can be clarified by exploring the chronology of substance use relative to the onset and course of mood symptoms, to distinguish substance-induced mood disorder from independent mood disorder. The timeline follow-back method can be used to help patients recall their patterns of substance use and significant life events over a given time period.[7]
Table 2.
Differential diagnoses of bipolar disorder
| Diagnosis | Differentiating features |
|---|---|
| Major depressive disorder | Predominantly depressed mood only, insomnia, reduced appetite, weight, late onset, negative family history of bipolarity, manic or hypomanic episodes not present. |
| Substance-induced mood disorder | History of substance or medication use that can produce mood symptoms, such as alcohol, cannabis, synthetic cannabinoid, opioid, and so on. Mood episodes associated with intoxication or withdrawal. |
| Secondary mania | Neurological conditions (stroke, epilepsy, head trauma), iatrogenic drug use (e.g., corticosteroids), electrolyte imbalance, thyroid disease, dementia. |
| Personality disorders | More pervasive course, lack of inter-episodic well-functioning intervals, significant issues in interpersonal relationships, sense of abandonment. |
The most common diagnostic dilemma, particularly when patients present with a first episode of depression, is in distinguishing BD from major depressive disorder (MDD). Table 3 lists the differentiating features of unipolar vs bipolar depression.[8]
Table 3.
Differentiating symptom profiles of unipolar and bipolar depression
| Unipolar depression | Bipolar depression |
|---|---|
| Later onset (third or fourth decade of life) Insomnia Reduced appetite Reduced weight Negative family history of bipolarity Manic or hypomanic episodes are not present Long duration of depressive episodes |
Younger onset (second or early third decade of life) Frequent episodes Psychomotor retardation Psychotic features Catatonic symptoms Past suicide attempts Family history of bipolarity Atypical depressive symptoms Antidepressant-induced manic symptoms |
Assessment of confirmed bipolar disorder
Assessment of the current episode must include an evaluation of the severity, polarity, risk of suicide, agitation, presence of psychotic symptoms, and functional impairment [Table 1]. Use of rater-administered tools such as the Young Mania Rating Scale (YMRS) for manic episode and the Hamilton Depression Rating Scale (HDRS) for depressive episode helps assess baseline symptom severity, informs triaging and management plans, and supports tracking improvement over time. Self-report measures such as the Patient Health Questionnaire (PHQ)-9 for depression help save clinician resources; however, there is a dearth of similar translated and validated self-report measures for mania. While severe disruptions in mood are easily identifiable, it may not be the case with milder presentations. When in doubt, daily monitoring of mood symptoms through mood charting can help confirm a diagnosis of BD.
Suicide is one of the leading causes of death in patients with BD. Hence, it is crucial to monitor the risk of suicide and suicidal ideation. Sociodemographic and clinical risk factors can help determine the level of suicide risk. Factors associated with an increased risk of suicide attempts in BD include female sex, younger age at onset, predominant depressive polarity, greater number and longer duration of episodes, persistent residual symptoms, comorbid substance use and personality disorders, rapid cycling, family history of suicide, previous suicide attempts, and comorbid anxiety, substance use, and borderline personality disorder.[9] A comprehensive suicide risk assessment is essential to identify and mitigate the risk.[10]
Clinicians may use the National Institute of Mental Health Life-Chart Method (NIMH-LCM) for systematic assessment of the long-term course of BD.[11] NIMH-LCM helps assess different phases of BD and the response to treatment. It also supports illness severity stratification (mild/moderate/severe) based on a distinct shift from normal mood and association with functional impairment. Typically, mild episodes are associated with little or no functional impairment, moderate episodes with notable functional difficulty, and severe episodes with marked functional impairment.
Many patients with BD have comorbid psychiatric and medical conditions. All patients with BD, particularly those with early onset or adolescent onset, must be carefully evaluated for psychiatric comorbidities, including attention-deficit/hyperactivity disorder (ADHD), impulse control disorder, anxiety disorder, borderline personality disorder, and substance use disorder. The presence of psychiatric comorbidities increases the complexity of presentation and functional impairment. Common medical comorbidities in BD include metabolic syndrome, hypertension, diabetes mellitus, and endocrine disorders [Table 4].[12] Given the serious consequences of medical comorbidity in BD,[13] we emphasize the need for a comprehensive physical examination and adequate physical workup in BD.
Table 4.
Common medical and psychiatric comorbidities in bipolar disorder
| Medical comorbidities |
| Metabolic syndrome Hypertension Diabetes mellitus Hypothyroidism |
| Psychiatric comorbidities |
| Substance use disorder Anxiety disorder Obsessive-compulsive disorder Personality disorder Attention-deficit/hyperactivity disorder |
A comprehensive medical assessment should be performed before initiating pharmacotherapy in patients with BD, including physical examination, body mass index (BMI), and baseline investigations. Clinical examination should be conducted as soon as possible in patients who are uncooperative. Pregnancy should be ruled out in women of childbearing age.
Assessment of caregivers
Assessment of caregivers of patients with BD involves evaluating their knowledge about the illness and their attitudes toward management [Box 1]. Addressing burnout, perceived stigma, and emotional burden among caregivers is also essential. The Family Burden Interview Schedule (FBIS)[14] and Burden Assessment Schedule (BAS)[15] can be used to quantify caregiver burden in this group.[16] Readers are referred elsewhere for more information, suggestions, and resources for caregivers.[17]
Box 1: Key domains in the assessment of caregivers of patients with bipolar disorder
Assess for burden, stress, and burnout
Presence of psychiatric disorders
Overall physical health and medical comorbidities
Perceived social support
Knowledge and attitudes to BD and treatment
Perceived stigma
Quality of life
PHARMACOLOGICAL MANAGEMENT OF MANIC EPISODES
Treatment of acute mania
The goals of pharmacological management in acute mania are to rapidly and safely alleviate symptoms, minimize risk of harm to self or others, and restore psychosocial functioning.[18] Rapid control of symptoms may strengthen the therapeutic alliance. If excitement, aggression, or impulsivity is marked and accompanied by definitive risk of harm to self or others, it may be necessary to admit the patient to enable more intensive and effective management.
Management of psychomotor excitement or agitation
Agitation and psychomotor excitement are common, important, and often immediate foci of attention, when managing acute mania. Verbal de-escalation techniques should be tried first, followed by oral agents, and then parenteral agents. Since agitation is part of the clinical manifestations of mania, specific anti-manic treatments listed in the next section should be considered first because it is assumed that effective treatment of mania will also effectively control agitation. However, for agitation that persists despite adequate pharmacotherapy for mania or when the agitation and psychomotor excitement are severe enough to warrant independent and immediate attention, the following options may be considered.
First-line pharmacological treatment options for severe agitation in mania include intramuscular (IM) lorazepam, IM haloperidol + IM promethazine,[19] and IM olanzapine; second-line options include sublingual asenapine, IM haloperidol + IM midazolam, and olanzapine orally disintegrating tablets (ODT). Third-line options are per oral (PO) haloperidol, PO quetiapine, and PO risperidone.[20] Round-the-clock safety monitoring (vitals and adequate hydration) is mandatory for all patients on parenteral agents for control of agitation. At the time of writing, sublingual dexmedetomidine, approved by the United States Food and Drug Administration (FDA) for treatment of agitation associated with bipolar type I disorder (BD-I) and BD-II, has not yet been introduced in India.
Treating drug-naïve patients
The choice of initial treatment should be guided by factors such as efficacy and safety considerations, need for rapid symptom resolution, availability, accessibility, costs, and, finally, their efficacy in preventing long-term manic or depressive relapses. Below, we list the evidence-based monotherapy and combination therapy agents, along with their respective doses and titration protocols. For agents discussed in this section, only additional information, if relevant, is presented in subsequent sections. For all agents discussed in this section, it is preferable to continue treatment for at least 1–2 weeks,[20] after which efficacy and tolerability may be reevaluated, and treatment may be modified, as appropriate.
Before starting treatment, the first step is to assess the patient’s medication status. For patients in their first episode of the illness or carrying a lifetime BD diagnosis and have either defaulted or are not on any active maintenance treatment, the first-line medications are lithium, divalproex, risperidone, quetiapine, aripiprazole, asenapine, and cariprazine[20]; all these agents have replicated evidence of efficacy and may be considered first-line monotherapy options. It should be noted that most antipsychotics, including first-generation ones, are efficacious in mania; however, the suggested first-line agents are preferred with the intent to continue them into the maintenance phase, when clinically indicated. In patients with higher index severity of symptoms or those with psychotic symptoms, a combination of any of the first-line antipsychotics, along with lithium or divalproex, may be considered. Oral benzodiazepines (such as clonazepam or lorazepam) may be added to the treatment regimen for managing daytime agitation and insomnia in mania as a temporary measure.
Limited evidence from trials suggests that combination therapy may be superior to monotherapy in acute mania.[21] However, this must be balanced against the increased risk of adverse events with combination therapy. Agents such as carbamazepine, olanzapine, ziprasidone, and haloperidol may be considered second-line agents primarily due to their relatively less favorable safety profile rather than efficacy considerations. This is an important consideration because efficacious acute-phase treatments are often continued into the maintenance phase.
If first-line monotherapy or combination therapy does not elicit a response at adequate doses within 2 weeks[20] (for most anti-manic agents, noticeable benefits are seen during week 1 itself) or if the first-line treatment is not tolerated, an acceptable approach would be to try an alternate first-line agent. As a general recommendation for all illness phases, whether to switch or add-on depends on the extent of response, presence of adverse effects, and severity of manic (or illness) symptoms; if the first treatment has elicited some response, then consideration may be given to dose optimization or adding another first-line agent. A treatment switch may be considered if the treatment is deemed a failure or not tolerated.
If multiple trials of first-line agents have failed, a trial of monotherapy with second-line agents or a combination of a second-line agent with a first-line agent (such as lithium plus olanzapine) may be considered. Readers may note that the combination of lithium and valproate, though often used by clinicians, derives its evidence base for acute mania largely from uncontrolled studies.[22,23] Brief pulse electroconvulsive therapy (ECT) may be considered as a second-line treatment option or even earlier during treatment if severe aggression or agitation needs to be controlled or when there is a need for rapid response. Bifrontal electrode placement in ECT has been associated with faster response and fewer cognitive adverse effects compared to bitemporal placement.[24,25]
Third-line options for acute mania with more limited evidence include monotherapy or combination therapy with chlorpromazine or clozapine, and combination treatment with haloperidol and carbamazepine or oxcarbazepine, or other combinations of first-line agents not tried earlier. Endoxifen has a limited evidence base for acute mania and is discussed later (see subsection on “Role of ketamine/esketamine and endoxifen in management of bipolar disorder”). One Indian randomized controlled trial (RCT) found benefits for adjunctive, high-frequency, suprathreshold, right prefrontal repetitive transcranial magnetic stimulation (rTMS) in acute bipolar mania[26]; however inconsistent findings were noted in trials conducted elsewhere.[27] Figure 1 summarizes the pharmacological algorithm for managing acute mania, while Table 5 summarizes the target doses of commonly used anti-manic agents.
Figure 1.
Algorithm for acute pharmacological management of mania
Table 5.
Dosing suggestions for treatment of acute manic episode[20]
| Name of agent | Dosing suggestions |
|---|---|
| Mood stabilizers | |
| Lithium | Administer 600–1200 mg/day. For acute mania, aim for a serum level of 0.8–1.0 meq/l in medically healthy individuals and 0.6–0.8 meq/l in older adults or those with relevant medical issues. |
| Divalproex | Initiate at 250 mg twice or thrice daily. Aim for a weight-based dosing of 20–30 mg/kg/day based on tolerability. Target serum levels are 50–125 μg/ml (serum level monitoring is not mandatory). Oral loading with 20–30 mg/kg/day may be considered in severely ill patients, where rapid response is essential. |
| Lamotrigine | Initiate at 25 mg daily for 2 weeks. Increase by 25 mg every 2 weeks. Once the dose reaches 100 mg, dose increments of 50 mg can be made every 2 weeks. Use a slower titration protocol when co-prescribing enzyme inhibitors (e.g., valproate) and allow faster titration when co-administered with enzyme inducers (e.g., carbamazepine). |
| Carbamazepine | Initiate at 200 mg daily in divided doses. Titrate gradually to 15–20 mg/kg/day. The usual target dose is 800–1000 mg per day. |
| Antipsychotics | |
| Risperidone | 2–6 mg/day |
| Quetiapine | 400–800 mg/day |
| Aripiprazole | 15–30 mg/day |
| Asenapine | 10–20 mg/day |
| Cariprazine | 3–12 mg/day |
| Olanzapine | 10–20 mg/day |
| Ziprasidone | 80–160 mg/day |
| Haloperidol | 5–20 mg/day |
| Benzodiazepines | |
| Lorazepam (intravenous or oral) | 2–12 mg/day (short-term use is recommended) |
| Clonazepam (oral) | 1-4mg/day (short-term use is recommended) |
| Other agents | |
| Endoxifen | 8 mg/day |
Treating patients already on maintenance agents
For patients already on treatment, it is prudent to determine whether the relapse occurred due to poor adherence, explore the reasons for non-adherence, and address them first. If the reason for non-adherence is adverse effects, consider dose reduction or switch to an agent with a better tolerability profile. Non-adherence often requires tailored, multipronged strategies, including motivational interviewing that is discussed later (see subsection on “Strategies for assessing and improving treatment adherence in BD”).
If the relapse occurs despite adequate adherence, it may indicate that the ongoing treatment is not effective at the prescribed doses. If tolerability is not an issue, dose optimization may be considered first. For instance, if a patient is on lithium, it may be checked if the serum concentrations are within the therapeutic range; if not, dose escalation and serum level monitoring must be done. Likewise, for most agents, the highest recommended therapeutic dose may be targeted, while monitoring for adverse effects. If the maximum tolerated dose is achieved and poor symptom control persists, augmentation with first-line antipsychotics, in case of ongoing mood stabilizers, or vice versa, may be considered.
Treatment of specific presentations
No specific agent is more effective for mania with a seasonal pattern; therefore, general recommendations may be followed. Likewise, for psychotic presentations of mania, no monotherapy or combination therapy has demonstrated consistent superiority. A combination of mood stabilizers with antipsychotics may be considered for presentations with mood-incongruent psychotic symptoms or when schizoaffective disorder (bipolar type) is being considered as a differential diagnosis.
For rapid cycling presentations, a good initial step is to assess and control contributory factors such as use of antidepressants or stimulants, hypothyroidism, substance use, traumatic brain injury, and epilepsy.[28,29,30] No agent has demonstrated consistent superiority for rapid cycling; so, an appropriate agent may be selected primarily based on maintenance efficacy and safety considerations. Often, combination therapy may be necessary due to the challenging nature of rapid cycling presentations.
Readers may note that the oft-repeated clinical aphorism that lithium is less effective than valproate in rapid cycling is not based on head-to-head trials comparing the two agents in rapid cycling BD, but on post-hoc subgroup analyses of data within lithium trials or comparison with historical controls. The message is that lithium should not be discarded as an option when treating rapid cycling presentations; on the contrary, combination therapy with lithium may help in managing rapid cycling presentations of BD.[31] Interestingly, an Indian multicentric study on remitted patients with BD found that those with a rapid cycling course had a higher likelihood of being treated with lithium.[32]
Good practice suggestions for psychopharmacology
Lithium
Before starting lithium, screening for renal, thyroid, and cardiac conduction abnormalities must be performed [Table 6]. For reproductively active women, a urine pregnancy test is recommended. In physically healthy individuals, lithium does not require titration; it can be directly initiated at 600–900 mg/day, and the first serum level can be obtained 12 hours post dose after 5 days of initiation or following a change in dose. This approach saves time as the therapeutic effects of lithium may take up to 3 weeks to manifest. A “start-low and go slow” approach is recommended for older individuals or those with physical issues. The target serum lithium levels for acute phase efficacy are between 0.6 and 1.2 meq/l,[20] with higher doses providing superior response but with potentially greater adverse effects. For older adults, a serum level of 0.4–0.8 meq/l may suffice.
Table 6.
Baseline investigations to be done before starting lithium and monitoring for side effects
| Test | Baseline | Repeat every 6–12 months (as indicated) |
|---|---|---|
| Complete hemogram | x | |
| Serum electrolytes (including calcium) | x | x |
| Serum urea and creatinine* | x | x |
| Thyroid function test | x | x |
| Electrocardiogram | x | x |
| Urine pregnancy test | x | |
| Weight (BMI) | x | X |
BMI: Body Mass Index; Evaluation of serum osmolality, 24-hour urine osmolality, proteins, volume, and monitoring of glomerular filtration rate (eGFR) may be additionally considered in indicated cases
*More frequent monitoring may be needed for older adults and those receiving concurrent medications like diuretics, non-steroidal anti-inflammatory drugs, or angiotensin converting enzyme inhibitors, and in those with renal impairment.
Monitoring serum lithium levels: The first serum lithium level may be obtained 5 days after dose initiation. The sample must be drawn 11–13 hours after the last dose (and prior to the next dose in case of BD or TID dosing). Once the dosing has been stabilized, the blood levels may be monitored less frequently (typically 3 monthly).
Side effects to check at each visit: polyuria/polydipsia, gastrointestinal side effects, tremor, dysarthria, ataxia.
Obtaining a fasting lipid profile and fasting glucose or HbA1c at baseline is also beneficial
It is a good practice to initiate immediate-release (IR) lithium in divided doses to reduce peak serum level-related adverse effects and later shift to a once-daily nightly regimen. This once-daily shift increases compliance, reduces side effects (due to dissipation of peak adverse effects during sleep), and is, importantly, renal sparing.[33] Sustained release (SR) preparations of lithium may be preferred over the IR preparation in case of upper gastrointestinal side effects (e.g., nausea, which is lower with the SR preparation); the vast majority of patients, nonetheless, should receive IR preparation dosed once daily. Regardless of the preparation used, serum levels should always be estimated at 12 hours post-dose; if divided dosing is followed, samples may be drawn before the morning dose.
Serum lithium level monitoring may be continued regularly until stable values are observed, following which levels may be monitored every 3 months for the first year and every 6 months thereafter, in healthy individuals.[34] Patients must be given adequate instructions about diet, hydration, and drug interactions to prevent lithium toxicity. Glomerular filtration rate (eGFR) and endocrine (thyroid) function should be checked every 6 months, or more frequently, in older adults or if there is evidence of any abnormality. Table 6 summarizes the baseline investigations before initiating lithium in BD and monitoring for side effects.
Divalproex
Before starting divalproex formulations, screening for hepatic and hematological functions are recommended. As weight gain is a concern with divalproex, a metabolic screen comprising fasting serum lipids and a glucose check is preferable. Divalproex may be initiated in low doses of 250 mg twice or thrice daily, followed by titration to a target level of 20–30 mg/kg body weight, based on response and side effects. Relatively little data exist correlating serum valproate levels with efficacy compared to lithium; therefore, serum valproate levels need not be routinely monitored unless there is a lack of therapeutic response, prominent side effects, or if compliance is suspect.
In patients with severe index presentations and where rapid response is desired, loading dose divalproex given at 20 or 30 mg/kg/day in divided doses for days 1 and 2 (followed by 20 mg/kg/day and adjusted at the physician’s discretion)[35,36] is an option to rapidly bring serum concentrations to therapeutic levels. Once dosing is stabilized, patients may be transitioned to once- or twice-daily doses for improved compliance. Delayed or extended release (ER) preparations of divalproex are often preferred to circumvent early side effects and for better compliance, but the bioavailability of ER preparations is up to 20% lower than IR preparations.[37] Accordingly, the dose must be increased by 20% when transitioning from IR to ER preparations.
When testing for serum valproate levels is indicated, the blood draw should be performed 24 hours after the last dose, regardless of the dosing schedule. The target serum valproate level is 50–125 µg/ml,[38] with a linear dose-response relationship between serum valproate concentrations and response in acute mania, where the target blood level may be about 100 µg/ml.[39] Because obtaining a 24-hour post-dose sample poses practical issues with nightly dosing, patients may be shifted to a morning dose for 5 days to support morning blood draws for serum level monitoring. Table 7 summarizes the baseline investigations before starting valproate in BD and monitoring for side effects.
Table 7.
Baseline investigations to be done before starting anticonvulsant mood stabilizers and monitoring for side effects
| Test | Baseline | Repeat every 6–12 months (as indicated) |
|---|---|---|
| Complete hemogram† | x | x |
| Liver function test† | x | x |
| Renal function test* | x | x |
| Urine pregnancy test | x | |
| Weight (BMI) | x | x |
| Fasting lipid profile | x | x |
| Fasting glucose or HbA1c | x | X |
BMI: Body Mass Index; *For those taking carbamazepine
Symptoms of abdominal pain and vomiting in a patient prescribed valproate or divalproex should prompt an assessment that includes a serum amylase and lipase.
Monitoring serum valproate levels: Routine serum valproate monitoring may not be necessary or cost-effective in all patients. When indicated (e.g., poor therapeutic response or doubts about compliance), the first serum valproate level may be drawn 5 days after the last dose increase, collected in the morning, before the first dose of the day (trough levels). The target serum valproate level in bipolar disorder is 50–125 mcg/ml. For patients on 24-hour extended-release preparations administered at night, trough levels would require the blood to be drawn in the night, just before the nighttime dose. Because this can be inconvenient, the patient may be switched to morning dosing for five days, and a morning blood sample may then be drawn just before the morning dose. For patients on 24-hour extended-release preparations administered in the morning, draw blood the next morning before the morning dose.
†For those on carbamazepine, hemogram and liver function test may be repeated fortnightly for the first two months, and if no abnormalities are detected, then it may be repeated less frequently.
Monitoring serum carbamazepine levels: Therapeutic serum levels have not been established for acute bipolar mania. Many clinicians target levels of 4 to 12 mcg/mL based on epilepsy literature. Carbamazepine is typically dosed twice daily. The sample for blood level testing may be drawn 5 days after the last dose increase, collected in the morning, before the first dose of the day (trough levels).
Patients taking carbamazepine must be monitored for drug-related skin rash, particularly during the first eight weeks of therapy, as the treatment is associated with life-threatening rashes (Stevens-Johnson syndrome and toxic epidermal necrolysis). Carbamazepine should be promptly discontinued in such events.
Serum ammonia levels do not need to be routinely obtained in valproate-treated patients. They should be obtained if valproate-treated patients develop unexplained nausea, vomiting, lethargy or altered consciousness
Readers may note the increased restrictions on the use of sodium valproate over the past year; specifically, the new Medicines and Healthcare products Regulatory Agency (MHRA) regulations, categorically state that “valproate must NOT be started in new patients (male or female) younger than 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment, or there are compelling reasons that the reproductive risks do not apply.”[40] Similar recommendations have been made by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency, effective January 31, 2024.[41] Awareness of these regulations must be combined with an individualized and holistic view of the patient when making treatment decisions, particularly since divalproex has consistently been one of the most prescribed drugs for maintenance therapy in BD across countries.[42,43]
Lamotrigine
Lamotrigine is recommended as a maintenance treatment for BD, with greater efficacy for the prevention of depressive than manic episodes. Its use in acute management is, however, limited by the need for slow dose titration to prevent the dreaded complications of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis.[44] Rapid titration is a frequent cause of skin rash with lamotrigine[45]; hence, clinicians are advised to always follow the recommended titration protocol. The target dose in BD is usually 200 mg/day,[46] though some patients may require higher dosages.
The general rule with lamotrigine is to start low and go slow. So, lamotrigine may be initiated at 25 mg daily for the first 2 weeks and subsequently increased by 25 mg daily every 2 weeks.[47] Once the dose reaches 100 mg, subsequent increases can be in doses of 50 mg weekly or every other week till the target dose of 200 mg is reached. Limited evidence exists for a faster titration protocol[48]; therefore, no recommendations can be made based on current evidence. A slower titration protocol must be followed for patients, who are co-prescribed enzyme inhibitors, such as valproate. Conversely, if used concurrently with enzyme inducers, such as carbamazepine, a faster titration protocol may be followed. Readers may note that co-prescribed oral contraceptive pills can reduce lamotrigine clearance by up to 50%; once these are stopped, the levels may go up twofold. Clinicians must consider these factors when deciding on target doses and titration protocols for lamotrigine.
Carbamazepine
Carbamazepine may be started after screening for blood dyscrasias and hepatic dysfunction. The starting dose is usually 200 mg daily in divided doses and can be up titrated to 15–20 mg/kg body weight; most patients require 800–1000 mg daily. Therapeutic serum levels in BD are not well established; a serum level of 4–12 µg/ml, recommended in epilepsy,[49] is followed for acute mania as well; one Indian study used a target serum level of 8–12 µg/ml. As with lithium and valproate, serum levels may be obtained 5 days after initiation.[50] Table 7 summarizes the baseline investigations before starting carbamazepine and monitoring for side effects.
Antipsychotics
Antipsychotics have positive evidence for the management of both acute and maintenance phases of BD; recommended dosages are summarized in Table 5. Table 8 summarizes the baseline investigations before starting antipsychotics and monitoring for side effects.
Table 8.
Baseline investigations to be done before starting antipsychotics and monitoring for side effects
| Test | Baseline | 4 weeks | 8 weeks | 12 weeks | Quarterly | Annually |
|---|---|---|---|---|---|---|
| Weight (BMI) | x | x | x | x | x | |
| Waist circumference | x | x | x | |||
| Blood pressure | x | x | x | x | ||
| Fasting lipid profile | x | † | x | x | ||
| Fasting glucose or HbA1c | x | x | x | |||
| Electrocardiogram | x | x | x |
BMI: Body Mass Index; †For those taking Clozapine/Olanzapine/Quetiapine
Serum prolactin monitoring is not routinely indicated in all patients before starting antipsychotics. It may be obtained before initiating antipsychotics in patients experiencing symptoms suggestive of hyperprolactinemia (e.g., amenorrhea or irregular menses in women, or sexual dysfunction, decreased libido, and galactorrhea in both sexes). Prolactin levels should be obtained at follow-up whenever indicated by the clinical history or when prolactin-raising antipsychotics are prescribed; in case of the latter, an annual prolactin check may be performed
Benzodiazepines
These are often used as adjunctive agents in the management of acute mania and help control psychomotor agitation and excitement, with evidence supporting the use of flexibly dosed lorazepam for short-term management of agitation.[51,52]
Indicative Indian data
An Indian Psychiatric Society survey of prescribing practices in the treatment of BD[53] found that most respondents (65%) preferred a combination of mood stabilizer (lithium, valproate, and carbamazepine/oxcarbazepine) with antipsychotic (mostly second-generation) followed by mood stabilizer with or without adjunctive benzodiazepine treatment (24%). Antipsychotic monotherapy came a distant third, preferred by a minority (8%), for the treatment of acute mania.
A 2-week open-label trial compared intravenous sodium valproate with intravenous haloperidol in acute mania. Although response rates did not differ, the valproate group experienced a faster onset of response.[54] Intravenous sodium valproate was found to be superior to oral valproate, when combined with risperidone, for acute anti-manic efficacy in another open-label trial.[55] An RCT found that asenapine is an effective and safe alternative to olanzapine when used in combination with divalproex for short-term treatment of acute mania.[56] Two studies assessing the prevalence of cutaneous side effects of lithium in BD found a prevalence of 19.8%,[57] and 38.5%,[58] respectively; the most common lesion was acneiform eruptions. Another RCT found that the addition of sodium chloride (1 g/day) resulted in decreased fluctuations in serum lithium levels compared to the control group, who were advised not to take additional salt.[59]
Two RCTs have been conducted on endoxifen in acute mania with or without mixed features. One was a 3-week phase II trial, which showed that endoxifen (dosed at 4 mg or 8 mg) was efficacious in controlling manic and mixed features and did not significantly differ from the comparator group (divalproex) on efficacy measures at the study endpoint.[60] The other was a larger, 3-week, phase III study that compared daily 8 mg endoxifen with 1000 mg divalproex. This study also noted the efficacy and safety of endoxifen for manic/mixed features.[61] Interestingly, studies have noted deficits in lithium-related knowledge and attitudes among patients on long-term treatment,[62] which were found to influence medication adherence.[63]
Many studies have been conducted to assess the acute and maintenance effects of traditional mood stabilizers such as lithium, valproate, and carbamazepine. Most of these studies were small, open-label, uncontrolled, short-term observations and they demonstrated good acute efficacy; a few also showed good maintenance effects. These studies have been summarized in a review.[64] A 3-week RCT found that risperidone was superior to placebo for acute anti-manic efficacy.[65] Finally, in an informative long-term longitudinal study, Khess and colleagues compared lithium, valproate, carbamazepine, and antipsychotics for their effectiveness in relapse prevention. They found that those on lithium had the best outcomes.[66]
As regards other treatment modalities, two Indian studies[67,68] found that ECT was efficacious for the acute manic phase in BD, though it was more often used for depression than mania. Two sham-controlled RCTs[26,69] supported the efficacy of adjunctive high-frequency suprathreshold rTMS of the right prefrontal cortex in acute bipolar mania. For a more comprehensive overview of Indian literature on clinical aspects of BD, readers are referred to the review by Narula and colleagues.[70]
PHARMACOLOGICAL MANAGEMENT OF MIXED EPISODES
Treatment of a mixed episode aims to manage the acute symptoms, restore functioning, and prevent exacerbation or switch to the opposite pole.
Acute treatment of mixed episodes
The first step in the management of mixed episodes in BD-I is cessation of agents that can potentially exacerbate mixed presentations. These include substances (alcohol, stimulants, opioids, etc.) and antidepressants (particularly dual uptake inhibitors). The use of antidepressant monotherapy in mixed states is associated with exacerbations,[71] increased risk of manic switch,[72] and suicide.[73] However, Indian evidence on the use of antidepressants in mixed episodes is lacking.
Atypical antipsychotics, especially aripiprazole, asenapine, olanzapine, and ziprasidone, have shown efficacy in the treatment of mixed mania, either as monotherapy or adjunctive treatment.[74] A recent meta-analysis[75] also showed significant benefits with cariprazine in the treatment of mixed episodes, relative to placebo, while a post-hoc pooled analysis of data from three trials[76] showed that it effectively treated manic and depressive symptoms in mixed episodes. Lurasidone has also demonstrated benefits for the treatment of mixed presentations, albeit in a post-hoc analysis of major depressive disorder with mixed features and anxiety.[77] Nonetheless, it may be considered in the treatment of depressive mixed states in BD-I due to the paucity of direct evidence surrounding the treatment of mixed episodes or mixed state presentations.
Insufficient evidence exists for agents such as risperidone and paliperidone (as monotherapy or combination therapy) and quetiapine (as monotherapy). Clozapine[78] has some positive evidence in the treatment of mixed states, though much of the evidence is from open-label studies and chart reviews. A recent, placebo-controlled RCT showed that lumateperone (42 mg) was safe and effective for bipolar depression with mixed features.[79]
Divalproex may be considered a second-line agent for acute mixed presentations, particularly for mixed mania. The evidence comes mainly from post-hoc analysis of mania with mixed features[80] where it was shown to be equally efficacious for treating mania and mania with mixed features and superior to lithium in attenuating manic symptoms in mixed presentations. Carbamazepine may also be considered a second-line option, based on its efficacy in DSM-IV-defined mixed episodes.[81] Treatment with ECT may be considered for those with catatonic symptoms or stupor, high suicide risk, or difficult-to-treat patients where a faster response is desired.
Good practice suggestions for psychopharmacology
Screening before therapeutic drug initiation, drug dosing, and monitoring for adverse effects follow the same principles as explained in the corresponding section for bipolar mania. Figure 2 summarizes the pharmacological algorithm for acute management of mixed episodes, while Table 9 summarizes the target doses of commonly used agents for managing mixed episodes.
Figure 2.
Algorithm for acute pharmacological management of mixed episodes in bipolar type I disorder
Table 9.
Dosing suggestions for acute treatment of mixed episodes in bipolar type I disorder (presented order reflects suggested order of agents)[20]
| Name of agent | Dosing suggestions |
|---|---|
| Mood stabilizers | |
| Divalproex | Recommended as a first-line treatment option for acute phase treatment of mixed mania. Dosing suggestions are the same as for acute bipolar mania. |
| Carbamazepine | Recommended as a second-line treatment option for acute phase treatment of mixed episodes. Dosing suggestions are the same as for acute bipolar mania. |
| Lithium | Recommended for maintenance phase treatment. Dosing suggestions are the same as for acute bipolar mania. |
| Antipsychotics | |
| Aripiprazole | 10–30 mg/day |
| Asenapine | 10–20 mg/day |
| Olanzapine | 10–20 mg/day |
| Cariprazine | 3–12 mg/day |
| Ziprasidone | 80–160 mg/day |
| Lurasidone | 40–120 mg/day |
Indicative Indian data
To our knowledge, no Indian data exists specifically on the treatment of mixed presentations in BD, DSM-5, or ICD-11-defined mixed states or mixed episodes, respectively. However, many efficacy trials of antipsychotics,[65] and agents such as endoxifen[60,61] in acute mania have also included patients with mixed episodes or mixed features. Since these trials have shown positive evidence of efficacy in such mixed samples, and in line with findings from the global literature, it may be inferred that agents with proven anti-manic efficacy may also be efficacious in mixed presentations.
PHARMACOLOGICAL MANAGEMENT OF DEPRESSIVE EPISODES IN BIPOLAR TYPE I DISORDER
The diagnostic criteria for a bipolar depressive episode are the same as those for a unipolar depressive episode, though there may be differences in clinical presentation. Though a manic episode is the defining feature of BD-I, depressive episodes in BD are important to treat because of the higher risk of suicidality, greater risk of symptom persistence, and resultant impairment in occupational, social, and family functioning, compared to mania.[82] Hence, they must be treated early and effectively.
Treatment of acute depression
The goals of pharmacological management of acute bipolar depression are to restore euthymia as early as possible (because even untreated depressive episodes resolve spontaneously), prevent a manic/hypomanic switch, and improve psychosocial functioning. The locus of management depends on the nature and severity of symptoms, associated risk of harm to self, ability to adhere to a management plan, and availability of social and psychological support network. Information about history of mania and its presentation like acuity of onset, presence of aggression, and extent of impairment is helpful to assist the choice of medication.
Pharmacotherapy is the most evidence-based and practical treatment. However, psychosocial therapies such as psychoeducation about the disorder to patients and caregivers have also been found to be effective in relapse prevention. Combined pharmacological and psychosocial treatment of bipolar depression may help promote treatment engagement, medication adherence, and support symptomatic and functional recovery.
Treating drug-naïve patients
The choice of first-line agents is based on considerations such as availability, evidence base, side-effect profile, past response history, patient preferences, and affordability. For acute and maintenance phases of illness, first-line evidence-based treatment options in acute bipolar depression include olanzapine-fluoxetine combination (OFC), quetiapine, lurasidone, and cariprazine; a caveat here is that Indian evidence for these agents is relatively limited. Lumateperone has also been approved for BD-I depression, but since it has only recently come into the Indian market, there is little experience; therefore, we have not included it as a first-line treatment option.
It is important to note that lithium is not approved as a first-line treatment for acute bipolar depression due to mixed and inconsistent evidence in clinical trials. Nonetheless, guidelines such as the Canadian Network for Mood and Anxiety Disorders (CANMAT),[20] position lithium as a first-line agent for acute bipolar depression primarily because of its evidence in preventing new episodes of both mania and depression and in managing acute mania. Because an important goal of treating acute bipolar depression is to prevent a manic switch or natural cycling into mania, and because of other considerations such as the presence of suicidality, clinicians may consider adding lithium alongside first-line treatment options when managing acute bipolar depression. On a similar note, lamotrigine is usually not preferred for the acute management of bipolar depression due to its prolonged dose titration phase, but it can be started alongside a first-line treatment if the goal is to prevent depressive relapses, for which it has considerable evidence.[83]
In a recent network meta-analysis[84] of the efficacy and tolerability of pharmacological treatments of acute bipolar depression (101 RCTs; pooled N = 20,081), OFC had the highest effect size. However, several guidelines[20,85] have placed OFC as a second-line treatment option due to concerns about adverse effects such as weight gain. Since it is often the case that the efficacious acute-phase treatment is continued into the maintenance phase, clinicians need to factor in this possibility when deciding to initiate OFC for bipolar depression. At the very least, it may be avoided as a first-line agent in those with higher BMI or a family or personal history of diabetes, and regular metabolic monitoring should be advised alongside initiation of OFC. Although approved dose ranges are 6–12 mg (Olanzapine) and 25–50 mg (Fluoxetine), in India, the combination is available in strengths of 5 mg + 20 mg and 10 mg + 20 mg.
All first-line treatments must be tried for an adequate dose and duration (at least 6–8 weeks) before concluding efficacy or lack thereof. Switching or augmenting with alternate first-line options may be considered for ineffective or sub-optimally effective treatments, respectively. As discussed earlier, it is often the case that a treatment is started to address several goals; for instance, if lithium initiated for acute bipolar depression was found ineffective, the clinician may decide to add-on lurasidone or quetiapine to the treatment regimen for acute response and continue lithium for long-term manic and depressive prophylaxis. As a rule, a careful risk-benefit analysis and relevant discussions with the patient and caregiver(s) must precede all decisions regarding combination treatments, as they can increase morbidity and impact functional recovery in BD.
Second-line treatment options for acute bipolar depression include divalproex, adjunctive treatment with an antidepressant (preferred ones are selective serotonin reuptake inhibitors [SSRI] or bupropion due to their lower switch rate) and lithium or divalproex. The use of antidepressants in bipolar depression remains controversial and needs a cautious interpretation of the evidence. Antidepressant monotherapy or “unopposed antidepressant” treatment is NOT recommended in bipolar depression. The current understanding is that antidepressants may be prescribed in combination with an adequate dose of mood stabilizing agent(s) for carefully selected patients with bipolar depression. These may include those with a previous history of response to antidepressants, a history of relapse when taken off antidepressants, or those with inadequate response to first-line agents.[86,87] In all cases where an antidepressant is initiated, patients and caregivers should be educated about behavioral changes or early warning signs of a manic switch, and antidepressants must be promptly discontinued in case of a treatment-emergent affective switch.
ECT may be considered as a second-line treatment option for bipolar depression, particularly in psychotic presentations. It may be considered earlier whenever a rapid response is desired, such as for patients with high suicide risk and catatonic or stuporous presentations of bipolar depression; in these scenarios, ECT may be considered a first-line treatment due to the sound evidence base and need for rapid response. All second-line agents must be trialled at an adequate dose and duration before concluding that they are ineffective and initiating a third-line agent.
Third-line options in bipolar depression include monotherapy with carbamazepine or olanzapine and adjunctive treatment with aripiprazole, modafinil, ketamine, pramipexole, repetitive transcranial magnetic stimulation, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase (MAO) inhibitors; these agents have limited supporting evidence. Readers may note that serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and MAO inhibitors have been associated with higher manic switch rates.[20] Therefore, these agents must be initiated only under the cover of adequate anti-manic prophylaxis and in carefully preselected patients (such as those with symptoms refractory to the antidepressant effects of mood stabilizers such as lithium).
Ketamine may be considered in situations where high suicide risk is present or when rapid response is desirable and when ECT services are unavailable; the intravenous route is the most studied and has good evidence for safety and efficacy.[88] Though case reports documenting treatment-emergent affective switch with ketamine are available,[89,90] the evidence is not conclusive, and this should not deter the use of ketamine in BD, when clinically indicated. Other third-line options with lesser evidence include adjunctive bright light therapy, N-acetylcysteine, and eicosatetraenoic acid.
Treating patients already on maintenance agents
If a person on maintenance treatment experiences a depressive relapse, the first step is to check their adherence to the treatment plan and implement strategies to improve it based on the identified causes of poor adherence. If adherence is satisfactory, the next step is to assess whether dose optimization is feasible. For instance, if lithium is prescribed, one should assess whether serum levels fall within the therapeutic range; if not, the dosing should be appropriately adjusted.
If dose optimization yields unsatisfactory results, consider adding another first or second-line acute-phase treatment, in that order. The same principles followed for acute-phase management described in the preceding section may be followed with due consideration to patient preference, tolerability, high suicide risk, or need for rapid response. If a response is observed, the treatment may be continued till the end of the acute phase (remission) and into the maintenance phase; dosage reductions in the maintenance phase for bipolar depression are not specifically recommended unless there are intolerable side effects.
Treatment of specific presentations
Olanzapine-fluoxetine[91] combination and lurasidone[92] have demonstrated benefits in improving mixed symptoms in bipolar depression. ECT can be considered earlier in the treatment hierarchy for melancholic or psychotic presentations of bipolar depression; no specific pharmacological agent has shown superiority in these presentations. Likewise, there is no evidence for the superiority of any agent for rapid cycling or seasonal presentations of bipolar depression; an appropriate agent may be selected based on efficacy considerations for acute and maintenance phases. Antidepressants are not favored in managing rapid cycling BD due to concerns about potential destabilization, even when combined with mood stabilizers.[93]
Good practice suggestions for psychopharmacology
Screening before therapeutic drug initiation, drug dosing, and monitoring for adverse effects have been explained in the corresponding section for bipolar mania. Figure 3 summarizes the pharmacological algorithm for managing acute bipolar depression, while Table 10 summarizes the target doses of commonly used agents for managing acute bipolar depression.
Figure 3.
Algorithm for acute pharmacological management of depressive episodes in bipolar type I disorder
Table 10.
Dosing suggestions for treatment of acute depression in bipolar type I disorder (presented order reflects suggested order of agents)[20]
| Name of agent | Dosing suggestions |
|---|---|
| Mood stabilizers | |
| Lithium† | Administer 600–1200 mg/day. For acute depression, aim for a serum level of 0.8–1.2 meq/l in medically healthy individuals and 0.6–0.8 meq/l in older adults or those with relevant medical issues. For maintenance treatment, follow the same suggestions as for bipolar mania. |
| Lamotrigine† | Initiate at 25 mg daily for 2 weeks. Increase by 25 mg every 2 weeks. Once the dose reaches 100 mg, dose increments of 50 mg can be made every 2 weeks. Use a slower titration protocol when co-prescribing enzyme inhibitors (e.g., valproate) and allow faster titration when co-administered with enzyme inducers (e.g., carbamazepine). Target dose is≥200 mg for bipolar depression, though some patients may respond at lower doses and others may need higher doses. |
| Divalproex | Initiate at 250 mg twice or thrice daily. Aim for a weight-based dosing of 20–30 mg/kg/day based on tolerability. Target serum levels are 50–125 μg/ml (serum level monitoring is not mandatory). |
| Carbamazepine | Initiate at 200 mg daily in divided doses. Titrate gradually to 15–20 mg/kg/day. The usual target dose is 300–800 mg per day. |
| Antipsychotics | |
| Quetiapine* | 300–600 mg/day (lower doses may suffice for some) |
| Lurasidone* | 40–120 mg/day |
| Caripirazine* | 1.5–3 mg/day |
| Lumateperone | 42 mg/day |
| Olanzapine | 5–20 mg/day (given as part of OFC) |
| Aripiprazole | 10–30 mg/day |
| Antidepressants (monotherapy is NOT recommended) | |
| Fluoxetine | 20–40 mg/day (given as part of OFC) |
| Sertraline | 100–150 mg/day |
| Escitalopram | 10–15 mg/day |
| Bupropion | 100–300 mg/day |
| Venlafaxine | 75–225 mg/day |
| Imipramine | 50–150 mg/day |
| Tranylcypromine | 20–30 mg/day |
| Other agents | |
| Modafinil | 100–200 mg/day |
| Pramipexole | 1–3 mg/day |
| Ketamine | 0.5 mg/kg administered intravenously over 40 min. A typical “course” of ketamine involves six sessions, scheduled thrice-weekly. Some patients may require longer “maintenance” ketamine sessions, like maintenance ECT. |
*Indicates first-line treatments; †Though not recommended explicitly for acute bipolar depression, these agents are often initiated alongside first-line agents as they have a good safety and efficacy record for depressive prophylaxis; ECT: Electroconvulsive therapy; OFC: Olanzapine-Fluoxetine combination
Indicative Indian data
An Indian Psychiatric Society survey of prescribing practices in the treatment of BD[53] found that most respondents preferred a combination of mood stabilizer with SSRI followed by a combination of mood stabilizer with quetiapine and OFC for treating acute bipolar depression. A vast majority of respondents (95%) preferred using antidepressants to treat BD-I depression. About two-thirds opined that antidepressants are less efficacious in bipolar depression, relative to unipolar major depressive disorder. Another Indian multicentric study found that one-third of patients with remitted BD were prescribed concomitant antidepressants.[94]
An RCT that compared intravenously administered ketamine versus ECT in an episode of major depression (unipolar or bipolar) found significant within-group improvements in both groups, but ECT outperformed ketamine on most efficacy outcome measures.[95] Three Indian studies, two of which used adjunctive high-frequency repetitive transcranial magnetic stimulation,[96,97] and one that used continuous theta-burst stimulation,[98] found evidence for efficacy in acute bipolar depression. An Indian RCT found that 52-week adjunctive antidepressant maintenance treatment offered no significant advantage over 8-week adjunctive antidepressant maintenance treatment among BD-I patients, who had recently remitted from a depressive episode.[99]
PHARMACOLOGICAL MANAGEMENT OF BIPOLAR TYPE II DISORDER
The lifetime prevalence of BD-II ranges from 0.4% to 1.2%[100,101]; an Indian multicentric study found a prevalence of 7.63%.[102] There is limited literature on the management of BD-II disorder. The risks associated with the use of antidepressants may be lower in BD-II vs BD-I; a recent individual participant data mega-analysis noted superior short-term effectiveness for antidepressant monotherapy compared to lithium alone, without a significant increase in treatment-emergent hypomanic symptoms.[103]
Acute management of hypomania
The goals of pharmacological management of hypomania are to alleviate symptoms and maintain functioning. As an initial step, discontinuing medications that can potentially worsen symptoms, such as antidepressants or stimulants, is recommended. It is essential to initiate pharmacotherapy for hypomania, especially when the episodes are severe, frequent, and prolonged. For those already on treatment, it is vital to establish the reasons for relapse and address them.
Medication adherence is of paramount importance. If the relapse occurred despite adherence, one may optimize ongoing medication(s) or shift to another medication if the ongoing treatment is ineffective. Pharmacological agents used for the management of acute mania, including lithium, divalproex, and atypical antipsychotics, can also be used for the management of acute hypomania, if only because of a distinct lack of clinical trial evidence specific to acute hypomania. Due consideration may also be given to the risk-benefit profile, need for serum monitoring with agents such as lithium, and the extant restrictions on the use of divalproex in reproductively active women (and men) when choosing agents for hypomania.
Acute management of depressive episodes in bipolar type II disorder
The goals of pharmacological management of bipolar depression are to alleviate symptoms and prevent iatrogenic switch into mania or a mixed state. Till recently, quetiapine was the only approved agent for treating depression in BD-II.[20] It may be considered as a first-line treatment option, particularly in drug-naïve patients, if well tolerated. In June 2021, lumateperone, dosed at 42 mg daily, was approved for treating BD-II depression after being found effective in primary[104] and secondary[105] analyses of RCT data. However, Indian experience with lumateperone is limited. Other antipsychotics or agents that may be extrapolated for use in BD-II depression, based on their efficacy for BD-I depression, include OFC (with due consideration for its metabolic side effects), lurasidone, and cariprazine.
Antidepressants have a more favorable risk-benefit profile in BD-II, relative to BD-I, but the literature on antidepressants in BD-II is insufficient to make firm recommendations. Based on current evidence, it may be used cautiously in BD-II, preferably in combination with a mood stabilizer. Patients and caregivers should be educated about symptoms of treatment-emergent hypomania or mania, and treatment may be promptly discontinued in such an event. Antidepressants may be preferred in BD-II patients with “pure” (non-mixed) depression, history of good response to antidepressants, and a history of relapsing when taken off antidepressants.[20] Sertraline and venlafaxine may be preferred antidepressants for BD-II depression.
Mood stabilizers such as lithium and lamotrigine have inconsistent evidence for acute BD-II depression and cannot be recommended as sole first-line agents in the acute phase. However, as expounded earlier, they may be commenced for their more robustly demonstrated efficacy in preventing depressive relapses in BD-II.[20] Modified ECT can be considered as a second-line treatment option in patients who respond poorly to pharmacological treatment, or as a first-line option for those at high risk of suicide or needing a rapid response.
Third-line options for the management of BD-II depression include monotherapy with divalproex and fluoxetine, and adjunctive bupropion, ketamine (intravenous route for those with suicidal risk or needing a rapid response), N-acetylcysteine, pramipexole, and thyroid hormones.
Good practice suggestions for psychopharmacology
In the absence of specific dosing data for BD-II depression, the dosing suggestions given for BD-I depression may be followed; the same applies for BD-II hypomania in that the dosing suggestions for BD-I mania may apply. Figure 4 summarizes the pharmacological algorithm for managing acute depression in BD-II.
Figure 4.
Algorithm for acute pharmacological management of depressive episodes in bipolar type II disorder
Indicative Indian data
The Indian Psychiatric Society survey of prescribing practices in the treatment of BD[53] found that OFC (23%) and co-treatment with a mood stabilizer and SSRI (21%) were the favored treatments for acute BD-II depression. This was followed by a combination of mood stabilizer and quetiapine (14%) and quetiapine monotherapy (10%).
PSYCHOSOCIAL MANAGEMENT OF BIPOLAR DISORDER
Though pharmacotherapy is the mainstay of treatment in BD, adjunctive psychosocial interventions support treatment outcomes and recovery. Specifically, evidence suggests that adjunctive psychosocial interventions can help alleviate acute depressive symptoms in BD and contribute to relapse prevention, maintain treatment adherence, improve functioning, and enhance quality of life for the patient and family when given as a maintenance treatment. Regardless of the psychosocial treatment offered, adequate attention must be paid to the quality of the therapeutic alliance, which may influence treatment adherence and outcomes in BD.
Psychoeducation
Psychoeducation is a simple, low-burden, evidence-based intervention that should be offered to all patients with BD and their caregivers. It involves providing information about illness and treatments to help patients and their families cope with the disorder more effectively. Key elements of psychoeducation include increasing knowledge about illness aetiology, symptoms, course, and outcomes, detection of early warning signs of a relapse, developing problem-solving skills, importance of stress management and healthy lifestyle practices, providing information about treatment options, educating the importance of treatment adherence, enhancing adaptive coping to deal with illness-related issues, and promoting self-monitoring of mood and sleep patterns [Box 2]. Psychoeducation can be offered in individual or group formats, depending on feasibility and patient needs.
Box 2: Basic elements of psychoeducation in bipolar disorder
Information about the illness
Signs and symptoms of depression, mania, hypomania, and mixed episodes
Etiological and triggering factors
Illness course, prognosis, and outcome
Available treatment options, their adverse effects, and monitoring
Emphasis on treatment adherence and its benefits
Early signs of relapse, risk factors for relapse, and benefits of detecting relapse early
Coping strategies to deal with daily stressors
Regular exercise and sleep pattern
Avoidance of substance use
Lifestyle modifications
Reducing stigma by highlighting the medical model of illness
Where relevant, discuss issues surrounding pregnancy, lactation, management of comorbid medical conditions, and legal concerns (issues with employment, finance, and preparing advance directives)
Before beginning the process, clinicians can assess the knowledge of the patient and caregiver to identify myths and misconceptions about BD and areas to focus on during the psychoeducation sessions. Psychoeducation is thought to work more effectively when active learning is involved. This may include assessing the level of understanding among patients and caregivers regarding the information provided as part of psychoeducation, focusing on skill development, and providing opportunities for clarifying any queries that arise. To implement this more effectively, feedback may be obtained before each psychoeducation session about what was discussed in the previous session. Psychoeducation is best considered an ongoing, iterative process that addresses patients’ and families’ evolving concerns about illness and treatment, rather than a one-time event.
Evidence-based psychoeducation models for BD include the Barcelona BDs Program (21 sessions across 6 months)[106] and the Life Goals Programs (6 weekly sessions in phase I).[107] Both are developed for euthymic individuals, designed to be delivered in a group format, and have been shown to prevent relapses.[108] They can also be administered to individuals. Group psychoeducation sessions are associated with better adherence to treatment and reduction of stigma, whereas family psychoeducation sessions increase knowledge of caregivers and reduce caregiver burden.[109] For optimal benefits, psychoeducation needs to be delivered over several structured sessions.
In the Indian context, clinicians may also educate patients about disability benefits and other concessions available to the patient and family due to the diagnosis of BD. This may potentially reduce treatment burden, improve adherence, mitigate caregiver burden and expressed emotions, and enhance relationship functioning within the family context, all of which can potentially improve treatment outcomes.
Cognitive behavioral therapy (CBT)
CBT can be considered for patients with BD, especially those with predominant depressive episodes or illness-related maladaptive thoughts, feelings, and behaviors. CBT addresses cognitive distortions and dysfunctional attitudes in patients with BD, and improves outcomes by fostering problem-solving and stress management skills.[110] Clinicians can use CBT to help patients cope with their illness and psychosocial stressors while also improving medication and treatment adherence and preventing a relapse.[111] It is typically delivered in 20 individual sessions over 6 months[112]; however, the number of sessions may be tailored to an individual patient’s requirements.
Interpersonal and social rhythm therapy (IPSRT)
This therapy is based on the premise that disrupted daily routines can cause circadian rhythm instability, leading to the precipitation of mood episodes in vulnerable individuals. IPSRT aims to address this by stabilizing social rhythms or routines through regulating sleep and daily activities. IPSRT implemented during the acute phase in BD was found to decrease the number of subsequent episodes.[113] Clinicians can choose to deliver IPSRT components as part of a general psychoeducation program or as a separate intervention in BD. Patients are advised to maintain a consistent daily routine and a regular sleep-wake cycle. They are taught skills to handle interpersonal issues and encouraged to pay attention to events that disrupt their daily routines. Additionally, they are provided with information on how the impact of such events can be mitigated. IPSRT is typically delivered in 24 individual sessions over 9 months[114]; however, the exact number of sessions may be adjusted based on the patient’s needs.
Family-Focused Therapy (FFT)
Family members play a significant role in decisions related to treatment and in supervision and monitoring of medications, especially in the Indian setting. FFT in BD aims to increase family members’ support and positive participation to improve patient outcomes in BD. It focuses on reducing expressed emotions, improving communication styles, enhancing relationship functioning, and resolving marital relationship issues that may contribute to poor illness outcomes. It is an evidence-based treatment in BD that can effectively prevent relapse and improve adherence.[115] It is typically delivered over 21 sessions in 9 months.[116]
Mindfulness-based cognitive therapy (MBCT)
MBCT incorporates cognitive therapy elements and mindfulness-based stress reduction principles to enhance coping skills by developing non-judgmental attention to inner and outer experiences in the present moment.[117] Studies evaluating the effectiveness of adjunctive MBCT in patients with BD found that it reduced depressive and anxiety symptoms. However, controlled studies using MBCT in BD showed no significant effects.[118] One randomized controlled trial also found no beneficial effects on relapse prevention.[119]
Lifestyle and dietary modifications
Patients with BD are at increased risk of metabolic side effects due to the need for long-term medications. Hence, advising the patients about lifestyle modifications is essential.[120] This includes suggestions on promoting positive lifestyle behaviors like a healthy diet, regular exercise, and avoiding smoking, alcohol, and other substance use.
Cognitive remediation (CR) and functional rehabilitation
Patients with BD often present with significant cognitive impairment both during and in between episodes. CR involves various behavioral interventions to address these impairments and improve cognitive functioning. CR also focuses on enhancing problem-solving skills to compensate for the neurocognitive deficits associated with BD. Available models for cognitive[121] and functional[122] rehabilitation have mixed evidence for improving functioning and may need to be culturally adapted to suit local contexts and requirements. Readers are referred elsewhere for more information on cognitive domains to be assessed in BD and simple bedside tests for each domain.[123]
Internet-based/digital therapies
Clinicians can also utilize online tools in the psychosocial management of BD, enabling patients and family members to self-monitor and self-manage their illness. Such treatments may be more acceptable today, but real-world evidence is limited.
Interventions to improve treatment adherence
Strategies to maintain and improve adherence to treatment recommendations are an essential element of psychosocial interventions in BD. These are discussed separately in a subsequent sub-section of the guideline (see subsection on “Strategies for assessing and improving treatment adherence in BD”).
In the Indian context, elements of CBT, IPSRT, and FFT can be incorporated into psychoeducation if sufficient expertise to deliver these specific manualized therapies is not available, affordable, or accessible.
Indicative Indian data
Indian studies have evaluated various psychosocial interventions in BD, including psychoeducation, FFT, and CBT. One RCT compared the effect of psychoeducation delivered as 30-min sessions once a month for 4 months versus treatment as usual (TAU) among patients with BD. Although there was no significant difference in treatment adherence, the intervention group demonstrated improvement in knowledge and attitudes among patients with BD.[124] Another RCT comparing brief CBT sessions conducted weekly over 2–3 months versus TAU found significant differences in mood symptoms, medication adherence, and dysfunctional attitudes in the intervention group.[125] Caregivers form the primary source of support for patients with BD, particularly in the Indian context. In this context, a 12-session FFT demonstrated reductions in family stress and expressed emotions, as well as improved functioning in patients.[126]
MAINTENANCE THERAPY IN BIPOLAR DISORDER
The management of mood episodes in BD is divided into acute, continuation, and maintenance phases. In general, the agent(s) found effective in the acute phase should be maintained in the continuation phase, which begins after the acute episode has remitted, and may last for up to 6 months.[127] The main goal of the continuation phase treatment is to prevent a relapse of the same episode. Following this, the maintenance phase of treatment starts, where the goal is to prevent a recurrence of (new) mood episodes. In this guideline, we have subsumed the continuation phase under maintenance therapy.
In addition to preventing relapse/recurrence, the goals of pharmacological maintenance treatment in BD are to consolidate the treatment gains made in acute phase treatment, reduce residual symptoms, and restore psychosocial functioning. Without treatment, it is estimated that 23%–40% of patients will relapse every year, compared to 19%–25% among those on treatment.[128] In a long-term naturalistic follow-up study, those who continued lithium following successful maintenance monotherapy experienced one-third of the relapses suffered by the discontinuation group.[129]
The concept of life-long prophylaxis in BD has been debated; opponents of this approach point to the lack of a robust evidence base for “infinite” maintenance treatment, while proponents highlight the evidence of clinical progression and neuroprogression to justify long-term maintenance treatment. A reasonable approach may be to individualize maintenance treatment plans based on a patient’s prior illness course, context, and needs through shared decision-making.[130]
Indian evidence suggests that long-term maintenance therapy helps prevent relapses in BD.[131] If it is decided to discontinue maintenance treatment, tapering in small steps with close monitoring, providing education on early warning signs of relapse, preparing effective contingency plans, and ensuring clinician accessibility during the discontinuation process are essential. Interestingly, an Indian study found that 80% of patients, who underwent planned discontinuation of lithium, following extended periods of maintenance treatment and clinical euthymia, had relapsed within 10 months of discontinuation.[131]
Agents positioned as first-line maintenance therapies for BD, due to their broad evidence base, include lithium, divalproex, quetiapine, and lamotrigine; all these agents have evidence for the prevention of manic and depressive episodes.[20] For the prevention of mixed episodes, evidence is limited; a recent umbrella review[132] found that divalproex was superior to placebo and comparable to olanzapine for preventing relapse of mixed episodes. Lamotrigine has stronger evidence for depressive than manic prophylaxis.[20] Hence, depending on the predominant polarity, lamotrigine may be used alone or in combination with agents such as lithium to support the prophylaxis of mania.
There is supporting literature to show that asenapine[133] and aripiprazole,[134] are also effective in preventing mood episodes, with evidence mainly stemming from manic than depressive episode prevention. Agents such as olanzapine[135] and risperidone[136] are also widely used in India for maintenance treatment of mania and have a positive evidence base, albeit stronger with olanzapine.[137] However, the propensity of olanzapine to cause metabolic side effects calls for a cautious risk-benefit assessment before initiation.
A general caveat is that maintenance treatment dosages may need to be adjusted; typically, patients do not tolerate the same dose used in the acute phase. On a related note, the suggested maintenance treatment serum levels for lithium are 0.6–0.8 meq/l in medically healthy individuals and 0.4–0.6 meq/l in older adults or those with relevant medical issues.[138,139]
If monotherapy proved insufficient, combination therapy with an atypical antipsychotic and lithium/divalproex may be considered. Evidence indicates that such combinations, when used during the acute manic phase and continued for up to 6 months following treatment response, are associated with a reduced risk of mood episode recurrence.[137] If combination therapy with first-line agents is not effective, a switch to an alternative first-line agent or adding an alternative first-line agent may be considered.
After multiple sequential trials of first-line agents, an appropriate second-line agent may be chosen for maintenance treatment. Second-line agents for maintenance therapy in BD include olanzapine, carbamazepine, ziprasidone (adjunctive), or risperidone. For those with recurrent adherence issues, a trial of long-acting injectable (LAI) preparation may be considered; LAIs for BD are discussed in a subsequent section within this guideline (see subsection on “Use of Long-Acting Injectables (LAIs) in BD”).
If second-line agents are also ineffective, an appropriate combination therapy of first- or second-line agents, or a trial of clozapine, may be considered. If an antidepressant was initiated in the acute phase, an individualized decision to discontinue it may be taken after remission is sustained for 8–12 weeks. Importantly, Indian evidence suggests that the time to relapse for depressive episodes is significantly longer with concurrent prescription of antidepressants and mood stabilizers compared to placebo with mood stabilizers. Notably, the rate of treatment-emergent affective switching was comparable between the two groups.[99]
The first-line agents for maintenance treatment in BD-II include quetiapine, lithium, and lamotrigine. If monotherapy is not effective in the prevention of relapse, a combination of first-line agents can be considered. Based on RCT evidence, venlafaxine,[140] or fluoxetine[141] may be considered in patients experiencing inadequate symptom control with first-line medications. Other agents with lesser evidence include carbamazepine, divalproex, escitalopram, and risperidone.
Adjunctive psychosocial interventions may help reduce recurrence rates in BD[20] and should be offered for all patients. Psychoeducation has the maximum evidence base and should be offered as a first-line maintenance treatment.[108] Other treatments, such as FFT, CBT, and IPSRT, should be offered based on the available resources and individual needs.
SPECIAL POPULATIONS AND TREATMENT CONSIDERATIONS
This section outlines the common issues and considerations in clinical care of BD, with an emphasis on strategies to manage them effectively. We also discuss treatment considerations in special populations and management of common comorbidities in BD.
Strategies for assessing and improving treatment adherence in bipolar disorder
Nonadherence is a significant determinant of poor outcomes in BD, affecting 40%–60% of BD patients.[142,143,144] Poor adherence is linked to more severe illness trajectories, including more relapses, hospitalizations, and poorer functional outcomes.[143,144] Timely treatment has the potential to improve long-term outcomes in BD, while delayed treatment and longer duration of untreated illness are associated with more suicide attempts and worse outcomes in BD.[145]
Assessing for adherence
Adherence should be routinely and periodically evaluated in BD.[20] Failure to recognize partial adherence (typically taking some prescribed medications rather than all or none of it) or non-adherence may result in unwarranted medication switches or polypharmacy. Self-reports of adherence are convenient and widely used but can be unreliable. Corroborative information should be obtained from caregivers whenever possible. Supplementary, objective methods to check adherence include prescription renewal, pill counts, medicine procurement bills and, where applicable, pharmacy refill records. The gold standard measure of adherence is serum drug levels. For certain drugs such as lithium and valproate, serum drug levels can offer valuable information about adherence. Apart from medication, one must also evaluate adherence to lifestyle changes (e.g., increased physical activity) or psychosocial interventions (e.g., problem-solving approaches), if these were advised as part of the management.
When suboptimal adherence is suspected, clinicians should assess its potential underlying causes. Table 11 summarizes the key patient-, illness-, and treatment-related factors that are associated with poor adherence in BD.[20,142,144]
Table 11.
Correlates of poor adherence in bipolar disorder
| Category | Key correlates |
|---|---|
| Patient-related | Younger age, male gender, low education, unmarried or single, cognitive issues, negative/ambivalent attitudes and beliefs about illness and treatment, perceived stigma, cultural factors, financial constraints |
| Illness-related | More severe or psychotic symptoms, mixed features or rapid cycling, residual symptoms, low insight, comorbid psychiatric or substance use disorders |
| Treatment-related | Adverse effects, perceived lack of efficacy, complex medication regimens, high pill burden, poor therapeutic alliance, cost and access issues |
Strategies to improve treatment adherence
A meta-analysis of RCTs on adherence in BD found that interventions increased adherence relative to the control group.[146] Furthermore, these effects were durable, lasting up to 2 years after cessation of the intervention. Psychoeducation was the most studied intervention, followed by CBT. Below, we list evidence-based strategies and considerations to improve adherence in BD:
Establishing a good therapeutic alliance.
Psychoeducation about illness and the need for continued treatment.[20,147]
Active involvement of family caregivers in consultations.[63]
Collaborative or shared decision-making encourages a sense of responsibility for treatment choices.[20,147,148]
Simplified medication regimens (e.g., once daily).
Adverse effects should be mitigated to the extent possible by dose adjustments/reductions or switching between formulations and adding adjunctive medication.
Enquire and be vigilant about affordability issues compromising adherence.
LAI antipsychotics may be considered for patients with repeated non-adherence and high relapse risk.[20]
In the Indian context, telephone-based short message service reminders improved medication adherence compared to treatment as usual, with effects persisting after discontinuation.[149] Smartphone app-based tools may aid adherence, especially among urban, digitally literate patients. Finally, tele-consultations could potentially improve adherence among patients, who are geographically remote and face cost and access issues.[150]
Use of Long-Acting Injectables (LAIs) in bipolar disorder
LAIs offer a valuable treatment option for patients with a recurrent pattern of non-adherence and a high risk of relapse or severe episodes. LAIs can reduce hospitalizations, improve adherence, and support functional stability in BD.[151,152]
A recent multinational Asian study reviewed prescriptions to explore the real-world use of LAIs and found their utilization in 5% of cases with BD. Interestingly, no LAI prescription was found for the BD sub-sample from India, highlighting significant cross-national variations.[153] Barriers to using LAIs may include patient acceptability, availability constraints, and the clinician’s preference or comfort levels. Below, we list a synthesis of current evidence on LAI use and efficacy in maintenance treatment of BD:
Second-generation LAIs appear well tolerated and effective for preventing recurrences (mainly manic relapses) in BD-I disorder.[151,154]
There is insufficient evidence for LAI efficacy for preventing depressive relapses or for maintenance treatment of BD-II disorder.
Risperidone LAI biweekly formulation has the strongest evidence, followed by aripiprazole monohydrate monthly LAI.[136,151,154,155] Unfortunately, the latter is not yet available in India, and the former is expensive.
Paliperidone palmitate LAI has shown efficacy in small non-randomized studies. For olanzapine LAI, evidence is primarily based on case reports, and the need for post-injection monitoring can pose practical challenges.[136,154]
Regular monitoring for adverse effects is essential, including extrapyramidal symptoms, tardive dyskinesia, metabolic changes, and prolactin-related side effects.
First-generation LAIs are best avoided for patients with BD due to the risk of worsening dysphoric or depressive symptoms and safety concerns.[136]
Role of polypharmacy in the management of bipolar disorder
Polypharmacy has been variably defined in BD, though recent research defines complex polypharmacy as the use of ≥3 concurrent psychotropic medications.[156] A review of prescriptions across several Asian countries revealed that 20.3% of those with BD received three or more medications.[157] Factors associated with polypharmacy were old age, female gender, history of psychosis, severe depression, suicide attempts, and co-occurring psychiatric or medical conditions.[156]
The impact of polypharmacy on treatment outcomes in BD remains uncertain. Polypharmacy is associated with greater side-effect burden, more drug-drug interactions, reduced adherence, and higher healthcare costs.[158] The following principles may guide clinical practice in terms of polypharmacy in BD[159,160]:
Favoring rational polypharmacy by prioritizing evidence-based combinations, considering risk-benefit profile, and setting clear treatment goals. For instance, combining lithium and lurasidone in acute bipolar depression is supported by literature, and both agents have different goals; while lithium targets the prevention of further depressive episodes, lurasidone targets the acute symptoms.
Deprescribing when feasible by periodically reassessing the need for multiple agents and tapering any non-essential/non-effective medications through careful review of history and shared decision making. This may reduce adverse effect burden and increase adherence.
Use of antidepressants in bipolar disorder
Depression in BD-I
Little tangible data exists for the long-term benefits of antidepressants in BD-I depression. Despite this lack of evidence, real-world prescription data reveal that antidepressants were prescribed to 20% of Asian BD patients[161] and approximately one-third of clinically stable BD patients in India.[94]
The following points may inform the clinical approach and considerations in using antidepressants in BD-I depression[20,162,163,164,165]:
Antidepressants should not be used as monotherapy in BD-I depression due to the risk of manic switch and lack of evidence for efficacy (as monotherapy).
Antidepressants with a lower risk of switch (such as SSRIs or bupropion) may be preferred for treatment of acute BD-I depression not responding adequately to first-line treatment choices.
Adjunctive antidepressants are associated with reduced symptoms of BD-I depression; however, the overall magnitude of benefit is small to modest.
Anti-depressant exposure may be avoided in BD patients with mixed episodes or mixed depressive states, as these patients are particularly vulnerable to worsening of course or cycle acceleration. For the same reasons, antidepressants should also be avoided or used with extreme caution in rapid cycling patients.
When initiating antidepressants, clinicians should simultaneously educate patients and families to recognize early symptoms of mania, such as decreased need for sleep or irritability or any atypical behavior patterns, so that it can be managed promptly.
Antidepressants should be tapered and stopped soon after the acute episode remits (typically within 6–8 weeks) to minimize the risk of a switch or illness destabilization and owing to a lack of evidence for later discontinuation in terms of relapse prevention.[99]
Depression in BD-II
Limited evidence supports the efficacy of antidepressants in BD-II depression. Both venlafaxine and sertraline monotherapy demonstrated short-term benefits, with good response and remission rates across included trials.[166] Rates of antidepressant-associated affective switch are significantly lower in BD-II, relative to BD-I.[167] Switch rates may remain low even with the use of antidepressant monotherapy.[87] A recent systematic review[166] concluded that antidepressant monotherapy is well tolerated in BD-II. Overall, antidepressants have a more favorable risk-benefit profile in BD-II compared to BD-I.
Management of anti-depressant induced mania in bipolar disorder
Treatment-emergent affective switch (TEAS) is a broader term for hypomania, mania, or mixed states triggered following the initiation or dose escalation of pharmacological or somatic treatments for depression, with operational criteria developed by the International Society for Bipolar Disorders.[168] Estimates of TEAS vary by study design, but randomized trials suggest a rough prevalence of 12%.[169] The risk of switch is higher with antidepressant monotherapy and lower when co-prescribed with mood stabilizers or second-generation antipsychotics.[170,171,172] Risk also varies by medication class (tricyclics and SNRIs >SSRIs and bupropion) and by diagnosis (BD-I > BD-II > MDD).
Potential risk factors for TEAS in depression include BD-I illness subtype, rapid-cycling course, co-morbid substance use disorder (SUD), prior history of TEAS, more prior depressive episodes, previous suicide attempt, baseline mixed features (concurrent symptoms of manic pole), and family history of BD.[169,172] Given the clinical importance of an antidepressant-induced switch in BD management,[173] we offer the following suggestions to prevent and manage such instances:[20,163,164,174,175]
Screen for known risk factors, including a history of TEAS, before initiating antidepressants in BD.
Provide psychoeducation to patients and caregivers about early signs of manic or mixed features and how to identify them.
Prioritize mood stabilizers and second-generation antipsychotics (SGAs) in the management of BD-I depression and use adjunctive antidepressants as a second-line treatment option.
After initiating an antidepressant in BD, schedule frequent follow-ups and monitor closely for TEAS in follow-up consultations.
Rather than checking for expansive features, clinicians may evaluate for behavior activation (such as marked irritability, psychomotor agitation, and psychic tension) in patients with bipolar depression as markers for TEAS.[164]
-
In the absence of robust empirical data, expert consensus currently guides the management of TEAS. We offer the following suggestions for management of suspected or confirmed TEAS[162,163,174]:
Discontinue the antidepressant, particularly in BD-I. In case of hypomanic switch in BD-II, the antidepressant dose may be tapered with close monitoring for improvement.
Remove other potential precipitants (such as stimulants or substance use) and deprescribe non-essential co-medications.
Start or optimize antimanic treatment (e.g., lithium, valproate, or a second-generation antipsychotic), especially if symptoms are consistent with syndromal mania.
Manage agitation and insomnia with short-term benzodiazepines and measures to restore the sleep-wake cycle.
Assess risk and escalate care for severe mania, mixed features, or suicidality; consider hospitalization if indicated.
Document the switch in clinical records for future reference and arrange close follow-up monitoring even after the patient improves to observe for any depressive relapse.
Approach and considerations pertaining to TEAS in BD patients with co-morbid obsessive-compulsive disorder (OCD) are covered under the relevant sub-section on psychiatric comorbidities later in this guideline.
Addressing the hesitancy to utilize conventional mood stabilizers in bipolar disorder
Over recent years, there has been a gradual shift from traditional mood stabilizers (such as lithium or divalproex) toward greater reliance on SGAs in the treatment of BD. However, treatment with lithium offers multiple benefits in BD apart from protection against relapses. This includes a reduction in suicidality, prevention of dementia, attenuation of the risk of osteoporosis and cancer, and lowering all-cause mortality.[176,177,178,179] However, its use has declined over recent decades, partly due to long-term safety concerns,[179] even though these can be mitigated through patient education and regular monitoring. Similarly, with the advent of SGAs, divalproex is relatively less preferred even for those outside the reproductive age group, despite evidence supporting its use for acute mania and relapse prevention in BD.
There is a trend towards an early and continued reliance on SGAs across a longer illness course, presumably because they require less safety monitoring and have a rapid onset of action. Further, SGAs have increasing literature support for their use in BD; several SGAs are listed among first-line treatments for BD in standard guidelines.[20] However, in contrast to lithium, SGAs lack the same level of longitudinal evidence for functional recovery and mortality reduction. SGAs also carry substantial risks of metabolic syndrome, weight gain or sedation, which can affect long-term outcomes and pose a significant medical burden.[180] Further, the newer SGAs, though metabolically safe, lack long-term efficacy and safety data, particularly in different phases of BD. Excessive reliance on SGAs risks overlooking the unique strengths and evidence base of mood stabilizing agents. Choosing between antipsychotics and conventional mood stabilizers for maintenance treatment of BD is discussed in the expert consensus section, later in this document.
Management of common comorbidities in bipolar disorder
Individuals with BD have higher rates of lifetime medical/psychiatric comorbidities, excess all-cause mortality, and shorter life expectancy.[20,181,182] Common psychiatric comorbidities are anxiety disorders, OCD, SUDs, personality disorders (borderline), and ADHD.[20] Indian national mental health survey data for BD reported tobacco use disorder (33.3%), other SUDs (14.6%), and anxiety disorders (10.4%) to be common comorbidities.[3] Another Indian study found that nearly two-thirds of patients with BD have physical comorbidity, commonly cardiovascular diseases (20%).[183] Table 12 summarizes the cross-cutting issues and considerations in managing comorbid medical or psychiatric conditions in patients with BD.
Table 12.
General considerations in clinical care for comorbidities in bipolar disorder (BD)
| Domain | Key considerations |
|---|---|
| Assessment | Take a thorough baseline and ongoing history for psychiatric and medical comorbidities. Differentiate BD symptoms from comorbidity in view of potential overlap/influence on clinical presentation. |
| Prioritization | Prioritize the acute or severe condition first (e.g., mania, suicidality, uncontrolled medical illness). Manage substance use concurrently or in sequence, depending on severity and contribution to mood instability. |
| Mood stabilization | This is the foundation of clinical care in BD. Stabilize mood first before adding any medication for comorbidity that may potentially worsen mood or lead to a switch. |
| Pharmacological strategy | Prefer treatments with dual efficacy across BD and comorbidity (e.g., quetiapine for BD + anxiety). Avoid agents that worsen the course of BD. Monitor for drug interactions and avoid cumulative side effects, to the extent feasible. |
| Medical monitoring | Routine (and periodic) screening for metabolic parameters. Address obesity, metabolic risk, and cardiovascular risk factors. |
| Psychosocial interventions | Psychoeducation, CBT, lifestyle interventions. Discuss strategies for optimizing adherence and regular follow-ups |
| Care model | Emphasize shared decision making. Coordinate care across psychiatry and medical specialty services. |
CBT: Cognitive behavior therapy
Anxiety disorders
Between one-third and one-half of individuals with BD have a comorbid anxiety disorder, a finding also supported by Indian data, though rates vary.[184,185,186] Data from Asia and elsewhere consistently show that comorbid anxiety disorder worsens the course and outcomes of BD, with prolonged symptomatic periods, more depressive episodes, higher suicidality, poorer psychosocial functioning, and reduced treatment response; even subthreshold anxiety is associated with poorer outcomes.[187,188,189]
Evidence from treatment trials for BD with comorbid anxiety disorders remains scant.[190] Based on the limited evidence, the following considerations may apply:[20,191,192]
CBT remains a safe first-line treatment for anxiety disorders with modest, but clinically significant, benefits in euthymic patients with BD.
Mood stabilization should be the primary goal before adding specific agents for anxiety.
Quetiapine has the strongest evidence from RCTs, showing benefit over placebo or divalproex in BD with comorbid generalized anxiety disorder (GAD) or panic disorder.[193] Secondary analyses also support the efficacy of quetiapine monotherapy in reducing GAD and panic symptoms during bipolar depression. Limited evidence suggests anxiolytic effects of olanzapine in lithium-treated patients, while risperidone showed no efficacy in a controlled trial.[194]
Adjunctive gabapentin may be considered as it reduced anxiety symptoms in BD in open-label studies.[20] Pregabalin lacks specific trials in comorbid BD.
Divalproex sodium has preliminary evidence from open-label studies for panic disorder or non-specific anxiety symptoms in BD.
Post-hoc analysis of a placebo-controlled RCT indicated efficacy of lurasidone for anxiety disorder comorbid with BD.[195]
Antidepressants should be used with caution, particularly in BD-I. If necessary, they are to be used under adequate mood-stabilizer cover. No large RCTs have tested SSRIs in BD-anxiety comorbidity; hence, evidence from anxiety disorders may be cautiously extrapolated.
Benzodiazepines can provide rapid short-term relief of anxiety but should be restricted to the lowest effective dose and for the shortest duration feasible.
Obsessive-compulsive disorder (OCD)
A recent meta-analysis reported a pooled prevalence of 21.7% for OCD in BD-I disorder.[196] OCD may precede or follow bipolar illness onset, and the course may be episodic or fluctuating with mood states, worsening during depression, and remitting in mania. This comorbidity is linked to earlier onset of BD, more frequent episodes, rapid cycling course, substance use, seasonality, suicidality, and poorer functioning.[20,197] The following considerations may be helpful while treating OCD in the context of BD:
Mood stabilization with mood stabilizer/SGAs is the primary goal.[20,198]
OCD symptoms may remit with mood stabilization alone in some cases, obviating the need for antidepressants.
If antidepressants are used, SSRIs are preferred under adequate mood stabilization coverage. However, the need to continue SSRI over a longer time should be periodically reviewed, particularly in BD-I.
Clomipramine is better avoided due to a higher risk of manic switch.
Potential of co-prescribed SGAs to induce or exacerbate OC symptoms, especially at higher doses, must be noted. For management of treatment-emergent OC symptoms with SGAs, readers are referred to the relevant section in the clinical practice guidelines on OCD in this issue.[199]
Among antipsychotics, aripiprazole and risperidone, as adjunctive therapy with divalproex, may be preferred for treating co-morbid OCD in BD.[200] Quetiapine has a single positive RCT supporting its use.[201] These may be tried in OCD-BD comorbidity, especially if the possibility of an affective switch with SSRIs is concerning.
One RCT showed that memantine is an effective adjuvant agent for reducing co-morbid OC symptoms.[202]
A small case series from India reported that adjunctive transcranial direct current stimulation (tDCS) reduced OC symptoms in three patients with co-morbid BD-OCD.[203]
Borderline personality disorder (BPD)
Comorbidity of BPD in BD is common (15%–20%). Patients with BD-BPD have longer hospital stays, higher ECT utilization, and an elevated suicide risk compared to BD alone.[204,205] From a treatment perspective, evidence is sparse for comorbid BD-BPD populations. Current approaches combine treatments established for BD and BPD separately.[20,205] Mood stabilizers and SGAs remain the treatment mainstay for BD, while structured psychotherapies for BD, such as dialectical behavior therapy (DBT) can be added. One preliminary trial in patients with BD-BPD comorbidity reported the efficacy of Systems Training for Emotional Predictability and Problem Solving (STEPPS) in reducing borderline trait severity and improving mood regulation by combining DBT elements and skills for emotion regulation.[206]
Attention-Deficit/Hyperactivity Disorder
Recent Western data suggest ADHD is comorbid in 10%–20% of patients with BD and is associated with adverse illness course, suicidality, and functional impairments.[20,207] In adults, diagnosis may be particularly challenging due to symptom overlap and confounding factors. Both over- and under-diagnosis of ADHD must be avoided. Indian data comprises a few hospital-based studies that document BD-ADHD comorbidity in children/adolescents,[208,209] with scant published data for adults. In an exploratory study from a tertiary care center,[210] those diagnosed with comorbid BD-ADHD (13–40 years) had an earlier age of onset, severe clinical course, and poorer functional outcomes compared to BD without comorbid ADHD. Similar findings were reported in a euthymic adult sample with BD who screened positive for ADHD, but a diagnostic assessment was not conducted in this study.[211]
Robust treatment trials for comorbid ADHD-BD are lacking. For milder ADHD symptoms, non-pharmacological interventions such as psychoeducation and behavioral strategies remain first-line treatments. Adjunctive bupropion may be preferred, particularly for those with frequent depressive episodes.[212] Stimulant medication, such as methylphenidate, may be considered after sustained remission and long-term mood stability has been achieved, under the cover of maintenance agents, along with monitoring for mood switch.[20] However, the lack of robust data from randomized trials necessitate caution.
Substance Use Disorders (SUD)
Substance use interferes with treatment adherence, treatment response, and worsens illness outcomes in BD.[213] Bipolar spectrum disorders are common among SUDs, and often go unrecognized.[214,215] Management for BD and SUD may be initiated simultaneously, especially when withdrawal from substance use is deemed to contribute to mood instability.[216,217]
The sparse available literature is summarized here.[213,216,217] For alcohol use disorder comorbid with BD, a randomized trial found that the combination of lithium and divalproex was more effective than lithium alone in reducing drinking frequency. Lamotrigine and divalproex monotherapies (if hepatic function is intact) may offer modest benefit. Adjunctive gabapentin and topiramate show some efficacy, but the evidence is indirect. Naltrexone has limited and inconsistent efficacy data. Disulfiram is not recommended due to its potential to exacerbate mania and the risks associated with impulsivity.[20]
For comorbid cannabis use disorder, evidence is again sparse. Lithium and divalproex may offer some benefit. Olanzapine add-on therapy was reported to reduce manic symptoms and substance-related cravings among hospitalized patients. Aripiprazole may reduce both alcohol and cannabis cravings.[20,214]
Metabolic syndrome
Metabolic abnormalities are highly prevalent in BD, with population studies reporting 2-3 times higher rates of obesity, metabolic syndrome, type 2 diabetes, dyslipidemia, and hypertension in BD compared to the general population.[188] Indian studies report metabolic syndrome in around one-third of BD patients.[180,218] A 5-year longitudinal study from India reported that the prevalence of metabolic syndrome increased from 54% to 66% in patients with BD.[219] Metabolic derangements contribute significantly to cardiovascular burden and psychiatric outcomes, underscoring the need for screening, prevention, and management in patients with BD. The following considerations may apply to the management of metabolic changes in BD[20,188]:
Routine, periodic screening of metabolic health should be part of usual care for BD. Metabolic parameters to be monitored for different treatment agents are summarized in Tables 6-8 of this guideline.
Lifestyle risk factors (e.g., sedentary lifestyle, irregular sleep, substance use, etc.) should be systematically assessed.
Agents with lower metabolic adverse effects, such as lamotrigine, lithium, lurasidone, or aripiprazole, may be preferred for first-line treatment of BD. Agents such as olanzapine, with a more adverse metabolic risk profile, may be considered second-line agents.
Evidence supports the use of metformin in mitigating antipsychotic-induced weight gain and insulin resistance/diabetes in BD. GLP-1 agonists, such as semaglutide, are emerging agents with a growing evidence base for antipsychotic-induced weight gain.[220]
Early detection and adequate control of comorbid physical conditions are required; collaboration with physician specialists is desirable.
Management of treatment-resistant bipolar disorder (TRBD)
Treatment resistance in BD is typically defined as non-response to adequate trials of two or more evidence-based agents.[221,222] Treatment refractoriness must first be distinguished from pseudo-resistance, which can be identified by reviewing common factors that may interfere with treatment response [Table 13].[20,221]
Table 13.
Checklist of common reasons for treatment resistance in bipolar disorder (BD)
| Factor | Action points |
|---|---|
| Review diagnosis | Ensure an accurate diagnosis or re-evaluate the diagnosis if necessary. |
| Secondary BD | Exclude BD secondary to an organic condition. |
| Comorbidity | Poor treatment response may be explained by comorbidity (e.g., hypothyroidism, personality disorder). |
| Pharmacokinetic reasons | Treatment response may be impaired by factors related to drug pharmacokinetics (e.g., smoking or co-medications inducing metabolism of the treatment agent). |
| Tolerability | A lack of response may be due to treatment intolerance, which compromises adequate dose titration. |
| Adherence | Ensure that patient adherence is optimal before concluding treatment resistance. |
For mania, in case of failure to respond to conventional evidence-based treatments, subsequent options may include using combinations of mood stabilizers or mood stabilizers with antipsychotics that have lower evidence for efficacy. Typical antipsychotic agents, such as haloperidol, may be used in combination with mood stabilizers, if not yet tried. Available evidence suggests the efficacy of clozapine for treatment-resistant acute mania. Among mood stabilizers, carbamazepine/oxcarbazepine may be used alongside lithium (more commonly) or valproate. ECT is an important option in managing resistant manic episodes, besides treating acute, severe mania where rapid response is desired and first-line agents are not working optimally.
For bipolar depression, in case of failure to respond to conventional evidence-based treatments, adjunctive treatments such as olanzapine, modafinil, SNRI, monoamine oxidase inhibitors, and rTMS may be considered, though evidence is limited. ECT should also be considered, if not yet tried.[221,223,224,225,226] Non-invasive brain stimulation, such as accelerated intermittent theta-burst stimulation, has also been effectively tried for resistant bipolar depression.[227] Options such as ketamine, pramipexole, levothyroxine, N-acetyl cysteine, light therapy with or without sleep deprivation, among others, have limited evidence for efficacy. A recent systematic review of RCT data on treatment-resistant bipolar depression found short-term efficacy of adjunctive pramipexole, modafinil, and racemic intravenous ketamine.[224] Celecoxib augmentation of escitalopram and treatment with metformin in BD patients with insulin resistance showed some promising results.[224,228] Adjunctive psychosocial interventions must be offered wherever feasible.
Role of clozapine in bipolar disorder
Clozapine remains understudied and underutilized in BD. Limited available evidence suggests a potential benefit, particularly for treatment-resistant acute mania and those with a refractory illness course.[229] Efficacy of clozapine appears comparable to other antipsychotics in acute mania, with likely superiority in treatment-resistant cases.[221,229] Reported benefits in BD include improvement in manic, depressive, rapid-cycling, and psychotic symptoms, reductions in psychiatric admissions, bed-days, psychotropic co-medications, contacts for self-harm, and gains in social functioning.[229] Reflecting this promising but limited evidence, clozapine is recognized as a third-line option for acute mania and a potential adjunct for maintenance treatment in available treatment guidelines.[20]
Real-world utilization of clozapine in BD remains strikingly low; prescription data from Asian countries show it was prescribed to only about 2% of patients. These patients were typically older, male, hospitalized, manic, and on multiple antipsychotics.[230] Despite its proven efficacy, concerns about agranulocytosis and the burden of hematological monitoring remain key barriers to wider use of clozapine in BD. In patients with BD and comorbid OCD, there is a risk of worsening of obsessive-compulsive symptomatology with clozapine treatment.[231]
In 2025, the FDA removed the registration mandate under the Risk Evaluation and Mitigation Strategy (REMS) program for patients to receive clozapine.[232] This step was based on the premise that REMS was unnecessary to ensure clozapine’s benefits outweighed its hematological risks. Readers may note that hematological monitoring with clozapine, as updated in the product labelling and medication guide, is still recommended; only the REMS registration mandate for patients, prescribers, and pharmacies was removed to remove barriers to the wider use of clozapine.
Similarly, in January 2025, the European clozapine task force issued a joint expert statement revising blood monitoring rules after the first 18 weeks (till which time weekly absolute neutrophil count [ANC] monitoring is still recommended). Specifically, the requirement has been relaxed to monthly ANC testing after 18 weeks, quarterly after one year, and annually after two years in patients without prior neutropenia. Importantly, monitoring is based solely on ANC.[233] This relaxation was based on growing evidence indicating a low incidence of clozapine-induced agranulocytosis after one year of treatment initiation.[234,235] Since product labels may still reflect older requirements, they should be followed until any changes are made. We suggest clinicians rely on a clearly documented rationale and use a shared decision-making approach to justify any deviation from product label instructions.
To summarize, clozapine can be considered for resistant manic episodes and for treatment-refractory BD. Given limited RCT evidence, its use should be selective, closely monitored, and grounded in shared decision-making based on individualized risk-benefit analysis. Clinicians may note the revised hematological monitoring guidelines but employ a shared decision-making approach and document a clear rationale when deviating from package insert guidelines for blood monitoring.
Role of modified electroconvulsive therapy (MECT) and non-invasive brain stimulation (NIBS) in the management of bipolar disorder
MECT is a well-established, effective intervention that is widely available in India.[70,236,237] Among patients with BD, it can be used for all phases (manic, mixed, or depressive) of illness, particularly when episodes are severe, psychotic, catatonic, suicidal, stuporous, or warranting a rapid response. It is also recommended for BD-II depression in similar indications. ECT is also considered relatively safe in pregnancy and postpartum BD.[163,238,239] Evidence suggests remission rates of up to 70% in acute mania and 50%–60% in bipolar depression; response rates are typically higher.[67,240] Among patients with BD, who received ECT in an Indian tertiary care center, bipolar depression exceeded bipolar mania, with half of them experiencing >90% improvement.[67] Box 3 lists the contextual indications for ECT in BD.
Box 3: Contextual indications for modified electroconvulsive therapy in bipolar disorder
As a first-line treatment
Severe depression
Suicidality
Severe psychosis where rapid response is desired
Catatonic presentations
Depression with compromised oral intake worsening general medical status
Extreme, delirious mania
As second-line or third-line treatment
Treatment-resistant patients (for any phase of illness)
Some caution is required when conventional mood stabilizers are prescribed for patients posted for ECT.[241,242] Anti-epileptic mood stabilizers such as valproate or high-dose benzodiazepines may increase seizure threshold and interfere with ECT efficacy. Co-prescribed lithium may increase the risk of prolonged seizures and neurotoxicity with ECT. These considerations are typically addressed through dose adjustments (such as skipping the night dose of valproate on the day before ECT); however, clinicians may need to make decisions based on seizure quality and observed efficacy of ECT. Cognitive adverse effects can be minimized by optimizing electrode placement (e.g., right unilateral), using ultra-brief or brief pulse widths, and adjusting the stimulus dose or treatment frequency of ECT, among other strategies. Continuation-ECT may be required in a few patients with TRBD if other treatments have not worked. Available data on continuation or maintenance ECT for BD is quite limited, and it may be used only after a careful review on a case-by-case basis.
NIBS techniques, mainly rTMS and tDCS, show modest antidepressant effects in bipolar depression, but evidence is more limited compared to disorders such as MDD.[243] Available evidence supports NIBS as an adjunctive treatment for bipolar depression.[243] A meta-analysis showed that high-frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC) was superior to sham rTMS in acute bipolar depression.[244] No additional risk of a switch to mania was noted. Adverse effects were comparable to those observed in studies on unipolar depression. A recent meta-analysis of seven randomized sham-controlled trials (N = 168) showed superior antidepressant efficacy of theta burst stimulation [TBS] (standardized mean difference = 0.67; 95% confidence interval [CI], 0.03 to 1.31). The odds ratio (OR) for clinical response favored TBS (OR = 2.93, 95% CI, 1.32–6.52) and acceptability of treatments was comparable.[245]
A network meta-analysis that compared NIBS treatments for bipolar depression showed that high-frequency deep TMS and bilateral TMS (high-frequency rTMS to left DLPFC plus low-frequency rTMS to right DLPFC) had comparable efficacy.[246] Short-term tolerability is generally good and switch risk appears low when patients are adequately covered with mood-stabilizers, but durability and long-term outcomes remain uncertain.
For bipolar mania, an Indian sham-controlled RCT showed that adjunctive rTMS (20 Hz, 110% of motor threshold, 20 trains, 10 s intertrain interval) over the right DLPFC for 10 days was superior and well-tolerated.[26] A recent meta-analysis examining the use of rTMS in bipolar mania noted high between-study heterogeneity and the use of lower stimulation intensity in many trials.[244] Based on this, the authors called for more stringent RCTs in the future.
Role of ketamine/esketamine and endoxifen in the management of bipolar disorder
Ketamine demonstrates rapid antidepressant and anti-suicidal effects in treatment-resistant MDD, but evidence in bipolar depression is relatively less. Available studies on patients with BD, including a few small randomized trials, indicate that intravenous ketamine can produce marked improvements in mood and suicidality within hours[247]; response is typically less robust and durable, compared to that seen in MDD. Ketamine has a favorable short-term safety profile with a low risk of treatment-emergent mania. However, these benefits are short-lived, often waning within days. Potential for dissociation and abuse warrants careful monitoring and use of ketamine only in therapeutic contexts with therapeutic doses under supervision.
A recent review of ketamine research from India identified only a few studies in bipolar depression, with findings consistent with the broader international literature.[248] Esketamine data in bipolar depression are limited to small samples using intranasal or subcutaneous routes, but suggest efficacy in TRBD, including improvements in anhedonia.[249] The role of ketamine/esketamine in the routine clinical care of bipolar depression is not well-established. However, it may be considered as a short-term adjunct in treatment-resistant cases of bipolar depression, especially as an alternative to ECT, when it is unavailable or unacceptable to the patient.[248]
Endoxifen has limited evidence as a potential treatment for acute mania,[250] with methodological concerns.[251,252] Available clinical evidence comprises two RCTs of short duration (21 days each) and a few case reports.[60,250] These studies suggest a reduction in manic symptoms; however, due to the limited evidence, no recommendations can be made. Further, there is no data on its long-term safety. Endoxifen may be tried as an adjunct treatment for acute mania, particularly when concurrent impulsivity or aggression is marked, and other treatment options are either not viable or exhausted.[253]
Gender differences in the management of bipolar disorder
Although the overall treatment principles remain broadly similar across both genders, certain distinctions in clinical presentations and special considerations are worth noting, as they can help individualize clinical care where relevant:
Women tend to show a depressive-predominant polarity, more rapid cycling and mixed features, and higher rates of BD-II. In contrast, men have an earlier onset of BD and higher rates of comorbid SUDs.[254,255]
Females with BD have more suicide attempts, while males have higher suicide-related mortality; no apparent sex differences emerged in terms of suicidal ideation.[256]
Hormonal fluctuations can influence symptoms in women, with worsening during premenstrual or late-luteal phases in a subset of women.[257]
Women with BD also show greater medical burden, notably higher rates of co-morbid thyroid dysfunction, migraine, and elevated cardiometabolic burden.[258,259]
Gender-specific considerations may also influence treatment choices. For instance, carbamazepine can reduce the efficacy of oral contraceptive pills, necessitating alternative contraception measures. Women are more susceptible to lithium-induced hypothyroidism. Besides, specific adverse effects, such as hyperprolactinemia and consequent amenorrhea, are especially distressing and stigmatizing for women.
Treatment issues surrounding pregnancy and the peripartum period are discussed in the next section.
Considerations in pregnant and lactating women
Pharmacological treatment during pregnancy requires a careful weighing of the risk-benefit profile of psychotropic drug exposure. Ideally, such discussions should begin 4–6 months before the pre-conception period. In real life, however, most pregnancies are unplanned or unrecognized in early weeks. Therefore, contraceptive counselling should be offered to all reproductive-age women with BD on treatment, and the reproductive safety of an agent must be considered, while planning prophylaxis in this group.[260,261]
Further, while starting/restarting psychotropic medications, an inquiry into the last menstrual period must be taken. If required, a urine pregnancy test must be performed as part of routine clinical care. Optimal control of comorbid conditions, healthy lifestyle measures, and prenatal vitamins with folic acid supplementation (typically 5 mg/day) should be recommended during the pre-conception period.[260,261]
Decisions on whether to continue maintenance treatment during pregnancy should be based on a careful risk-benefit analysis, including illness considerations (such as, but not limited to, duration of remission, illness course, episode severity, suicidality risk, past treatment response, etc.), and patient preferences.[262] The following are possible options:
Continue drugs but with minimum medications (preferably monotherapy) at the minimum effective dose.
Discontinuation or drug-free period (with psychological interventions, if indicated).
Substitution (gradual cross taper) with a reproductively safer agent before conception.
Clinicians should provide patients with clear information on medication and illness-related risks, alongside individualized clinical guidance, to support informed decision-making. Information provided may include evidence on teratogenicity, poor neonatal adaptation following delivery, and potential long-term neurobehavioral sequelae. Documenting the risk—benefit discussion and the shared decision-making process in the patient’s medical records is equally important. Table 14 summarizes the reproductive safety of drugs commonly used in BD.[260,261,262,263,264,265,266,267,268,269]
Table 14.
Reproductive safety of psychotropic medications for bipolar disorder[260,261,262,263,264,265,266,267,268,269]
| Mood stabilizers | Safety data | Clinical considerations |
|---|---|---|
| Lithium | Small absolute risk of Ebstein’s anomaly (0.05%–0.1% of live births) with first-trimester exposure (twenty times higher than the general population rate). Slightly increased risks of preterm birth and low birth weight. Risks of cardiac malformation could be dose-dependent.[265] |
Fetal echocardiography is advised at 16–20 weeks. Frequent serum lithium level monitoring may be necessary due to hemodynamic changes. (monthly till 36 weeks, weekly from 36-40 weeks; twice each week in the first 2 weeks postpartum) |
| Valproic acid/Divalproex | High risk of major congenital malformations (8%–10%), including neural tube defects. Linked to later neurodevelopmental disorders.[266] | Contraindicated in pregnancy. |
| Carbamazepine | Risk of major congenital malformations (3%–6%). Risk of neonatal bleeding diathesis from vitamin K deficiency. | Avoid to the extent possible. Supplement with high-dose folic acid before conception (though evidence remains unclear). Provide maternal vitamin K late in pregnancy and neonatal vitamin K supplementation at birth. |
| Oxcarbazepine | The risk of major congenital malformations appears comparable to the general population rate (≈3%).[267] | It can be used during pregnancy, although safety data are limited. |
| Lamotrigine | The malformation risk (≈3%) is similar to the baseline population risk.[267] No definite evidence of neurobehavioral sequelae. |
Preferred agent if clinically indicated (e.g., bipolar depression or depression-predominant course). Dose adjustment is often required due to increased clearance during pregnancy. Monitor the infant for skin rash. |
| Second-generation antipsychotics (SGAs) | ||
| Olanzapine, Quetiapine, Aripiprazole, Risperidone | The major malformation risk is approximately 4.5% in exposed individuals versus 3.5% among unexposed individuals; no significant increase was observed after adjustment, except for a small increase associated with risperidone.[267] Another large recent study did not replicate the risperidone signal.[268] Maternal risks: weight gain, gestational diabetes, large-for-gestational-age infant. |
These SGAs appear to be relatively safe. Monitor maternal weight and glucose (with quetiapine/olanzapine). Consider using ultrasound to assess fetal size in late pregnancy.[269] Monitor maternal weight and glucose (with quetiapine/olanzapine). |
| Clozapine, Ziprasidone, Lurasidone | Available safety evidence is limited. | If clozapine is used, monitoring of the neonatal blood count is crucial. |
| Antidepressants and sedative-hypnotic agents | ||
|
SSRIs (Fluoxetine, Escitalopram, Sertraline, Paroxetine, Fluvoxamine) |
Slight increased risk of spontaneous abortion, preterm birth, and low birth weight. Small increased absolute risks of cardiac defects with paroxetine (2/1000). Conflicting evidence on persistent pulmonary hypertension (3rd trimester). Neonatal adaptation difficulties may occur in one-third of late-exposed infants. |
Generally safe, if indicated. Avoid paroxetine. |
|
Non-SSRI antidepressants(Bupropion, Mirtazapine, Venlafaxine, Duloxetine) |
Limited safety data are available, but malformation risks appear to be similar to those of SSRIs. | Use if SSRIs are not suitable. |
| Benzodiazepines | Older studies suggested a risk of oral clefts (not confirmed in recent meta-analyses). Other concerns include neonatal toxicity/withdrawal, including floppy infant syndrome. | Reserve for acute/short-term use. Taper before delivery, if feasible. |
SSRI: Selective Serotonin Reuptake Inhibitors
The postpartum phase is a particularly high vulnerability period for relapse in women with BD. To reduce this risk, maintenance therapy should be resumed promptly after childbirth, particularly for those who are off medications and considered to be at higher risk of relapse.[270] Close observation is essential for all patients for detecting early signs of maternal relapse. Medications (e.g., lithium, lamotrigine) uptitrated during pregnancy may be brought back to pre-pregnancy doses, with close monitoring for adverse effects and serum levels, as applicable.
Though older evidence suggested a high relative risk of Ebstein’s anomaly with first-trimester exposure to lithium, it may be noted that the absolute risk is small (0.05%–0.1%)[265]; hence, lithium may be considered during pregnancy as a maintenance medication for those in whom only lithium has worked in the past after a careful risk-benefit analysis and employing a shared decision-making approach. In all pregnancies with first-trimester lithium exposure, a 20-week fetal cardiac anomaly scan is recommended.[271]
Breastfeeding is usually encouraged, unless there are reasons to advise against it [e.g., risk of harm to the child, use of lactation-incompatible (co)medications, etc.]. Family’s assistance with nighttime infant feeds and baby care can help reduce maternal sleep disruptions. Feeding just before the next medication dose (trough feeding) helps minimize drug transfer through breastmilk. The mother should be educated to recognize adverse effects in a breast-fed infant.
Current evidence suggests that quetiapine and olanzapine are safe during breastfeeding[272,273]; lactation data remain somewhat limited for other SGAs. Indian data suggest that dopamine agonists, specifically aripiprazole, are associated with lactation failure. In a retrospective analysis of 60 women, 74% of mothers who were exposed to aripiprazole during pregnancy and postpartum periods experienced lactation failure, and about 11% experienced insufficient milk production.[274] These findings have implications for the selection of antipsychotics in the antepartum period and shared decision-making.
Clozapine should not be prescribed during breastfeeding because of rare but serious adverse effects warranting blood monitoring. Among mood stabilizers, breastfeeding is generally avoided with lithium due to the risk of neonatal toxicity and the need for infant serum drug level monitoring; divalproex is considered relatively safer in breastfeeding. However, breastfeeding during lithium treatment may be considered in healthy, full-term infants with close monitoring,[275] if only because treatment discontinuation may pose greater risks. Lamotrigine has limited data; if used, the infant must be carefully monitored for skin rash. Adjunctive SSRIs, if indicated, are relatively safe for breastfeeding, with sertraline having the most substantial evidence of lactation safety. Collaborative care is required, particularly in the peripartum period, to optimize psychiatric and reproductive outcomes.
CONSENSUS OPINION ON KEY CLINICAL QUESTIONS
In this section, we present our consensus opinions on key clinical questions and dilemmas in the management of BD, tailored for the Indian setting. Readers are advised to exercise their clinical discretion while considering the views mentioned below when making clinical management decisions.
1. What is the role of antidepressants in Bipolar I Depression? How does it differ from Bipolar II Depression?
The role of antidepressants in BD-I remains controversial. Evidence suggests that antidepressants, at best, provide modest efficacy in BD-I depression.[20,86,87] Further, their use is limited by an adverse safety profile (risk of inducing mania, rapid cycling, and symptom destabilization).[172] We recommend that antidepressants should never be started as monotherapy in BD-I, but only as an adjunct to mood stabilizers and antipsychotics, and that too, only in cases of moderate or severe depression where optimization of ongoing maintenance treatment does not work. Other situations where adjunct antidepressants may be considered in BD-I depression are when there is a previous history of good response to antidepressants and a history of relapsing when taken off antidepressants. As a note of caution, add-on antidepressants may be avoided in those experiencing depression with prominent mixed features (e.g., irritability, increased agitation, racing thoughts, etc.).
In contrast, the risk-benefit profile of adjunct antidepressants in BD-II depression is relatively more favorable. Patients with BD-II are reportedly less prone to experience a treatment-emergent affective switch, and studies suggest greater efficacy for antidepressants in this diagnostic sub-group. Nevertheless, regardless of the diagnosis (BD-I or BD-II), when antidepressants are initiated in BD, the patient and family must be educated about symptoms of mood destabilization, kept in close follow-up, and the offending antidepressant must be promptly discontinued when a manic switch is suspected.
2. Should maintenance treatment be considered following the first manic episode, and for how long should it be continued?
BD is a chronic illness with a variable course and cycle length between patients. It is not possible to know the long-term course at the initial presentation. Most guidelines recommend maintenance treatment following the first manic episode,[34] particularly if there are indicators of severity, such as psychotic symptoms or requiring hospitalization, apart from a strong family history of BD. We reiterate the recommendations of the guidelines. We strongly recommend starting maintenance treatment for the first manic episode when there is a positive family history of BD, the episode was severe and/or required hospitalization, or when the social and economic implications of another relapse are significant. We also recommend that the need for and duration of maintenance treatment should be guided by a careful, individualized risk-benefit assessment, particularly given the potential risks associated with long-term use of commonly prescribed mood stabilizers. In all cases, we suggest that decisions regarding maintenance therapy be made through a shared decision-making approach with the patient and family, considering individual risk-benefit considerations.
Even where indications for life-long prophylaxis are not prominent, maintenance treatment should be continued for at least 12–18 months after stabilization of a manic episode,[127] with further continuation depending on a discussion with the patient and family, and continued risk-benefit analysis. All decisions to discontinue treatment must be individualized and consider episode severity, family history, and the risks/costs of another relapse, and carried out after due discussion with the patient and family. Any drug discontinuation must be done under the supervision of a clinician and following the general deprescribing guidelines.[276] It is also essential to choose the right time for tapering medications; such decisions may be deferred if significant life events or stressors are anticipated in the near term. For a patient with a well-established course of BD, maintenance treatment must continue indefinitely.
3. How to choose between antipsychotics vs mood stabilizers in maintenance treatment of bipolar disorder?
Whereas traditional teaching favored mood stabilizers for long-term maintenance treatment in BD, recent guidelines[20,147] have positioned antipsychotics as a viable option for long-term maintenance treatment. While this is based primarily on evidence, we believe that a search for newer maintenance agents is also partly driven by the perceived risks and intolerance to existing long-term mood stabilizer therapy (e.g., concerns about risk of deterioration in renal function with long-term lithium therapy and need for periodic blood monitoring of serum lithium levels, risk of weight gain and hair loss with valproate).
We recommend that the selection of a maintenance treatment agent in BD be based on individual patient factors, such as clinical symptom profile, psychiatric and medical comorbidities, prior or family treatment response history, and special considerations, including suicidality. Lithium may be preferred as a first-line treatment in those with a positive family history of bipolar disorder, family history of lithium response, prominent suicidality, good social support, and the possibility of good treatment compliance. Maintenance antipsychotic treatment may be considered when there are comorbid psychotic features or when the risk-benefit profile of traditional mood stabilizers is unacceptable to the patient and family, or when there is poor response to lithium or divalproex.
4. Apart from psychoeducation, which is the feasible minimum psychosocial intervention that should be recommended to patients with bipolar disorder in the Indian setting?
While we concur with the evidence that psychoeducation is the cornerstone of psychosocial management of BD due to its broad evidence base and low burden, the most feasible next evidence-based intervention in the Indian setting may be family-focused therapy. Given the central role of the family in the caregiving and decision-making process, brief family-focused interventions focusing on alleviating caregiver burden, mitigating expressed emotions, enhancing relationship functioning, and reducing perceived stigma can potentially improve support, medication adherence, and long-term illness outcomes.[125,126] Other evidence-based interventions, such as CBT and IPSRT, while offering additional benefits, are limited in feasibility due to resource constraints, including a lack of trained therapists.
5. What are the differences in the pharmacological management of hypomania in bipolar II disorder vis-à-vis mania in bipolar I disorder?
The treatment approaches to mania and hypomania, in BD-I and BD-II, respectively, vary in intensity and pharmacological requirements. Typically, BD-I mania requires prompt initiation of a combination of mood stabilizers, antipsychotics, and benzodiazepines. Frequently, patients may need admission due to acute excitement and the consequent risk of harm to themselves or others. Infrequently, they may even require ECT for acute symptom control based on symptom severity and need for rapid response.
In contrast, BD-II hypomania is a diagnostic challenge, less disruptive and usually does not impair. Typically, patients continue to function without interruption (some may even be more productive during this period), do not experience psychotic symptoms, and there is no need for hospitalization. Pharmacological treatment is not always mandatory if symptoms are mild and transient. When treatment is indicated, usually, monotherapy with a mood stabilizer or atypical antipsychotic suffices; combination therapy is rarely needed. The focus in BD-II management is on long-term depressive prophylaxis, which is the primary source of morbidity. Whereas, in BD-I, controlling and preventing acute mania assumes greater significance.
6. Why should mood episodes in bipolar disorder be treated early and adequately?
Prompt and adequate treatment of mood episodes in BD is essential for good short-term and long-term illness control. Early treatment reduces the risk of chronicity, improves chances of restoring psychosocial functioning, and may help reduce family burden and stigma. Inadequate treatment increases the chances of residual symptoms, neurocognitive and functional deficits, suicidal behavior, and a more virulent illness course. Inadequate treatment may allow neurobiological changes to accumulate in the brain, increasing the chances of illness kindling and neurobiological sensitization.[277] In the long term, early and adequate treatment can help in better symptom control and functioning, reduce disability and burden, limit neuroprogression, and psychosocial consequences.
7. What should be the goals of maintenance treatment in bipolar disorder for the Indian setting?
The goals of maintenance treatment in any setting should not be limited to mere prophylaxis. While relapse prevention is a major goal, an equally important target is complete symptomatic and functional recovery. This is because residual symptoms in BD are common in the Indian setting[278] and are an important source of morbidity, disability, and burden; hence, their control is critical to the long-term management of BD.
In the Indian context, engaging families in the long-term management of BD is essential to ensure ongoing support, optimize medication adherence, and compliance with follow-up visits. Family and community expectations may drive illness outcomes through expressed emotions. Hence, engaging the patient and family in a discussion about their expectations regarding functioning and recovery is vital. The rehabilitation and recovery process should be tailored to meet these demands, with a focus on social role functioning and occupational reintegration. Thus, the maintenance treatment should strive for a composite goal of relapse prevention, symptomatic and functional recovery, tailored to the patient and families’ needs and expectations.
CONCLUSION
There is insufficient Indian data on several issues, leaving many questions unanswered. Even if empirical data are available to support management algorithms, rigid adherence may be impractical and inappropriate, given the wide variation in available resources, accessibility, and affordability of treatment options across settings. These guidelines intend to promote adherence to core management principles by all mental health professionals involved in treating patients with BD. They are neither intended to replace formal education and training in the field, nor should they be regarded as the definitive gold standard of treatment in BD. Importantly, these guidelines should not constrain psychiatrists from exercising independent clinical judgment, tailored to local contexts and patient needs.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
We thank Dr Samir Kumar Praharaj, Professor of Psychiatry, Kasturba Medical College, Manipal, and Dr Shahul Ameen, Consultant Psychiatrist, St Thomas Hospital, Chethipuzha for their careful reading of a previous version of this guideline and helpful suggestions for its improvement.
Funding Statement
Nil.
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