Nuances in the Management of Bipolar Disorder

Episodes of depression, mania/hypomania, and mixed episodes characterize bipolar disorder (BD). In general, BD is considered to be an episodic illness, and the primary aim of management is to achieve euthymia. Currently, many clinical practice guidelines are available for the management of BD.[1–5] These guidelines recommend the use of pharmacotherapy, psychosocial interventions, somatic treatments (electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation, transcranial direct current stimulation), sleep-related interventions, sleep deprivation, light therapy, and lifestyle modifications to be used for the management of BD in different combinations as per the clinical presentation. These guidelines guide the management of various phases of illness, i.e., the acute phase and the maintenance phase.[1–5] The main aim of management in the acute phase is rapid control of symptoms and restoration of premorbid functioning. The main objective of the maintenance phase is to have no or minimum residual symptoms, prevent or delay the recurrence of episodes, and promote recovery. However, these guidelines generally do not provide much guidance about managing BD by considering the course of illness and other factors, which can also influence the selection of medications, especially for the maintenance treatment of BD. Due to this, clinicians often focus on managing the acute phase of illness, and the usual tendency is to start treatment by considering the most recent episode. Once the patient improves, the general tendency is to continue the same treatment. This approach often destabilizes the illness and can be detrimental in the long run. An approach that takes into account the current presentation and the longitudinal history usually helps decide about long-term management in a more informed way. This editorial focuses on some of these issues. CAN WE IDENTIFY BIPOLAR DEPRESSION FROM THE FIRST EPISODE OF THE ILLNESS? A patient with BD can present for the first time with a depressive episode or a manic/hypomanic/mixed episode. One of the most significant clinical challenges is to distinguish between unipolar depression and BD since the first episode of depression. Many studies have evaluated clinical characteristics that can distinguish bipolar depression from unipolar depression [Table 1].[6–9] Some of these features focus on the long-term course, and others focus on the symptoms during the acute phase. A study that included data from 386 patients with BD-I, 158 patients with BD-II, and 688 patients with major depressive disorder (MDD) initially evaluated 34 clinical features to be associated with BD or MDD. Later, these features were assessed in another sample involving 1000 patients with BD-I and 1000 MDD patients. The seven clinical features that were significantly associated with BD-I, when compared to MDD, were delusions, psychomotor retardation, a higher number of mixed symptoms, incapacitation, a higher number of episodes, a shorter duration of episodes, and a history of experiencing a high after treatment of depression. In the receiver operator curve analysis, these seven features could distinguish unipolar depression from BD-I, with the area under the curve being 0.83. The clinical features that distinguished BD-II and MDD were a higher number of mixed symptoms and experiencing a high after treatment with antidepressants.[10] A systematic review specifically evaluated the features associated with BD and MDD in the pediatric age group and suggested that compared to MDD, bipolar depression in the pediatric age group more often manifests with higher severity of depression, irritability, aggressive behaviors, hopelessness, suicidality, history of hospitalization, interpersonal difficulties, atypical features, comorbidity (conduct disorder, oppositional defiant disorder, attention deficit hyperkinetic disorder, anxiety disorder and substance use), family history of mood disorder, conduct disorder, and disability.[11] Considering these features right from the first episode can help in preventing misdiagnosing BD as unipolar depression. This can also help in deciding about the use of antidepressants, and discussing these issues openly with the patients can help in making an informed treatment decision.Table 1: Features that guide the first episode of depression being unipolar or bipolar depression[ 6–9 ]CLINICAL CHARACTERISTICS TO BE CONSIDERED WHILE CONSIDERING PHARMACOTHERAPIES Many of the clinical characteristics have been shown to influence the selection of particular psychopharmacological agent(s), and these can also have diagnostic implications. Hence, considering all these factors can help in better-informed decision-making [Table 2]. Properly understanding these variables can also help in the prognostication of treatment response and psychoeducation of patients and family members about the outcome.Table 2: Factors that can have diagnostic implications, selection of psychopharmacological agent(s), and psychosocial interventionsAge of onset Some data suggest that age of onset influences the treatment response. It is, in general, indicated that early onset (<18/21 years) is associated with poor response to treatment. Late-onset BD is understood as the age of onset after 50 years. There is some data also to suggest that early onset BD is more often associated with substance use disorders, psychiatric comorbidities, rapid cycling, mixed episodes, family history of BD, and higher levels of comorbidity with conduct disorders, alcohol abuse, drug addiction, suicidal attempts, and poor response to treatment. Further, it is suggested that early-onset BD is often associated with poor functional outcomes.[12–14] A study that compared patients with early onset BD (<18 years) and those with age of onset after 40 years reported that early onset BD is associated with significantly more number of episodes per year; is more often associated with irritability, motor activity-energy, sexual interest, depressed mood, delusions, and thought disorders, psychotic symptoms; more often have mixed episodes, have more manic episodes in the lifetime (inconsistent) and respond poorly to lithium (inconsistent).[15] Accordingly, it can be said that early-onset BD, in general, has a more severe course of illness and possibly responds poorly to lithium. Hence, this fact needs to be kept in mind while selecting a mood stabilizer for a patient with BD. In contrast, the late-onset BD (age of onset >50 years) is often associated with organicity.[16] Hence, such patients should be more thoroughly evaluated for organic factors by a detailed review of ongoing medications, substance use (type, frequency, and recent change in pattern of use), nutritional factors, and possible infective causes (for example, HIV). A detailed physical examination, review of cognitive function, and carrying out appropriate investigations based on the associated clinical features is also of paramount importance.[16] Patients with organicity may benefit from addressing the underlying cause rather than considering the use of mood stabilizers.[16] The polarity of the first episode in the lifetime Based on the first episode in the lifetime, BD is categorized as Depression-Mania-Interepisodic period (DMI pattern) and Mania-Depression-Interepisodic period (MDI). An important implication of understanding this in BD is that there is some data to suggest that patients with MDI illness pattern respond better to lithium when compared to those with DMI pattern.[13,17] The number of previous episodes A review of history for the total number of lifetime episodes may be critical because there is evidence to suggest that having more than ten episodes in the lifetime before lithium treatment may be associated with poor response to lithium.[17] On the other hand, it is recommended that valproate might be a better choice in patients with many previous affective episodes/hospitalizations, those with comorbid substance use disorders, and mixed episodes.[12] The course of illness It is essential to review a patient’s history for the types of episodes in the lifetime while considering various pharmacological agents. It is essential to understand that besides currently accepted nosological division into BD-I and BD-II, authors have described other subtypes too. These subtypes are based on predominant polarity, seasonality of episodes, rapid cycling, psychotic/non-psychotic episodes, and recurrent mania course. The subtyping also includes a description of BD-0 to BD-VI, depending on the presence or absence of a family history of BD, temperament, antidepressant-induced switch, the impact of substance abuse, mixed features, subsyndromal features, and age of onset.[18] It is well-known that some of these features influence the treatment response and selection of pharmacological agents.[1–4] In terms of response to lithium, in general, it is suggested that both the subtypes (BD-I and BD-II) respond well to lithium.[17] It is always necessary to understand the seasonality of the episodes because patients with seasonal affective disorder may benefit from light therapy.[1–3,5] Rapid cycling is understood as the presence of four or more episodes in a given year. Rapid cycling is more often associated with early age of onset, longer illness duration, BD-II, a higher number of lifetime episodes, poor response to treatment, presence of hypothyroidism, higher number of suicide attempts, atypical depressive symptoms, more often use of antidepressants, and comorbid substance use disorders.[19] In terms of treatment response, a systematic review of studies concluded that aripiprazole, olanzapine, and valproate are useful for the management of acute manic or mixed episodes, quetiapine is useful in acute depressive episodes, and aripiprazole and lamotrigine are useful in relapse prevention for patients with rapid cycling course.[20] Further, there is some evidence to suggest that there is no significant difference between lithium and valproate in terms of the rate of relapse into any mood episode and the time to relapse, and a combination of mood stabilizers is better than the use of single mood stabilizers.[21,22] It is also suggested that lamotrigine outperforms placebo in the prevention of recurrences of rapid-cycling patients, especially those with BD-II.[23] The concept of predominant polarity has recently received significant attention. It is defined using two definitions, i.e., Barcelona proposal and Harvard Index. According to the Barcelona proposal, a patient is considered to have a particular predominant polarity (i.e., depressive or manic) based on more than two-thirds of the episodes of a specific polarity.[24] In contrast, the Harvard index uses a more than 50% cutoff to consider a particular predominant polarity.[25] It is suggested that patients with predominant depression have a history of more suicide attempts, comorbid personality disorder, and BD-II.[26,27] On the other hand, patients with predominant hypomanic/manic polarity have comorbid substance use, psychotic symptoms, and BD-I.[25,26] Recently, some of the authors have tried to characterize the relative potency of various pharmacological agents for the prevention of depression and mania.[28] It is suggested that agents such as lamotrigine and lurasidone predominantly have antidepressant action in terms of prevention of future episodes.[28,29] In contrast, drugs such as aripiprazole, risperidone, and paliperidone have more antimanic effects for the maintenance treatment.[28] Accordingly, having an understanding of the predominant polarity can influence the selection of pharmacological agents. A significant proportion of patients with BD run a recurrent mania or unipolar mania course. Different studies have used different definitions to characterize recurrent or unipolar mania, and its prevalence is affected by the definition used.[30] A recent study from India that used multiple definitions for unipolar or recurrent mania estimated it to range from 5.4% to 20.3%.[31] An understanding of unipolar mania can again influence the selection of agents with more antimanic effects in terms of prevention of future episodes. There is some evidence to suggest that patients with unipolar mania respond poorly to lithium, whereas valproate is equally effective in patients with unipolar mania and classical BD-I.[30] Duration of illness, duration of episodes, and gap between the episodes Evaluation of the course of illness should also consider the duration of illness, the duration of each episode, the duration of the inter-episodic period, and the gap between the episodes. Understanding these variables can influence the decision to advocate for or against long-term maintenance treatment. In this context, some authors have described the concept of the affective morbidity index that considers the number of episodes, duration of episodes, and severity of episodes.[31] Many patients with BD maintain well for long periods without medications. A proper understanding of this can help determine the need for prophylaxis and the duration of treatment. While evaluating the inter-episodic period, it is important to review the history for residual symptoms versus side effects (for example, sleep disturbances, anxiety, etc.) and the impact of euthymia and treatment on comorbidity, functionality, disability, and cognitive functioning. PHYSICAL AND PSYCHIATRIC COMORBIDITY Comorbidity in BD is considered a rule rather than an exception. BD is characterized by high comorbidity, both psychiatric and physical. The commonly reported psychiatric comorbidities include anxiety disorders, substance use disorders, and personality disorders.[32] In terms of physical comorbidity, data suggest that compared to the general population, the prevalence of various physical diseases is higher among BD patients, and some of the studies indicate that about 90% of BD patients have at least one physical comorbidity and the mean number of medical diseases for a BD patient is reported to be 2.69.[33–36] It is further suggested that a high burden of general medical comorbidities (defined as Cumulative Illness Rating Scale total score ≥4) is related to increasing age, body mass index, and longer duration of illness after controlling for confounding factors.[37] In terms of specific physical comorbidities, according to one estimate, compared to the general population, patients with BD have been reported to have a higher prevalence of asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, hypothyroidism, hyperthyroidism, diabetes mellitus, hepatitis-C, human immunodeficiency virus infection, migraine, multiple sclerosis, epilepsy, hypertension, and coronary artery disease.[34] The prevalence of metabolic syndrome is estimated to range from 16.7% to 67%.[38] Physical comorbidity has also been shown to be associated with decreased life expectancy, increased mortality, increased mortality due to suicide, and increased mortality due to physical diseases.[39] In terms of the impact of physical diseases on BD, the presence of thyroid diseases, especially hypothyroidism, is associated with an increased risk of manic relapse in BD-I and rapid cycling course.[40] Similarly, metabolic risk factors have been reported to potentially alter the course of BD, with worse global functioning, poorer treatment response, chronic course of illness, and enhanced rapid cycling.[41] Severe premenstrual symptoms and premenstrual dysphoric disorder have been linked to a higher number of episodes, a higher number of depressive episodes, a shorter time to relapse to a sub-syndromal or syndromal episode of BD, earlier age of onset, a higher risk of rapid cycling, presence of a higher number of comorbidities (anxiety disorders, lifetime history of substance/alcohol abuse or dependence, lifetime history of bulimia nervosa, and adult attention deficit and hyperactivity disorder), cyclothymia and BD-II.[42] The comorbidity profile also influences the selection of treatment. For example, it is well known that valproate is the preferred mood stabilizer in patients with comorbid substance use disorders.[12] Similarly, in patients with comorbid migraine and epilepsy, antiepileptic mood stabilizers are considered to be the preferred agents.[43] PERSONAL CHARACTERISTICS It is also important to remember that valproate is to be avoided in young women due to the risk of the development of polycystic ovarian disease.[44] Valproate and carbamazepine use are also contraindicated during pregnancy.[44] It is suggested to avoid lithium during the first trimester of pregnancy. However, it can be used safely during the second and third trimester of pregnancy. Similarly, lithium should be used with caution during lactation. Valproate and lamotrigine are considered to be relatively safe during lactation.[45] Besides gender, other personal factors such as reaction to stress, coping, perceived stigma, attitude towards psychotropics, personality traits, and temperament can influence the outcome. Although these factors do not have a direct impact on the selection of psychotropics, they can influence relapse, medication-induced switches, and medication adherence. Symptoms during the current episodes Besides the type of episode (depression, mania, hypomania, and mixed features), many other clinical features during the current episode often play an essential role in decision-making for pharmacotherapy. Some of the crucial issues include the severity of the current episode, mixed episodes/mixed features, atypical depressive features, psychotic symptoms, suicidality, and catatonia. In this context, it is essential to understand that lithium has been shown to have an anti-suicidal effect.[1] The role of ECT in the management of acutely suicidal patients with depression is also well established.[1] The Diagnostic and Statistical Manual, fifth edition (DSM-5), has done away with the mixed episodes and defined the presence of mixed features as a specifier for BD, which can be present in both manic and depressive episodes.[46] This provides an opportunity to look for mixed features in all the episodes of BD, and antidepressants should be avoided in patients experiencing bipolar depression with mixed features.[2] Management of catatonia involves the use of lorazepam and ECT along with other phase-specific treatments.[1,2] The presence of atypical symptoms during the depressive episodes is considered to be an indicator of BD, in contrast to unipolar depression.[6–9] Data from the unipolar depression studies suggest that monoamine oxidase inhibitors may be more useful in the management of depression with atypical features. Hence, these can be considered, especially while dealing with resistant bipolar depression.[47] The presence of psychotic symptoms during the episodes necessitates the use of antipsychotics. However, it is important to remember that the presence of psychotic symptoms during the depressive episode is more often associated with antidepressant-induced switch.[48] TREATMENT HISTORY A review of treatment history is one of the most critical aspects of managing BD. This should focus on the type of response to and side effects of medications. 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