Mood Stabilizers vs Antipsychotics in Bipolar

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Experts question the rise of antipsychotics in bipolar

STUDY: Shah S et al, South Med J 2026;119(5)

STUDY TYPE: Integrative review

FUNDING: Independent

Background

Rif El-Mallakh’s papers are practical, scientific, and full of widsom. Here, he joins with colleagues from the University of Kentucky to argue that practice trends are out of sync with research. We ought to be using more mood stabilizers and fewer antidepressants and antipsychotics in bipolar disorder.

The Mechanistic Argument

Bipolar disorder is linked to elevated intracellular sodium and calcium, changes that alter neuron firing and track with mood state. Lithium and anticonvulsant mood stabilizers correct this directly. Antipsychotics correct it only indirectly, through dopamine D2 blockade. Antidepressants push intracellular sodium the wrong way.

Roughly 75 percent of genes linked to bipolar risk affect ion regulation, and intracellular calcium runs about 29 percent higher during mania or depression than euthymia (effect size 0.55). Lithium swaps directly for the excess intracellular sodium. Anticonvulsants block the same channels in an activity-dependent way, hitting the most overactive neurons hardest.

Antipsychotics and antidepressants modulate monoamines like dopamine and serotonin, but there’s no clear evidence that these neurotransmitters are implicated in bipolar disorder. The authors suggest that antipsychotics reduce symptoms without modifying the disease.

Dr. Aiken’s addendum: Lithium has three other disease-modifying properties. It corrects the biological clock, normalizes the expression of circadian rhythm genes, stabilizes the hyper-excitability of pleuripotent neurons (derived from the hippocampus of bipolar patients), and has broad neuroprotective properties.

The Clinical Argument

The paper doesn’t address clinical trials in detail, so I’ll fill in those gaps here. Bipolar disorder is a chronic illness, and long-term outcomes are better with lithium and anticonvulsants than antipsychotics. That includes lower relapse rates and better functioning.

Compared with other mood stabilizers, children who took lithium had half as many suicide attempts, better functioning, and less depression and aggression over ten years in an observational study.

Lithium was the only drug that lowered both psychiatric and physical hospitalizations in a Finnish study followed 60,045 patients for over nine years.  Carbamazepine cut medical admissions too. Several antipsychotics, including quetiapine, were associated with higher risks, though confounding can’t be excluded.

Mortality rates are also lower with lithium in bipolar disorder, from both medical and psychatric causes. In contrast, a five-year study of 49,293 patients found antipsychotics raised the risk of death overall and from heart disease, and the risk climbed with the dose.

Most of this long-term data is observational, but it is supported by a few controlled studies. In a randomized trial, patients had better cognitive outcomes (verbal fluency) after a year on lithium vs quetiapine, and their brain scans normalized faster, with slower loss of white matter.

Based on these findings, several practice guidelines recommend lithium first-line, particularly for patients in the early course of the illness. From the International Society of Bipolar Disorders Task Force:

“[In the] early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term.”

Practice Trends

Despite this, mood stabilizer use in outpatient bipolar care fell from 62 percent of visits to 26 percent between 1997 and 2016, while antipsychotic use rose from 12 percent to 51 percent. Antidepressant monotherapy nearly tripled. Four adequately powered placebo-controlled trials of antidepressants added to a mood stabilizer in bipolar I were all negative. Over the same two decades, disability-adjusted life years from bipolar disorder rose 54 percent, outpacing the 48 percent rise in incidence.

Practice Implications

1. Antipsychotics bring rapid symptomatic relief but their long-term risks are not well-balanced by long-term benefits. Few prevent depression robustly in bipolar disorder (quetiapine is an exception there).
2. Lithium, and to a lesser extent the anticonvulsants, address the underlying biology of bipolar, and their long-term risks are balanced by meaningful benefits, including higher functioning and lower mortality.

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

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