Bipolar Disorder Treatments: Lithium, Anticonvulsants, & SGA

Bipolar Disorder: Clinical Symptoms

• Bipolar disorder: characterized by alterations b/w depressive episodes & manic (Bipolar I) or hypomanic (Bipolar II) episodes

• Mania: more severe, last > 1 week, potential psychotic features

• Hypomania: less severe, shorter (>4 days), may not affect daily functioning

• Depressive symptoms have been the hardest to treat

• Mixed episodes include symptoms like depressed mood & impulsivity → increases risk of suicide

Bipolar Disorder: DSM-5 Clinical Symptoms (from book)

• distinct period of abnormally & persistly elevated, expanisve, or irritable mood, lasting at least 1 week

• during period of mood disturbances, 3 or more of the following symptoms have persisted & have been present to a significant degree:

  1. inflated self-esteem or grandiosity

  2. decreased need for sleep

  3. more talkative than usual or pressure to keep talking

  4. flight of idea or subjective experience that thoughts are racing

  5. distractibilioty

  6. increase in goal-directed activity

  7. excessive involvment in pleasurable activaties that have a high potential for painful consequences

• As w/ most mental disorders → there’s no definitive diagnostic lab test for bipolar disorder (e.g., blood work, distinctive brain activity), only a clinician’s judgment from symptoms

Bipolar Disorder: DSM-5 Clinical Symptoms

• Bipolar symptoms can be (& often are) misdiagnosed as part of:

  • Depression (MDD)

  • Schizophrenia

  • ADHD

  • Conduct disorder in children

  • substance-induced disorders

• Euthymia: normal, stable mood, free from extreme highs (mania) or lows (depression)

• most stable mood, mania always less than depressive episodes (BP-I)

Brain Differences in Ppl w/ Bipolar Disorder

• decreased cognitive control over thoughts, impulses & emotion is associated w/ bipolar w/ hypo-function:

  • dorsal ACC & PFC

  • hippocampus

• increased impulsivity, urges, motivated & emotionality associated w/ hyper-function:

  • ventral ACC & PFC

  • amygdala

  • nucleus accumbens

Bipoalr Disorder: “Treating from Above”

• Mania-Minded Treatments:

  • bring mania down - treatments to bring mania down

  • stabilize from above - treatments to prevent drop into depression

• Depression-Minded Treatments

  • treat from below - manage depressive symptoms

  • stabilize from below - prevent rise into manic episode

FDA-Approved Bipolar Medications

• Three pharmaceutical approaches for bipolar disorder:

  1. Lithium - good for Acute mania/mixed & mood stabilizer prophylaxis; drop in effectiveness for Acute bipolar depression

  2. Anticonvulsant Mood Stabilizers - Valproic Acid (Depakote); Lamotrigine

  3. Second Gen. Antipsychotics (SGAs) - olanzapine + fluoxetine (Symbyax); Quetiapine (Seroquel); Cariprazine (Vraylar)

Bipolar Medications: how do they work?

• Bipolar medications (e.g., lithium) may modulate intracellular activity by several mechanisms

  • ultimately results in more neurotrophic activity or neuroplasticity (e.g., through activity of CREB, BDNF, or others)

• GSK-3 → related to neuroplasticity

  • neurotrophic effects by inhibiting GSK-3

• Modulating 2nd messengers through GPCRs

  • when GPCRs are active ← modulate activity

• Modulating activity through ionotropic Rs

• overall => stabilize neurons

• PharmD vs relationships to symptoms of most bipolar meds, (litium, etc.) is complex, unclear → various drugs act as:

  • glutamate antagonists or GABA agonists (anticonvulsants)

  • DA agonists or antagonists; modulating 5-HT receptors (antipsychotics)

  • promotion of neuroplasticity (?)

    • ex: ppl w/ bipolar have less BDNF → less neuroplasticity

Lithium for Bipolar Disorder

• Lithium (lithium carbonate) Li+, an ion (similar to Na+)

  • effective on 70% of episodes, but 1/3 will relapse

  • historically most effective drug for all phases of bipolar (mania, depression, maintenance)

• PharmK: oral admin., peak plasma levels in 3 hrs.

  • metabolism: NONE (liver), only renal (kidney) in 18-30 hrs

• PharmD(???): DA & 5-HT agonist

  • may reduce PFC activity, modulate neuroplasticity in hippocampus

  • suppresses intracellular GSK-3 (glycogen synthase kinase)

• Levels

• Increase urination

• Thirsty tremors

• Hair thinning & hypothyroidism

• Interactions

• Upset Stomach

• Muscle weakness

• Skin effects

• Side effects: many; compliance huge issue

  • somatic: nausea, thirst, tremors, weight gain, urination, kidney/liver toxicity

  • cognitive: cog. impairments, lethargy, avolition (lack of motivation)

Anticonvulsant Mood Stabilizor

• lamotrigine (Lamictal): FDA-approved for maintenance

  • effective for depressive phase, but not acute mania

  • side effects: similar to lithium, but usually more minor, e.g., dizziness, tremor, nausea

  • exception is potentially severe skin rash (may require hospitalization)

• PharmK: half-life affected by other bipolar drugs, & hormonal contraceptives

• PharmD: unclear, suggested effects:

  • binds & inhibits voltage-gated Na+ channels

  • inhibits presynaptic glutamate release

Antipsychotic Drugs for Bipolar Disorder (all phases)

• quetiapine (Seroquel): FDA approved for all BD phases

  • good choice for manic symptoms

  • antagonist @ DA receptors

  • also approved for schizophrenia, & adjunctive for MDD

• olanzapine + fluoxetine (Symbyax): combination for mania & depression; good for maintenance

  • antagonist @ DA & 5-HT receptors

  • good example of treating “from above & below”

Antipsychotic Drugs for Bipolar: New FDA-approved (2019)

• caripiprazine (Vraylar): recently FDA-approved for all BD phases

  • esp. beneficial for depressive symptoms

• unique mechanisms of action

  • partial agonist @ DA receptors

  • partial or full agonist @ 5-HT receptors (depends on the type)

Other Large Studies of Bipolar Treatment (2005 ot 2013)

• Bipolar Affective Disorder: Lithium/Anti-Convulsant Evaluation (BALANCE)

• Goals?

  • which is superior for maintenance, lithium monotherapy, valproic acid monotherapy, or combination?

• Results?

  • indivitions who receibed combination treatment had fewer relapses than either medication alone

Lithium Treatment Moderate-Dose Use Study (LiTMUS)

• Goals?

  • does combining lithium w/ either mood stabilizers or SGAs result in better patient outcomes?

• Results?

  • no difference b/w age groups on changes in psychiatric symptoms

  • lithium add-on did mean less exposure to SGAs & their side effects