Introduction to Mood Stabilizers and Anticonvulsants

Primer

Mood Stabilizers and Anticonvulsants (Antiepileptics) are used to treat both epileptic and nonepileptic disorders such as bipolar disorder. Lithium is considered the gold standard mood stabilizer for bipolar disorder. Valproic acid can be more effective in patients who do not respond to lithium, and also has a more rapid anti-manic effect than lithium, with a therapeutic benefit usually seen in 3 to 5 days. Other mood stabilizers include newer anticonvulsants (e.g. - carbamazepine, lamotrigine). Of note, atypical antipsychotics are also “mood stabilizers” commonly used in bipolar disorder.

Definitions

The term mood stabilizer is not strictly defined.

  • Strictest definition: an agent that treats and prevents acute mania and depression
  • Intermediate definition: an agent that that is effective in either acute mania and its prevention OR acute depression and its prevention
  • Broadest definition: an agent that is effective at either treating or preventing mania, or in treating or preventing depression, and does not exacerbate symptoms.

Mechanism of Action

  • Most mood stabilizers have multiple mechanisms of action (MOAs), which include modulation of γ‐aminobutyric acid (GABA)-ergic and glutamatergic neurotransmission, and alteration of voltage‐gated ion channels or intracellular signalling pathways.
  • Mood stabilizers generally take 1-2 weeks for a good response to take effect, with some initial effects beginning within 48 hours.

Why are Antiepileptics Used to Treat Bipolar Disorders?

Bipolar disorder and epilepsy share common features including an episodic course of illness and kindling phenomena. The amygdala plays a role in both disorders as well. However, epilepsy and bipolar disorder are two distinct different diseases.[1]

Comparison of Mood Stabilizers

Valproic acid is effective in patients who don’t respond to lithium and has a more rapid antimanic effect than lithium and therapeutic benefit is seen in 3 to 5 days.

Comparison of Mood Stabilizers

Lithium Valproic Acid (VPA) Carbamazepine Oxcarbazepine Lamotrigine
Indications Bipolar disorder, depression Bipolar disorder Bipolar disorder Bipolar disorder Bipolar disorder
Approval in Youth No No No No No
Pharmacokinetics Not metabolised, excreted by kidneys Phase II 90% (glucuronidation), Phase I 10% Phase I CYP3A4, 2C19 (autoinducing) Minimal P450 interactions, does not autoinduce, more favourable side effect profile Phase II (glucuronidation)
Monitoring Lithium levels, kidney function, thyroid function Epival levels, albumin level, liver function Carbamazepine level, albumin level, liver function Oxcarbazepine metabolite level, albumin level, liver function No blood work, but important to monitor for skin rashes due to risk of SJS!
Side Effects Tremors, acne, thyroid disorders, hypercalcemia GI issues, weight gain, hair loss, tremor, PCOS, thrombocytopenia, hair loss, encephalopathy, cognitive dulling[2] Cognitive dulling, diplopia, nystagmus, vertigo, hyponatremia Cognitive dulling, hyponatremia Cognitive dulling
Adverse Reactions Renal impairment, nephrotoxicity Pancreatitis, hepatoxcitity Agranulocytosis, aplastic anemia, hepatotoxicity, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) Agranulocytosis, aplastic anemia, hepatotoxicity, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
Teratogen Ebstein's anomaly (cardiac) Neural tube defects Neural tube defects, cleft lip Neural tube defects, cleft lip Safe in pregnancy
Drug-Drug Interactions ACE inhibitors, angiotensin II receptor antagonists (ARBs), thiazide diuretics, NSAIDs, COX-2 Inhibitors The combination of VPA with lamotrigine can cause significant and dangerous increases of lamotrigine, due to inhibition of the glucuronidation. Potent CYP interactions with many drugs. Many!!! Most particular with VPA
Notes The gold standard treatment for bipolar disorder. In bipolar disorder, may be better for those with comorbid substance use, or traumatic brain injuries In bipolar disorder, may be better for those with comorbid substance use, substance use disorder, or a negative family history of bipolar disorder. Similar to carbamazepine, but has several advantages, including no autoinduction, and much less CYP P450 enzyme interactions Not useful as an anti-manic agent, and only works for bipolar depression. Takes a long time to titrate due to risk for SJS

Adverse Events

Suicide

  • In 2008, the FDA issued a healthcare alert about the increased risk (2 per 1000) of suicidal ideation and behaviours with any antiepileptic drug (AED) use.[3][4] However, statistical significance only found in only two antiepileptics (topiramate and lamotrigine) out of the eleven studied, and this broad warning for all AEDs has been criticized.[5] The actual true suicidal risk is yet to be established, but is likely very low, subsequent meta-analyses have found no evidence of increased risk.[6]

References

1) Bialer, M. (2012). Why are antiepileptic drugs used for nonepileptic conditions?. Epilepsia, 53, 26-33.
2) Eddy, C. M., Rickards, H. E., & Cavanna, A. E. (2011). The cognitive impact of antiepileptic drugs. Therapeutic advances in neurological disorders, 4(6), 385-407.
3) Ferrer, P., Ballarín, E., Sabaté, M., Vidal, X., Rottenkolber, M., Amelio, J., ... & Ibáñez, L. (2014). Antiepileptic drugs and suicide: a systematic review of adverse effects. Neuroepidemiology, 42(2), 107-120.
4) Britton, J. W., & Shih, J. J. (2010). Antiepileptic drugs and suicidality. Drug, healthcare and patient safety, 2, 181.
5) Mula, M., Kanner, A. M., Schmitz, B., & Schachter, S. (2013). Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia, 54(1), 199-203.
6) Ferrer, P., Ballarín, E., Sabaté, M., Vidal, X., Rottenkolber, M., Amelio, J., ... & Ibáñez, L. (2014). Antiepileptic drugs and suicide: a systematic review of adverse effects. Neuroepidemiology, 42(2), 107-120.