Drugs for Bipolar Disorder

Objectives

1. Define bipolar disorder and compare/contrast with major depression and Schizophrenia

2. Describe current pharmacological therapies in terms of relative usefulness for treatment of mania, depressive episodes and maintenance

3. Describe the adverse effects of lithium use for bipolar disorder

what are the 3 definitions we need to know when talking about bipolar disorder?

Mania/manic episodes

Hypomania

Depression

what is mania/manic episodes?

• Distinct period of dramatically elevated, irritable, mood lasting 1 week or more and impairing social functioning

what are some examples of symptoms of mania?

• Can include: inflated self-esteem, reduced need for sleep, verbosity (talking, rabbling), racing thoughts, distractibility, risky behaviour

what is hypomania?

• Briefer duration of manic symptoms; less severe

Bipolar is divided into Bipolar 1 and Bipolar 2. What are the differences between these?

• Bipolar I = Episodes of sustained mania, usually with intervening depressive episodes

• Bipolar II = Major depressive episodes with at least 1 manic episode

how does sex affected differ between Bipolar 1 and 2?

• Bipolar I = Equal rates in males and females; average onset at 21

• Bipolar II = More prevalent in females; age of onset similar to bipolar 1

how prevalent is Bipolar Disorder in north america?

• 1-3% adults affected (North America)

what causes Bipolar Disorder?

Neurochemical Theories

• Sensitization and kindling theory

• Permissive serotonin hypothesis

• Monoamine hypothesis

• Cholinergic hypothesis

BOTTOM LINE - Multiple defects, no solid grasp on mechanism

what are the 2 main ways to treat Bipolar disorder?

Non-pharmacological

Pharmacological

what are the non-pharmacological ways to treat Bipolar disorder and are they effective?

• Adjust sleep, nutrition, exercise, stress levels

• Not the most helpful in most people due to the severity of Bipolar Disorder

what are the pharmacological ways to treat Bipolar Disorder?

• Mood stabilizers

+ Lithium, Valproate, Lamotrigine, Carbamazepine

• Atypical antipsychotics - Bipolar 1 patients typically

• Adjunct therapy with benzodiazepines

Which drugs control manic episodes?

• Lithium

• Carbamazepine

• Valproate/Valproic acid

• Antipsychotics

• Benzodiazepines

what is Lithium effective at?

• 60-80% effective for manic phase, ~60% for maintenance.

Is Li ever used in conjunction with other drugs?

• Patients with mania possessing psychotic features often receive adjunct SGA (olanzapine). Usually start on low dose of lithium and increase over time.

What is a big pro to Li?

• Reduces risk of suicide 8-10 fold

what has reduced Li use?

• Slow onset of therapeutic effects and approval of olanzapine, valproate for manic phase has reduced lithium use.

What is the mechanism at play for Lithium?

• No unified theory

• Several effects reported

+ Reduced serotonin reuptake

+ Reduced dopamine synthesis

+ Increased GABAergic activity

+ Increased glutamate reuptake

+ Reduced neuronal calcium uptake

what is the major working hypothesis for the mechanism of Li?

• Major working hypothesis is that Li+ affects the IP3/DAG second messenger system by blocking inositol recycling

Adverse effects for Li can be broken down into early/acute and long-term/ chronic. What are the early effects?

• GI - nausea, vomiting, diarrhea

• Muscle weakness, lethargy (30%)

• Polydipsia with polyuria/nocturia (70%)

• Headache, confusion, tremour (40%)

• Nephrogenic diabetes insipidus

what is Polydipsia with polyuria/nocturia

excessive drinking with excessive urination, especially at night

what is Nephrogenic diabetes insipidus?

- excessive urination and therefore fluid loss due to kidneys inability to concentrate urine

Adverse effects for Li can be broken down into early/acute and long-term/ chronic. What are the long-term effects?

• Renal morphology changes (e.g. interstitial nephritis; 10-20%). Leads to chronic kidney disease

• Hypothyroidism and/or goiter

• Weight gain >10 kg (20%)

• Reduced libido, sexual dysfunction

• Edema

• Severe acne

• Cardiovascular - blood pressure, electrolyte retention, cardiac rhythms (arrythmias)

what are some other cons to Li?

• Low therapeutic index

• Problematic in renal insufficiency - do not give to those with kidney issues

• Drug interactions

what drug interactions are at play for Li?

+ Thiazide diuretics, NSAIDS, ACE inhibitors increase Li

+ Potassium-sparing diuretics reduce Li

+ Loop diuretics, Ca channel blockers may increase or decrease Li

What does carbamazepine do?

• Manic, depression and maintenance - not as well as Li

What are the adverse effects of carbamazepine?

+ Nausea, vomiting, diarrhea, hyponatremia (low Na levels), rash, leukopenia, fluid retention, drowsiness, dizziness, lethargy, headache

What are the benefits of carbamazepine over Li?

• Similar efficacy to Li, better for rapid cycling

• Adverse effects - less severe than Li

What is valproate used for?

• Approved for anti-manic effects

Why is Valproate sometimes preferred over Li?

• Strong efficacy in patients not responsive to lithium, better than Li for rapid cycling

• Generally well-tolerated

what are the adverse effects of Valproate?

+ Upward dose titration = nausea, weight gain, diarrhea, vomiting, hair loss, tremour

How are antipsychotics used in bipolar treatment?

• Used alone or with mood stabilizer - use in bipolar has really increased in past few years

how are Benzodiazepines used for Bipolar? Ex?

• Used with mood stabilizer

• Clonazepam is drug of choice

Why is benzodiazepine use limited?

• Limited by abuse potential beyond acute setting

What drugs control the depressive episodes in Bipolar?

• Lithium

• Lamotrigine

• Antipsychotics

• Antidepressants

What is Lamotrigine used for?

• Limited efficacy for mania

• Good control of depressive episodes

Why may someone prefer lamotrigine over Li?

• Alternative to lithium for maintenance

+ Weight neutral - no large weight gain

How does Lamotrigine work?

• Mechanism unknown

how are antipsychotics used for Bipolar disorder?

• Higher response rates than placebo

• Olanzapine + fluoxetine better than monotherapy

• Combination is FDA approved for bipolar depression

Do we use antidepressants for Bipolar disorder? Why or why not?

• STEP-BD study; Sachs GS et al. N Engl J Med. 2007;356(17):1711-22.

• No quantifiable advantage of monotherapy or combination therapy (mood stabilizer)

• Monotherapy may precipitate "switch" to mania

What drugs are used as Maintenance Therapies/Mood Stabilizers for Bipolar Disorder?

• Lithium

• Lamotrigine

• Valproate

• Carbamazepine

• All with psychotherapy

when may someone need lifetime pharmacotherapy?

• Lifetime = 3 or more manic episodes or 1 moderate to severe manic episode. This indicates long term pharmacotherapy is needed.

Drug Efficacy Overview

Summary and Conclusions?

• Bipolar disorder is a common and severe mood disorder treated both pharmacologically and non-pharmacologically

• Drug efficacy is assessed in 3 categories – mania, depression, maintenance

• Lithium is widely used, has efficacy in all 3 categories, but is associated with therapeutic lag and considerable adverse effects

Alternatives to lithium:

• Valproate, carbamazepine, SGAs, benzodiazepines are replacements and/or adjunct treatment options for manic episodes.

• Lamotrigine and SGAs (2ng gen antipsychotics) are useful replacements for or adjuncts to lithium for treatment of depression.

• Valproate, carbamazepine and lamotrigine are viable alternatives to lithium for maintenance therapy.