Transcript:

Mood stabilizing medications play a vital role in the treatment of mental health disorders, most notably bipolar disorder.

The history of mood stabilizers for the treatment of psychiatric conditions, particularly bipolar disorder, begins with the emergence of lithium.

In 1949, Australian psychiatrist John Cade published groundbreaking research showing that lithium is effective in treating manic episodes in patients with bipolar disorder.

Lithium was approved in 1970 for the treatment of bipolar disorder, and in1978 for maintenance therapy.

Lithium remained the only approved treatment for bipolar disease for several decades, but with several limitations.

Serum levels need to be assayed to avoid toxicity while ensuring that concentrations are in the therapeutic range. This can be a delicate balance.

Lithium can affect renal and thyroid function, necessitating monitoring.

Beginning in the 1960s, research began on 2 anticonvulsants; valproate – also formulated as divalproex – and carbamazepine, as mood regulators for patients with bipolar disorder.

Valproate and an extended-release formulation of carbamazepine were approved for the treatment of manic episodes in 1995 and 2004, respectively.

Research results for a third anticonvulsant, lamotrigine, were reported in 2003, and approval in this indication was granted later that year.

Like lithium, anticonvulsants also have significant monitoring requirements, including:

• Serum testing to ensure that drug concentrations are at therapeutic levels, but typically only during dose adjustments or after signs of toxicity emerge.
• Complete blood counts – CBC – and liver function testing are necessary during carbamazepine or valproate treatment due to untoward effects on blood counts and hepatic function.
• Lamotrigine is generally better tolerated, but has been associated with skin reactions, ranging from rash to Stevens-Johnson Syndrome. Slow titration is necessary to guard against this.

Despite different factors limiting their use, lithium and the 3 anticonvulsants all help modulate mood by regulating neurotransmitter activity and intracellular signaling pathways, but there remain subtle differences in the way this is accomplished.

Nonetheless, central to the MAO of each drug is a reduction of glutamate activity (the primary excitatory neurotransmitter in the brain) and enhancement of the activity of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter.

Lamotrigine only reduces the frequency of neuroexcitatory events, not their intensity; hence, it is only indicated for the prevention of manic episodes, not for treating them once they occur.

Lithium also inhibits dopaminergic neurotransmission, which is upregulated during manic episodes.

At this point in the history of mood stabilizers, there were 3 approved agents in widespread clinical use to treat manic episodes. Two had been approved for maintenance therapy to prevent manic/depressive episodes, but none to treat bipolar depression.

This was problematic.

• Patients with bipolar disorder experience  depression more often than mania.
• Patients are more likely to seek treatment when they are depressed than when they are manic, and as a result are often misdiagnosed with major depression.

Depressive episodes required heightened attention.

For acute depressive episodes, treatment options have included adding:

• Lamotrigine
• Bupropion
• An SSRI
• A selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• A monoamine oxidase inhibitor

For severe depression, treatment-resistant depression, or depression with psychotic or catatonic features, electroconvulsive therapy was an option.

Antidepressants appear to be effective in bipolar depressive episodes, but their 4-6 week onset of action is a limitation, and they increase the risk of cycling into manic episodes.

The risk of cycling is greatest with the SNRIs.

Drugs to treat the full mood spectrum in bipolar disease were sorely needed.

The first-generation antipsychotic agent chlorpromazine was approved to treat manic episodes in 1973, but this agent did not target depression and was limited by tolerability issues.

Since 2000, 7 second-generation – or atypical – antipsychotics have been approved for the treatment of manic episodes or as maintenance therapy in bipolar disorder, and 5 have indications for bipolar depression.

These agents inhibit the activity of dopamine at the dopamine D2 receptor, which has been associated with antidepressant efficacy in major depression, as well as bipolar disorder.

All atypical antipsychotics are available in oral formulations, and risperidone, ziprasidone, and aripiprazole are available as long-acting injectables.

These agents are not without their limitations:

As prophylaxis, risperidone, ziprasidone, paliperidone, and aripiprazole are mostly effective for reducing manic episode recurrence, not the occurrence of depressive episodes.

They have numerous potential adverse events, including hyperprolactinemia (with the exception of aripiprazole), cognitive impairment, metabolic effects, movement disorders, and cardiovascular effects that may limit treatment.

The array of mood stabilizers for patients with bipolar disorder has evolved in 3 waves. It has evolved from lithium – for a long time the only available option – and progressed through the subsequent introductions of anticonvulsants and finally, atypical antipsychotics for this indication.