Bipolar/Barbiturates

• Bipolar disorder (BPD)


  A severe biologic illness characterized by recurrent fluctuations in mood
• Characteristics of bipolar disorder

  • Pure manic episodes (euphoric mania)
  • Hypomanic episode (hypomania)
  • Major depressive episode (depression)
  • Mixed episode
• Manic episode


  Persistently heightened, expansive, or irritable mood—typically associated with hyperactivity, excessive enthusiasm, pressured speech, and flight of ideas
• Hypomania


  A mild form of mania where mood is persistently elevated, expansive, or irritable but symptoms are not severe enough to cause marked impairment or require hospitalization
• Major depressive episode


  Characterized by depressed mood and loss of pleasure or interest in all or nearly all of one's usual activities and pastimes. Associated symptoms include disruption of sleeping and eating patterns; difficulty concentrating; feelings of guilt, worthlessness, and helplessness; and thoughts of death and suicide
• Mixed episode


  Patients experience symptoms of mania and depression simultaneously. Patients may be agitated and irritable (as in mania) but may also feel worthless and depressed
• Not all patients alternate repeatedly between mania and depression. Some experience repeated episodes of mania, and some experience repeated episodes of depression with an occasional episode of mania
• Bipolar disorder subtypes


  • Bipolar I disorder—patients experience manic or mixed episodes and usually depressive episodes too
  • Bipolar II disorder—patients experience hypomanic or depressive episodes but not manic or mixed episodes
• Etiology of bipolar disorder

  Disruption of neuronal growth and survival. Prolonged mood disorders are associated with atrophy of specific brain regions, especially the subgenual prefrontal cortex. Mood-stabilizing drugs can prevent or reverse neuronal atrophy by influencing signaling pathways that regulate neuronal growth and survival
• Drugs used to treat bipolar disorder

  • Mood stabilizers
  • Antipsychotics
  • Antidepressants
• Mood stabilizers


  Relieve symptoms during manic and depressive episodes, and they prevent recurrence of manic and depressive episodes. They do not worsen symptoms of mania or depression, and they do not accelerate the rate of cycling
• Mood stabilizers


  • Lithium
  • Divalproex sodium
  • Carbamazepine
• Antipsychotics


  Can be given during severe manic episodes even if psychotic symptoms are absent. Usually combined with a mood stabilizer
• Antidepressants


  Can be given during depressive episodes. Almost always used with a mood stabilizer
• Preferred antidepressants for bipolar disorder

  • Bupropion
  • Venlafaxine
  • SSRIs (e.g. fluoxetine, sertraline)
• TCAs appear to promote more incidents of mania
• Preferred drugs for acute management of manic episodes

  • Lithium
  • Valproate
• If the patient does not respond adequately to lithium or valproate alone, the drugs may be used together
• Second-generation antipsychotics approved for management of severe mania as adjuntive with mood stabilizers

  • Aripiprazole
  • Asenapine
  • Cariprazine
  • Olanzapine
  • Olanzapine/fluoxetine
  • Quetiapine
  • Risperidone
  • Ziprasidone
• For severe mania, a benzodiazepine may be added to the regimen
• Treatment of depressive episodes

  May be treated with a mood stabilizer, an atypical antipsychotic, or a mood stabilizer or antipsychotic plus an antidepressant but rarely with an antidepressant alone (because hypomania or mania might result)
• If depression is mild, monotherapy with a mood stabilizer (lithium or valproate) may be sufficient
• If the mood stabilizer is inadequate, an antidepressant or antipsychotic can be added, but benefits may be limited with the addition of an antidepressant
• Preferred antidepressants for bipolar depression

  • Bupropion
  • Venlafaxine
  • SSRIs
• Purpose of long-term therapy

  To prevent recurrence of both mania and depression
• Long-term treatment options


  • One or more mood stabilizers
  • Valproate alone
  • Valproate plus lithium
  • Antipsychotic agents as monotherapy or in combination with a mood stabilizer
• Poor patient adherence can frustrate attempts to treat a manic episode. Patients may resist treatment because they fail to see anything wrong with their thinking or behavior and may enjoy the experience
• Short-term hospitalization may be required to ensure adherence, and collaboration with the patient's family may be needed
• Lithium


  Can stabilize mood in patients with bipolar disorder. Has a low therapeutic index, so toxicity can occur at blood levels only slightly greater than therapeutic levels. Monitoring levels is critical
• Mechanism of action of lithium

  May work by (1) altering glutamate uptake and release, (2) blocking the binding of serotonin to its receptors, or (3) inhibiting glycogen synthase kinase-3 β. Lithium also has neurotrophic and neuroprotective actions, which may protect against neuronal atrophy or promote neuronal growth
• Pharmacokinetics of lithium


  Well absorbed orally, distributes evenly to all tissues and body fluids, has a short half-life contributing to rapid excretion, excreted by the kidneys
• Lithium excretion is reduced when patients have low sodium levels, so lithium can accumulate to toxic levels in the presence of low sodium
• Therapeutic lithium levels


  0.8 to 1.4 mEq/L, must be kept below 1.5 mEq/L
• Adverse effects of lithium

  • At therapeutic levels (<1.5 mEq/L): GI effects, tremors, polyuria, muscle weakness
  • At 1.5-2.0 mEq/L: Persistent GI upset, coarse hand tremor, confusion, hyperirritability of muscles, ECG changes, sedation and incoordination
  • At 2-2.5 mEq/L: High output of dilute urine, serious ECG changes, clonic movement seizures, severe hypotension, coma, and eventually death
• Lithium can cause goiter and hypothyroidism, and is teratogenic
• Lithium levels must be monitored every 2-3 days initially and then every 3-6 months
• Drug interactions with lithium

  • Diuretics (decrease sodium levels)
  • NSAIDs (can increase lithium levels)
  • Anticholinergic drugs (due to urinary hesitancy)
• Lithium preparations


  • Lithium carbonate
  • Lithium citrate
• Lithium dosages are very individualized, with dosage adjustments based on lithium levels
• Other mood stabilizers used in bipolar disorder

  • Divalproex sodium (valproate)
  • Carbamazepine
  • Lamotrigine