Bipolar%20disorder Treatment

• Goals in treating bipolar patient are based on patient’s current stage of illness:
  • Treatment during the acute phase is centered in managing the patient’s safety and presenting symptoms; hospitalization is usually advised until symptoms are less severe
  • Continuation phase preserves the remission of symptoms and restoration of function, which usually lasts for weeks to month
  • Treatment in the maintenance phase aims to prevent occurrence of new mood episode, which lasts for months to year after recovery from the mood episode

• Choice of initial treatment is based on past response to medication, comorbid medical illness, present medications, drug interactions, side effect profile, specific symptoms, cost and side effects of the drugs
• Discontinuation of acute treatment in mania
  • Should be planned in consideration to the need for long-term maintenance treatment
  • Once full remission of symptoms have been achieved, reducing dose and discontinuation by tapering over 4 weeks or more may be done

Acute Treatment

Manic or Mixed Episode

• Aripiprazole, Asenapine, Cariprazine, Lithium, Paliperidone ER, Quetiapine, Risperidone, and Valproic acid, have been proven effective as 1st line monotherapy agents for acute mania
  • Carbamazepine, Haloperidol, Olanzapine, and Ziprasidone are 2nd line treatment options due to their safety/tolerability risks
• Lithium/Valproic acid + any of the following: Aripiprazole, Asenapine, Quetiapine, and Risperidone are effective 1st line combination agents for acute mania that show greater effectivity than monotherapy with Lithium or Valproic acid alone

• When adequate serum level is reached, drugs for the treatment of mania provide appreciable effects by day 10-14
  • If patient does not respond within 2 weeks, physicians can discontinue or change the drug, or add another drug

• Benzodiazepines combined with antimanic agents were recommended in managing behavioral disturbances during acute mania
• Carbamazepine, Haloperidol, Olanzapine, and Ziprasidone and are 2nd line monotherapy treatment options for acute mania while Olanzapine with Lithium or Valproic acid are the combination therapy treatment options for patients who are inadequately treated or unresponsive to 1st line agents
• Chlorpromazine, Clonazepam and Tamoxifen are 3rd line monotherapy treatment options for acute mania while Clozapine is used as monotherapy or adjunctive therapy

Depressive Episode

• Lamotrigine, Lithium, Lurasidone, and Quetiapine are considered 1st-line monotherapy treatments
  • While 1st-line combination treatments are: Lithium/Valproic acid +Lurasidone

• Adjunct SSRIs/Bupropion, Cariprazine, and Valproic acid are 2nd line monotherapy treatments
• Antidepressant monotherapy is not recommended as this may precipitate switch to mania
  • Antidepressant therapy may be gradually discontinued over several weeks while maintaining a mood stabilizer to prevent risk of manic switching and/or rapid cycling in patients who have remitted for at least 8 weeks from an acute depressive episode

• For severely ill patients, Lithium plus antipsychotic may be given

Maintenance Treatment

• Usually consists of the same regimen that was used in the acute mood episode
  • Empirical evidence proves the effectivity of Lithium and Valproate in maintenance therapy
  • Lamotrigine may also be used

• Generally recommended after a single manic episode
• In patients who were given antipsychotics during the acute episode, reassess the need for maintenance
  • Slowly taper and discontinue unless control of psychosis is required

• Simplify medication regimen
• Goal is to maintain patient with one mood stabilizer at the lowest possible dose
  • Taper and discontinue other medications
• In acute bipolar depressive episode, tapering of medications depends on the frequency of relapse, remission of condition, presence of psychosocial stressors, any comorbidity or personality disorders

Lithium

• Mood stabilizer with a long history of effectiveness in the treatment of bipolar disorder
  • Effective in treating mania, mixed state and moderate-severe hypomania
  • May be used to treat depressive episodes; may take longer (6-8 weeks) to see effects compared to its anti-manic effect
  • Considered 1st-line maintenance drug for preventing recurrence of bipolar mood episodes
  • Long-term treatment reduces the risk of suicide attempts and suicide deaths
  • Provides longer time to recurrence of mania or depression

• If discontinued within 2 weeks interval, may cause manic relapse
  • Gradual withdrawal from the therapy is suggested

Anticonvulsants

• Effective in treating elevated mood syndromes, either as monotherapy or in combination with antipsychotics
• Associated with risk of suicidal thoughts and behavior

Carbamazepine

• Typically considered as an alternative mood stabilizer to Lithium and Valproate
• Shown to be similar with Lithium and Chlorpromazine in comparison trials for treatment of acute mania
  • Small study shows that it may be less effective than Valproate
  • Studies showed similar efficacy with Lithium in preventing recurrence or hospitalization

Lamotrigine

• Effective in the treatment of bipolar depression
  • Limited efficacy in manic episodes

• One of the 1st-line drugs used in maintenance therapy
• Used for patients who remain at risk of relapse after treatment of an acute episode
  • Has been proven to increase the time to next depressive episode when given as maintenance therapy
  • May increase time to when additional pharmacotherapy is needed for breakthrough episode when given as monotherapy or combination

Oxcarbazepine

• An alternative to Carbamazepine due to their structural similarity
• Limited evidence showing efficacy to treat acute mood episodes
  • Better tolerated than Carbamazepine, fewer drug interactions and does not induce its own metabolism

Valproic Acid (Divalproex, Valproate)

• Mood stabilizer which has shown benefit in treating acute manic, mixed states or moderate-severe hypomanic episodes
• Divalproex may be preferred over Valproic acid because of better tolerability (causes lower gastrointestinal distress)
• Studies have shown Valproate to be more effective than Lithium for treating patients with mixed states or greater number of mood episodes and patients with rapid cycling
  • Inferior to Lithium when used as maintenance therapy

• Studies have shown efficacy in treating bipolar depression
• May be effective in decreasing dropout due to recurrence when used for maintenance treatment
• Avoid use in young girls and female of childbearing age group

Atypical Antipsychotics

• Shown to have some efficacy in the treatment of bipolar depression, in addition to their effects in mania
• Atypical antipsychotics tend to cause less side effects than conventional antipsychotics and are therefore preferred
  • Conventional antipsychotics are associated with extrapyramidal symptoms, akathisia and tardive dyskinesia

Aripiprazole

• Short-term trials have shown Aripiprazole to be superior to placebo in the treatment of bipolar mania and mixed episode associated with bipolar disorder
• May be useful in poorly compliant bipolar patients at high risk for relapse
• Considered as one of 1st-line maintenance therapies

Asenapine

• Two 3-week, double-blind clinical trials have shown the effectiveness of Asenapine as monotherapy for acute mania
  • New evidences shown that monotherapy and adjunctive therapy of Asenapine may be a 3rd line option for maintenance therapy

• Considered as 1st-line monotherapy treatment in acute mania

Clozapine

• Considered in patients unresponsive to 2nd-line treatments of acute mania or mixed states

Lurasidone

• Studies have shown that Lurasidone use as monotherapy or adjunct significantly reduce depressive symptoms in patients with bipolar I

Olanzapine

• Shown to be effective as monotherapy in treating acute manic episodes
  • It is effective when used in combination (ie with Fluoxetine) for acute depressive episodes with psychotic features and in patients with mixed, rapid cycling or euphoric acute mania
  • Study has shown benefit in combination with Lithium or Valproate
  • Has been shown to be an effective prophylactic agent, preventing both manic and depressive relapses

Paliperidone

• Studies have shown to be effective in patients with manic or mixed episodes, preventing relapses of any mood episodes and recurrence of mania
• Paliperidone >6 mg is recommended as one of the 1st line treatment in mania

Quetiapine

• 12-week trials have shown Quetiapine to be effective in the treatment of bipolar mania when used as monotherapy or when used as an adjunct to Lithium or Valproate
  • Combination therapy with Lithium or Valproate may be used for maintenance therapy in bipolar I disorder

• Used in patients not on long-term therapy, where an early treatment effect is needed
• Has been shown to be effective as single therapy
• Studies have shown Quetiapine to be effective in preventing manic, depressive, or mixed episodes

Risperidone

• Short-term trials have shown Risperidone to be effective in the treatment of acute bipolar mania or mixed episodes when used as monotherapy or when used as an adjunct to Lithium or Valproate
• May be useful in poorly compliant bipolar patients at high risk of manic relapse

Ziprasidone

• Short-term trials have shown effectiveness for acute manic or mixed episodes associated with bipolar disorder with or without psychotic features

Combination

• Lithium or Valproate combined with antipsychotic may be more effective and have a more rapid onset of action than with any of these agents alone in patients experiencing breakthrough symptoms
  • Aripiprazole combined with Lithium or Valproate delays any relapse in any mood and reduces manic relapse
  • Quetiapine combined with Lithium or Valproate causes delay in recurrence of any mood episode

Antidepressants

• Some evidence showed reserved efficacy in bipolar disorder
• Reduces the risk of recurrence of depressive mood but have a higher risk for inducing mania
• There is a risk of rapid switch to mania or inducing rapid cycling during treatment with antidepressant
  • Should only be given in combination with a mood stabilizer

Bupropion

• Shown to be effective in treating bipolar depression
  • Lowest risk to trigger manic episode

Citalopram

• Shown to be effective in treating bipolar depression when combined with Lithium, Valproate or Carbamazepine

Fluoxetine

• When given in combination with Lithium, it is shown to be more effective and better tolerated than Imipramine and placebo in the treatment of bipolar depression
• Studies have shown comparable results when used in combination with Olanzapine
  • Improved treatment-regimen  mania and functioning, less depressive symptoms and suicidal behavior

Venlafaxine and Tricyclic Antidepressants (TCAs)

• Have a greater risk of precipitating shift to mania as compared to other antidepressants
• Recommended only in patients who failed to respond to an initial treatment

Omega-3 Fatty Acids

• Due to the improvement of depression on omega-3 fatty acids than placebo it may be used as an adjunctive treatment for patients with bipolar depression especially those with increased cardiovascular risk

Specific Psychological Interventions

• Enhance care, increase functioning and treatment adherence and reduce the risk of relapse, mood fluctuations, need for medications and hospitalization
• Help patients accept their chronic illness and cope with the psychosocial consequences of prior mood episodes, ongoing subsyndromal symptoms, fear of future episodes
• Maintenance psychotherapy usually is the same therapy during acute mood episodes

Cognitive Behavioral Therapy (CBT)

• Treatment includes education about self-monitoring, problem-solving, motivation to take medicines reliably and preventive measures against active relapse
  • Aims to teach patient ways to monitor, examine and change the dysfunctional thinking and behavior associated with undesirable mood states
  • Train patient to identify, challenge and replace the unhelpful thoughts that are associated with undesirable mood states to more helpful ones

• Specifically designed for prevention of relapse in patients who have frequent relapses and improve adherence
• Based on the principle of inter-relation of thoughts, feeling and behavior
• Usually given in 20 individual sessions for 6 months with additional booster sessions most of the time
• Recommended as 2nd line adjunctive treatment for acute bipolar depression and maintenance treatment for patients with fewer episodes and less severe form of bipolar disorder

Interpersonal and Social Rhythm Therapy (IPSRT)

• Consists of interpersonal problem-solving, clarification and interpretation to help patients resolve related issues of grief, transitions in roles or interpersonal deficits
• Stress the role of dysregulation of social and circadian rhythm in the onset of manic episodes
  • Educates patients to regularize their sleep-wake patterns, work, exercise, meal and other daily activities
• Usually given in 24 individual sessions for 9 months
• Recommended as 3rd line adjunctive and maintenance therapy for acute depression

Family-Focused/Oriented Therapy

• Deals on psychoeducation about bipolar disorder, communication enhancement training and problem- solving skills training
• Designed to fasten stabilization, decrease early recurrences, improve family functioning and improve mood
• It is usually given to the family and patient in 21 sessions for 9 months that will focus on communication styles between them or marital relationships
• Recommended as 2nd line adjunctive and maintenance therapy for acute depression

Psychoeducation

• May be given individually or in group settings
• Focused on improving illness awareness, treatment compliance, early detection of prodromal symptoms and relapses and lifestyle regularity
• Appears to be a highly effective adjunct to pharmacotherapy in preventing recurrences and improving medication adherence
• Models of psychoeducation: Barcelona Bipolar Disorders Program (21 sessions for 6 months), Life Goals Program (phase I is 6 weekly sessions)

Early Warning Signal (EWS)

• Train the patients to identify and manage early warning signs of recurrence
• Aims to intervene early and self-manage manic and depressive symptoms

Electroconvulsive Therapy (ECT)

• Alternative treatment for unmanageable or life-threatening mood elevated syndromes or depression that do not respond to 1st-line medications
• Used in cases where medication is hazardous to the medical condition of the patient (eg pregnancy)
• Used as maintenance therapy to patients who respond to electroconvulsive therapy during the acute mood episodes and who have failed to respond to other maintenance medication and psychotherapy
• 2 or 3 treatments per week of brief pulse therapy has been used
• It is preferred to have bifrontal electrode placement than bitemporal because it has a faster treatment response and has fewer cognitive side effects
• May cause some short-term side effects which include confusion, disorientation and memory loss