Participants of expert group on CPG for Bipolar Affective Disorder
Vidhyadhar Watve, Mrugesh Vaishnav, Vivek Kirpekar, D.K. Sharma, Mahendra Jain, Asim
Kumar Mallick, C.L. Narayan, Anup Bharti, Madhu Nijhawan.
INTRODUCTION
Bipolar disorder (BPAD) is a serious mental disorder characterized by episodes of
depression, hypomania/mania and mixed episodes, with interepisodic recovery. However,
many patients with BPAD continue to exhibit residual symptoms in the interepisodic
period. The illness usually starts in adolescence or early adulthood and has significant
negative impact on the life of the sufferer and their caregivers. Patients with BPAD
encounter educational difficulties, job related problems, interpersonal difficulties,
psychosocial dysfunction, disability, marital problems, multiple suicidal attempts,
completed suicide and medication side effects. Additionally patients with BPAD have
high rates of physical and psychiatric comorbidity. The prevalence rates of BPAD vary
from country to country. A large multinational study suggests that lifetime prevalence
of BPAD-I ranges from 0-1% with a mean of 0.6 (SD-0.4). The prevalence rate of BPAD-II
ranges from 0 to 1.1% with a mean of 0.4 (SD-0.3). Additionally a significant proportion
of patients have been shown to have subthreshold BPAD with a range of 0.1 to 2.4%
with a mean of 1.4 (SD-0.8). There is no nationwide study to evaluate the prevalence
rates of BPAD in India. In a country like India, patients have limited resources,
poor knowledge about the disorder and treatment; have inadequate access to the health
care facilities, which makes treatment of BPAD a challenge. Indian Psychiatric Society
(IPS) made first attempt to formulate Clinical Practice Guidelines (CPGs) for management
of BPAD in 2005. Since then, over the last one decade there have been several developments,
especially in the form of emergence of new evidence for some of the pharmacological
agents. Accordingly, these new guidelines attempt to update the previous guidelines
published by IPS. These guidelines should be read along with the earlier version of
the CPGs, published by IPS in 2005.
ASSESSMENT AND EVALUATION [TABLE-1]
Table 1
Components of assessment and evaluation
Assessment of patients is an ongoing process and comprehensive assessment of a patient
involves the assessment of patients themselves and their caregivers. The role of taking
a proper history from the patient and all the available resources cannot be over-emphasized.
In addition to the history taking, proper attention must be paid to the mental status
examination. Diagnosis of BPAD is to be made on the basis of current diagnostic criteria,
because a diagnosis based on diagnostic criteria can be considered more reliable,
facilitates communication among various clinicians and paves the way for management
on the basis of evidence based recommendations. It is important to remember that especially
during the initial part of the illness, the symptoms may be confusing and at times
it may be difficult to distinguish symptoms of mania from other psychiatric syndromes
like schizophrenia, acute and transient psychosis and other psychiatric disorders.
A possibility of substance induced disorder or disorder secondary to organic causes
is to be considered, when the symptoms are atypical or there is evidence of the use
of substance or underlying organic causes. Occasionally establishing the definite
diagnosis of BPAD may require time.
The assessment may cover history of number of previous episodes, type of first episode
in lifetime, predominant polarity of illness, duration and severity of episodes, inter-episodic
recovery, presence or absence of suicidal behaviour, violence and agitation, seasonal
variation in onset of symptoms, presence of rapid cycling and features of ultra-rapid
cycling. Assessment of current episode may also focus on the issues of severity of
symptoms, suicidality and agitation. Understanding the role of various psychosocial
stressors and biological rhythms in onset of illness, precipitation of relapse and
continuation of symptoms need to be understood thoroughly.
A thorough assessment includes assessment of comorbid psychiatric and medical conditions.
It is important to remember that many a times; comorbidity is not very evident during
the acute episode of illness. The comorbid conditions become more evident when the
patient has come out of the acute episode of the illness. Evaluation of comorbid substance
abuse needs to consider the type and frequency of substance abuse. If the patient
does not provide adequate information about the substance use pattern, but there is
high index of suspicion, urine or blood screens (with prior consent) can be used to
confirm the existence of comorbid substance use/dependence, wherever such facilities
are available. Functional impairment in various domains of life including impact of
the illness on the family functioning and psychosocial impact of the illness on the
caregivers is not to be neglected. A thorough physical examination need to be done
to rule out presence of any physical illness and also to rule out episodes secondary
to physical illnesses. This may be supplemented by the judicious use of investigations.
Depending on the feasibility, unstructured clinical assessments need to be supplemented
by documentation of severity and extent of symptoms on appropriate standardized rating
scales. Patients with bipolar disorders also have cognitive deficits. Accordingly,
depending on the need, detailed cognitive testing may be undertaken. The use of neuroimaging
may be indicated in those with atypical features, neurological signs, non-response
to treatment and having first episode of illness at a later age and elderly. Caregiver's
assessment may involve evaluation of their knowledge about illness, knowledge about
treatment, their attitudes and beliefs regarding treatment, the impact of the illness
on them and their personal and social resources in the form of burden, distress, stigma,
personal and marital life etc.
In case patient has received treatment in the past, then it is important to record
the type of medications used, response to treatment, duration of use of treatment,
side effects experienced and reasons for discontinuation.
Importance of ongoing assessment cannot be underestimated. With progress in treatment,
new issues like response to treatment, side effects, treatment adherence, marriage,
pregnancy, disability, other health-care needs, ease of access to treatment team and
therapeutic alliance may need to be assessed from time to time.
FORMULATING A TREATMENT PLAN [FIGURE 1]
Figure 1
Initial evaluation and management plan for schizophrenia
Figure 2
Management of Hypomania/ Mania/Mixed Episode
Figure 3
Management of Bipolar Depression
Formulation of treatment plan will involve decision making about the treatment setting,
treatments to be used and areas to be addressed. Treatment plan need to be formulated
in consultation with patients, caregivers and other members involved in the treatment
team. Treatment plans may be guided by the needs and be practical, feasible and flexible.
Further, the treatment plan is be re-evaluated from time to time and be modified as
per the needs.
CHOICE OF TREATMENT SETTINGS
In general, most of the patients with BPAD are managed on the outpatient setting.
However, some patients may require inpatient care. Whenever possible patient admitted
to the inpatient setting should have accompanying family caregivers. In case inpatient
care is required and such facilities are not available, than the patient and/or family
need to be informed about the need for inpatient care and patient may be referred
to the nearest available inpatient facility and admission may be facilitated.
OPTIONS FOR MANAGEMENT OF BIPOLAR DISORDER
Treatment options for management of BPAD can be broadly classified as mood stabilizers,
antidepressants, antipsychotic medications, electroconvulsive therapy (ECT), adjunctive
medications and psychosocial interventions [Table-2]. Use of various treatment options
is guided by the phase of illness (mania/hypomania/depression/mixed) in which patient
presents to the clinician and past treatment history.
Table 2
Options for management for Bipolar disorder
PHARMACOLOGICAL MANAGEMENT OF BIPOLAR DISORDER
The mainstay of management of BPAD is mood stabilizers. The available mood stabilizers
include lithium, valproate, lamotrigine, carbamazepine/oxcarbazepine and topiramate.
Lithium
Lithium is the oldest mood stabilizer used in the management of BPAD. It has been
found to be efficacious in management of acute episode of either polarity and has
been found to be efficacious in prevention or relapse of episodes of either polarity.
Additionally, it has been shown to have a role in prevention of suicide in patients
with BPAD.
Prior to starting lithium, history need to be reviewed for the presence of physical
illnesses like renal dysfunction, thyroid dysfunction and cardiac conduction abnormalities.
Additionally information needs to be reviewed for presence of dermatological diseases.
In case of women, last menstrual period is to be ascertained and if required urine
pregnancy test need to be done. Further, prior to starting lithium, patients need
to be educated about the various side effects of lithium, use of salt-restricted diet
and avoidance of medications (diuretics, angiotensin-converting enzyme inhibitors,
non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, etc.) which can
increase serum lithium levels. Patients also need to be informed to avoid dehydration.
Whenever lithium is started, it need to be started in low doses, preferably in divided
doses and the dose need to be titrated upwards with monitoring of serum lithium levels.
As steady state levels of lithium are achieved after about 5 days of starting lithium
or dose increment, the levels are be done after 5 days of start of treatment or change
in the dose. However, the levels may be checked earlier if patient manifests features
of toxicity. The serum levels of lithium, which are usually required for management
of acute episode, are in the range of 0.6 to 1.0 meq/litre and for prophylaxis range
from 0.6 to 0.8 meq/litre; however, few studies suggest that serum levels as low as
0.4 to 0.8 meq/litre may be sufficient for prophylaxis, albeit are associated with
higher risk of relapse. Once the dose is stabilized, patient may be shifted to once
a day dose to reduce the side effects and improve the medication compliance. Serum
lithium levels may be monitored every 3-4 months. Renal function tests need to be
monitored once in every 2-3 months during the initial 6 months of therapy and thyroid
function tests need to be monitored once or twice during the first 6 months of treatment.
Later, renal and thyroid function tests may be monitored once in 6 months to 1 year
in clinically stable patients and more frequently if so indicated (see table-3). Lithium
is usually preferred in patients who have classical mania, bipolar depression, predominant
polarity of illness is that of depression, episodic course of illness, manic-depressive-euthymic
course, non-rapid cycling course of illness, lack of mixed episode, older age of onset
for BPAD, presence of family history of BPAD and presence of family history of lithium
response.
Table 3
Investigations prior to starting of lithium and while monitoring lithium therapy
Divalproex/valproate
Divalproex and its formulations (sodium valproate and valproic acid) have been found
to be useful in the management of BPAD. It has been found to be efficacious in management
of acute mania and mixed episodes. The evidence for its efficacy in acute depression
is not as robust as that for lithium. It is also efficacious in prevention of mania
and depression, when used during the maintenance phase. As with lithium, prior to
starting valproate, clinicians need to review the medical history for presence of
any hepatic, haematological and bleeding problems. Prior to starting of valproate,
patient is to be educated about the side effects, especially about signs and symptoms
of hepatic and haematological dysfunction. They need to be instructed to report to
the clinicians at the earliest if these signs and symptoms emerge. Prior to starting
valproate, it is important to investigate the patient for liver function test and
haemogram. In young women, last menstrual periods need to be ascertained and if required
urine pregnancy test need to be done to rule out pregnancy. As valproate is associated
with weight gain and metabolic abnormalities, it may be a good practice to evaluate
the lipid profile, fasting blood glucose levels and anthropometry (Table-4).
Table 4
Investigations prior to starting of valproate and while monitoring valproate therapy
Usually valproate is started in low doses, i.e., 250 mg BD or 250 mg TID and titrated
upwards with monitoring of side effects and serum levels. However, some of the studies
have also evaluated rapid titration of valproate dose with initial dose of 20-30 mg/day
and have shown that it is well tolerated. Maximum daily dose which is recommended
is 60 mg/day but most patients do not require such high doses. The usual therapeutic
serum levels which are considered to be efficacious vary from 50 to 100µg/ml. Once
the dose of valproate is stabilized, the dosing schedule need to be changed to OD
or BD dosing to reduce the side effects and improve compliance. In case OD dosing
is given, extended release formulation may be used. However, it is important to remember
that the bioavailability of extended release formulations is about 15% less than the
immediate release preparations and the dose is to be increased accordingly. Serum
valproate levels are to be done after 5 days of starting or increase in the dose of
valproate. The sample need to be collected after 12 hours in case patient is receiving
immediate release formulation, however, if the patient is receiving extended release
formulation, the sample may be collected after 21 to 24 hours (table-5). There is
evidence to suggest that patients with BPAD-II, dysphoric or mixed mania, rapid cycling
affective disorder, stable episode frequency, later age of onset of illness, shorter
duration of illness, long and severe course of illness respond well to valproate.
Other indicators for good response to valproate include presence of comorbid alcohol
use disorder, mental retardation, anxiety and panic attacks, post-traumatic stress
disorders, marked sleep disturbances, explosive dyscontrol and aggression and comorbid
migraine.
Table 5
Investigations prior to starting of valproate and while monitoring valproate therapy
Lamotrigine
The role of lamotrigine in management of BPAD has been well studied now and it has
been shown to be efficacious in management of bipolar depression and prevention of
relapse of depression. However, the most dreaded side effect of lamotrigine includes
skin rash, including Stevens - Johnson syndrome and toxic epidermal necrolysis. The
skin lesions can occur any time during the therapy, but are more often reported during
the initial phase of treatment and when used along with valproate. Evidence suggests
that the risk of skin rash can be reduced by slow upward titration of the dose. Accordingly,
while considering lamotrigine, patients need to be informed about the possibility
of rash and told to contact the treating psychiatrist in case rash is seen. When the
rash is more widespread, diffuse and associated with systemic symptoms like fever
or sore throat, lamotrigine may be stopped. When initiated, lamotrigine may be started
at the dose of 25 mg/day for initial 2 weeks, then it may be given at the dose of
50 mg/day during the 3rd and 4th week. After that 50 mg/day can be increased per week
depending on the therapeutic response.
Carbamazepine
Carbamazepine has been shown to be efficacious in the management of acute bipolar
mania and prevention of relapse. Prior to starting carbamazepine, clinician needs
to focus on the history of blood dyscrasias and hepatic dysfunction. When carbamazepine
is considered, patients need to be informed about the signs and symptoms of hepatic
dysfunction, haematological dysfunction and skin reactions and told to report to the
psychiatrist if these symptoms emerge. Baseline investigation prior to starting of
carbamazepine may include complete haemogram, liver function tests and renal function
test (Table-5). When used in elderly serum electrolytes may also be done, in view
of the risk of hyponatremia. Usual starting dose of carbamazepine is 200 mg/day given
in divided doses and titrated upward slowly. Once the dose of 800-1000 mg/day is reached
the increment of dose may be slower and the usual maintenance dose is about 1000 mg/day,
but it can vary from patient to patient and may be 200 to 1600 mg/day. The carbamazepine
therapeutic drug levels have not been established in patients with BPAD and the serum
levels of 4-12 µg/ml, which is recommended for seizure disorders is commonly used.
As with lithium and valproate the serum levels need to be done after 5 days of initiation
of treatment or increment of dose.
Other anticonvulsants
There is lack of data in the form of double blind randomized controlled trials for
Oxcarbazepine, but small open label studies suggests that it may be of some benefit
as monotherapy or add-on therapy in patients with refractory mania. The data from
open label studies suggest the usefulness of add-on therapy with topiramate in patients
with bipolar depression. Studies which have evaluated the role of gabapentin in management
of mania have yielded negative results.
Antipsychotics
Over the last decade or so, many large multicentric double blind placebo controlled
and active comparator randomised controlled studies have evaluated the role of various
atypical antipsychotics like olanzapine, quetiapine, aripiprazole, risperidone, paliperidone,
amisulpiride, asenapine, ziprasidone and haloperidol etc. in the management of bipolar
depression, bipolar mania and for maintenance phase treatment. Data from these studies
suggest that antipsychotics like olanzapine, quetiapine, aripiprazole, risperidone,
paliperidone and ziprasidone are effective in the management of acute mania. There
is evidence for use of quetiapine monotherapy, and olanzapine and fluoxetine combination
in the management of bipolar depression. There is evidence for lurasidone in the management
of acute episode of bipolar depression. Olanzapine and quetiapine monotherapy or as
adjunctive medications to lithium or valproate have been shown to be efficacious in
prevention of relapse of both depression and mania. Antipsychotics like long acting
risperidone, ziprasidone have been shown to be beneficial in prevention of mania as
monotherapy or as adjunctive medications to lithium or valproate.
Combination therapy
There is evidence to suggest that when lithium or valproate is combined with antipsychotics
in the management of acute mania, the efficacy is higher and the onset of action is
faster than that reported for single agent. Accordingly, depending on the severity
of mania, combinations may be used.
Electroconvulsive Therapy (ECT)
There is evidence for use of ECT in the management of acute mania, mixed episode and
bipolar depression. Indications for use of ECT are shown in Table-6.
Table 6
Possible indications of use of ECT in patients of schizophrenia
Benzodiazepines
Studies have evaluated the efficacy of adds-on benzodiazepines like clonazepam and
lorazepam to lithium and current level of evidence suggests that the antimanic properties
of these agents are difficult to distinguish from the sedative properties of these
agents. Accordingly, these agents are considered to be adjunctive agents, which may
be useful in management of acute episode. Further, there is evidence to suggest the
beneficial role of lorazepam in the management of agitation and catatonia.
Other agents
Many other medications like calcium channel blockers, zonisamide, levetiracetam, acamprosate,
omega-3 fatty acids, allopurinol etc, have been evaluated in small sample size trials
as monotherapy or add on agents. However, available the evidence is not sufficient
to recommend these medications as first line agents in management of bipolar mania
and depression.
Antidepressants
Conventionally antidepressants have been used in the management of bipolar depression.
However, over the last 2 decades or so, use of antidepressants in patients with bipolar
depression has emerged as a controversial topic in view of the risk of antidepressant-induced
manic/hypomanic switch. Evidence from metanalysis suggests that use of antidepressants
along with mood stabilizers is superior to use of combination of a mood stabilizer
and a placebo and is not associated with increased risk of manic switch. Most of the
studies which have not found adds-on antidepressants to be beneficial have involved
paroxetine, hence, if one want to avoid use of an antidepressant, paroxetine is to
be avoided. Among the various antidepressants, bupropion has been reported to be associated
with lowest risk of antidepressant induced switch. However, it is important to remember
that antidepressants should not be used as monotherapy, and in those with rapid cycling
affective disorder and mixed episodes.
Adequate trial
The minimum recommended duration of treatment to consider it to be an effective trial
for an acute manic episode is about 3-4 weeks. In case of bipolar depression, a 6
weeks trial is considered as an adequate trial.
NON-PHARMACOLOGICAL MANAGEMENT OF BIPOLAR DISORDER
Psychosocial management as an adjunct to pharmacotherapy has been shown to be of significant
benefit during the management of acute phase of bipolar depression and maintenance
phase of illness. Among the various psychosocial interventions, data supports the
use of psychoeducation (individual and group), interpersonal and social rhythm therapy
(IPSRT), cognitive behaviour therapy and family focused intervention. These psychosocial
interventions have been shown to be associated with reduced risk of relapses, better
functioning and better treatment adherence. The basic components of all these programs
involve informing the patients about their illness, identifying the early signs of
relapse, handling stress, maintaining social rhythms, addressing the interpersonal
issues and expressed emotions, problem solving and enhancing medication and treatment
adherence.
Psychoeducation for patients and or family (Table 7)
Table 7
Basic components of Psychoeducation
Psychoeducation may be considered both for the patient and family members (Table 7).
The aim is to be to educate the patient and family about the illness. They may be
provided simple explanations about the nature of the illness, treatment options, possible
side effects of medications and likely length of treatment etc. Caregivers may also
be provided with an opportunity to vent out their feelings and distress. Psychoeducation
may also address the important issue of treatment adherence and identifying early
signs of new episode. It is important to remember that psychoeducation is not a onetime
event and prior to every session, feedback of the previous sessions may be taken and
psychoeducation need to be tailored to the needs of the patient and the caregivers.
Interpersonal and social rhythm therapy (IPSRT)
This therapy is based on the theory that circadian rhythms in patients with BPAD are
vulnerable to external factors and any disruption of circadian rhythms can precipitate
an episode. Accordingly, it emphasizes on regularizing the social rhythms or routine
of the patient and improving the interpersonal relationships of the patients so that
they can derive more satisfaction in their social roles. The basic aim is to teach
the patient as to how they can prevent the development of a new episode (Table-8).
Patients are informed that new episodes can be precipitated by poor medication adherence,
stressful life events and disruption of social rhythms. Patients are provided with
skills as to how they can address interpersonal problems and issues in the social
roles. They are also advised to maintain a regular daily routine and pay attention
to the day to day stresses which can influence their daily routine and how they can
minimize the impact of these day to day stressors on their daily routine.
Table 8
Basic components of Interpersonal and social rhythm therapy (IPSRT)
Cognitive Behaviour therapy
Cognitive behaviour therapy (CBT) has been shown to be efficacious in the management
of bipolar depression and during the maintenance phase of treatment. The basic goals
of CBT is to educate the patient about the illness, teaching them cognitive behavioural
skills for coping with their illness and psychosocial stressors and problems arising
out of the same, enhance medication and treatment compliance, monitor the symptoms
to prevent relapse.
Family focused interventions
Family forms an integral part of treatment in Indian setting. They are involved in
treatment decision making, supervision of treatment and monitoring of treatment. However,
family members can also contribute to relapse due to constant criticism, poor supervision
or over-involvement. High expressed emotion leads to increased risk of relapse and
poor outcomes. Studies have shown that family focused interventions can reduce the
chances of relapse, improve medication adherence and reduce the frequency of depressive
episodes. Family focused interventions help the relatives and patients to integrate
the experiences associated with mood episodes, acknowledging the vulnerability of
having future episodes, accepting the need to continue with medications, educating
the family about the difference in patients personality and BPAD, recognising and
coping with stress and establishing a functional relationship (Table-9).
Table 9
Basic components of Family focused interventions
Advise for life style and dietary modifications
As it is well known that patients with BPAD are at increased risk for cardiovascular
mortality and develop metabolic side effects due to use of psychotropic medications,
all the patients need to be advised about life style and dietary measures to reduce
the risk of metabolic side effects and cardiovascular morbidity and mortality. These
include physical exercises, dietary modifications and abstinence from smoking, alcohol
and other substances etc.
Rehabilitation
Rehabilitation programmes may be culturally moulded and adapted to the needs of patients
and their families.
Treatment adherence
Mediation and treatment adherence is very important for management of patients with
BPAD. Available evidence suggests that 20-60% of the patients with BPAD become non-compliant
with medication and drop out of treatment. Hence, all efforts need to be made to enhance
the medication compliance and treatment adherence. Measures which can help in improving
the compliance are given in table-10.
Table 10
Measures which can improve medication compliance
MANAGEMENT OF DIFFERENT PHASES OF BIPOLAR DISORDER
Management of BPAD will depend on the phase of illness in which patient presents to
the clinician, i.e., bipolar depression, bipolar hypomania/mania, first episode hypomania/mania,
mixed episode or clinical remission. In addition to the phase of illness, factors
which may help in deciding about the pharmacological agent include past history (number
of episodes, type of episodes), comorbidity (comorbid psychiatric/physical disorders,
substance dependence disorder), past treatment history (response, side effects) and
clinical course (rapid cycling), associated symptoms (presence of psychotic symptoms)
etc. In general based on the level of evidence, various pharmacological treatments
are categorised as first line agents, second line agents and third line agents. Selection
of an agent on the basis of current polarity and past history can be of benefit, as
in most cases, same agent is continued in the maintenance phase.
The basic principles of management in the acute phase are shown in Table-11. Clinicians
may focus on carrying out a comprehensive assessment (psychiatric/medical/psychosocial),
decide about the treatment goals, ensure safety of the patient and others, decide
about the treatment setting, decide about the choice of medication in liaison with
the patient and the family by taking into account the clinical and treatment related
factors and institute psychosocial interventions at the earliest so as to provide
comprehensive management. If patient is using alcohol or other illicit substance,
all efforts are to be made to stop the same. Similarly, if a patient is on antidepressants
and presents with hypomanic/manic or mixed symptoms, these need to be stopped immediately.
Some of the indicators of inpatient care are shown in Table-12.
Table 11
Management in the acute phase
Table 12
Some indications for inpatient care during acute episodes
All treatment decisions need to be made in consultation with the patient and or family
members and need to be documented. Whenever mood stabilizers are used, the required
investigations need to be done prior to starting of mood stabilizers, patient's serum
levels of medications are to be monitored and other investigations need to be repeated
from time to time as indicated for various mood stabilizers.
The evidence for efficacy of various agents in management of different phases of illness
(mania, depression, maintenance phase) vary and it is important to be aware of the
same. Table-13, provides an update on the available level of evidence for different
phases of illness.
Table 13
Comparison of several monotherapy and combination Pharmacotherapies for bipolar disorders
MANAGEMENT OF HYPOMANIA/MANIA/MIXED EPISODE
The goal of management in mania/mixed episode is to control the aggression, agitation
and disruptiveness of patients at the earliest. Depending of the severity of symptoms,
inpatient care may be considered. If patient is on antidepressants then this is to
be stopped immediately.
In terms of pharmacological management, first line agent for management of mania may
involve use of lithium or valproate, olanzapine, haloperidol, quetiapine, aripiprazole,
risperidone, paliperidone or ziprasidone as monotherapy. Typical antipsychotics like
haloperidol, trifluoperazine and chlorpromazine have also been used in the Indian
scenario. These are very useful in the management of irritability, aggression, impulsivity
and psychotic features. However, these are associated with high incidence of extrapyramidal
reactions. However, there is some evidence to suggest that combining lithium or valproate
with an antipsychotic may be more effective than any of these agents when used alone.
Among these agents, lithium is thought to have slower onset of action. Accordingly,
it can be said that if the mania is less severe, monotherapy be considered. However,
if mania is severe and associated with significant disruption than combination therapy
need to be considered. Use of adjunctive benzodiazepines for short duration may be
required. Patients who refuse medications and are unmanageable may be given depot
antipsychotics like risperidone, paliperidone, olanzapine or a depot of typical antipsychotic
medication.
If a patient comes with a ‘breakthrough’ hypomanic/manic episode, then the first step
in the management involves optimization of the ongoing agent. The optimisation can
be done by monitoring the serum levels of agents like lithium and valproate. If required,
additional antipsychotics and benzodiazepines may be used, depending upon severity
of the episode.
If the first-line agent used in optimal dose fails (lack of significant clinical benefit
after 2 weeks of use), another first line agent need to be added to the ongoing treatment.
Alternative strategies may include changing lithium to valproate or vice versa, changing
to carbamazepine, adding antipsychotic medication if not used earlier, changing the
antipsychotic if used earlier. ECT may be considered if patient is very disruptive,
not responding to a trial of combination of medications, has history of good response
to ECT in the past, pregnancy and those experiencing mixed episode. Psychosocial interventions
like psychoeducation of patient and family and family focused intervention be started
at the earliest. Psychosocial interventions like CBT or IPSRT, focused specifically
on the patient, should be considered when patient is cooperative.
MANAGEMENT OF BIPOLAR DEPRESSION
The main goal of management is to achieve euthymia, normal level of functioning and
to avoid switching to hypomanic/manic episode. Among the various mood stabilizers,
there is ample evidence to suggest that lithium and lamotrigine may be used as the
first line medications in the management of bipolar depression.
If the patient presents with a breakthrough episode, the initial strategy is to check
the medication compliance and ensure adequate compliance. If compliance is not an
issue, initial strategy is to optimise the mood stabilizer which the patient is already
getting.
If the patient is not on any mood stabilizer, than lithium or lamotrigine may be considered.
Among the antipsychotics, data suggests that quetiapine monotherapy may also be beneficial.
There is evidence for use of olanzapine and fluoxetine combination too. If the patient
does not respond to monotherapy with mood stabiliser or antipsychotics, combination
of these agents with antidepressants may be considered. Use of antidepressants without
the use of concurrent mood stabilizer or an atypical antipsychotic is to be avoided.
Benzodiazepines may be used as per the need. Psychosocial intervention in the form
of CBT may also be considered when the depression is of mild to moderate severity.
ECT may be considered, if depression is severe, in presence of suicidality, risk of
harm to others, catatonic symptoms, psychotic symptoms, patient is pregnant, when
use of various psychotropics is limited due to concurrent medical illnesses. There
is preliminary evidence to suggest the beneficial effect of transcranial magnetic
stimulation and direct cranial stimulation.
RAPID CYCLING AFFECTIVE DISORDER
Rapid cycling affective disorder (RCAD) is characterised by having 4 or more episodes
(depression/mania/hypomania/mixed) in a single year. These episodes should be separated
from each other by partial or full remission for at least 2 months or a switch to
an episode of opposite polarity. Many risk factors (Table-14) have been identified
for development of RCAD. Accordingly, the first step in the management of RCAD is
to evaluate the patients for underlying medical conditions which may be contributing
to the RCAD. Among medications, use of antidepressants has been shown to increase
cycling.
Table 14
Risk factors for Rapid Cycling Affective Disorder
In terms of psychotropics, there is evidence to suggest that lithium or valproate
may be used as the first line agents. Other mood stabilizers which can be considered
include lamotrigine. If patient does not respond to monotherapy, then combination
of mood stabilizers or a combination of mood stabilizer and antipsychotic medication
may be considered.
MAINTENANCE TREATMENT FOR BIPOLAR DISORDER
The primary goal of maintenance treatment is to prevent the recurrence of episode
of either polarity, reduce/eliminate the residual symptoms and improve the overall
functioning of the patient. In terms of pharmaco-therapeutic agents, best evidence
for maintenance treatment is available for lithium and valproate. In recent years
evidence has also emerged for use of olanzapine and quetiapine in prevention of recurrence
of both depressive and manic episodes. However, these may be avoided because of associated
higher risk of metabolic side effects. Long acting risperidone has been shown to be
beneficial in prevention of recurrence. Lamotrigine has been shown to be efficacious
in prevention of depressive episodes, but not for prevention of manic episodes. Olanzapine,
aripiprazole, ziprasidone and asenapine has been shown to be of benefit in prevention
of recurrence of manic episodes, but not for depressive episodes. Carbamazepine has
also been shown to be effective in prevention of recurrence; however, it is less preferred
compared to lithium and valproate because of its side effect profile and drug interactions.
Studies have also evaluated the efficacy of lithium and valproate in combination with
various antipsychotics. Besides use of pharmacotherapy, there is evidence to suggest
the beneficial role of adjunctive psychosocial intervention in the management of BPAD.
Maintenance ECT may also be considered in patients who have responded to ECT during
their acute episodes.
The general principle of management during the maintenance phase of treatment is to
continue the medication started during the acute phase of illness. Accordingly, while
selecting the agent during the acute episode, clinicians may take into consideration
the patient's preference, clinical factors which may influence the long term outcome,
recurrence of episodes and side effects. If the patients have more manic episodes
then one may prefer lithium, valproate or carbamazepine while for more depressive
episodes one may consider Lithium, lamotrigine or quetiapine. In severe cases, combination
of lithium and valproate may be considered.
It is important to note that patients with mood disorders are more vulnerable to extrapyramidal
side effects like tardive dyskinesia with long term use of antipsychotics, especially
typical antipsychotics. Patients who have been treated with a combination of lithium
and antipsychotic or valproate and antipsychotic medication, the need for continued
use of antipsychotic need to be reassessed on the basis of longitudinal course. Similarly,
stoppage of antidepressants needs to be considered once bipolar depression remits.
Combination therapy during the maintenance phase is to be considered only for those
who have not responded to the optimal dose of monotherapy during the maintenance phase
of illness.
SPECIAL SITUATIONS
Clinicians often encounter certain clinical situations which either require special
attention or can influence treatment decisions. Management of these situations is
summarised in table-15.
Table 15
Issues related to special situations
SIDE EFFECTS AND THEIR MANAGEMENT
Various classes of psychotropic medications used for the management of BPAD are associated
with many side effects, which require intervention. The side effects associated with
antipsychotics are discussed in the clinical practice guidelines for schizophrenia.
The recommendations made for monitoring of metabolic side effects associated with
various atypical antipsychotics may also be followed in patients with BPAD, if long
term antipsychotic medications are considered.
Use of lithium is associated with multiple side effects. These side effects can be
classified on the basis of occurrence (i.e., those occurring during the early or late
phase of treatment) and frequency (Common, uncommon, rare and very rare) (Table-16).
Most of these side effects can be managed with reduction in dose of medication or
shifting to a sustained release preparation as the first line strategy.
Table 16
Side effects of lithium
The common management strategies for the side effects associated with lithium, valproate
and carbamazepine are shown in Table-17.
Table 17
Management of side effects of mood stabilizers
MANAGEMENT OF TOXICITY
Among the lithium, valproate and carbamazepine, valproate has a wide therapeutic window.
Lithium and carbamazepine toxicity may be fatal and are medical emergencies. The therapeutic
range for serum lithium levels varies from 0.4 to 1.2 meq/litre. Toxic effects of
lithium are usually seen when the serum levels of lithium rise above 1.5meq/litre.
When the levels exceed 2meq/litre, life threatening side effects may emerge. Various
signs and symptoms of toxicity with lithium, valproate and carbamazepine are shown
in Table-18. Management of lithium toxicity is an acute emergency and involves stoppage
of lithium, maintaining the airways, maintaining an intravenous line and use of haemodialysis
if serum lithium levels are more than 2.5 mEq/Litre. However, in patients with end
stage renal disease, haemodialysis may be considered in levels below 2.5mEq/litre
as well.
Table 18
Signs and symptoms of Toxicity of lithium, valproate and Carbamazepine
Management of valproate toxicity also involve use of haemodialysis. However, there
are no clear guidelines for the same. Management of carbamazepine intoxication involves
gastric lavage, hemoperfusion and use of supportive measures.
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Conflicts of interest
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