Helping Patients Tolerate Anti-Manic Treatments

May 7, 2026

Chris Aiken, MD. Editor-in-Chief, The Carlat Psychiatry Report. Assistant Professor, NYU Langone Department of Psychiatry. Practicing psychiatrist, Winston-Salem, NC.

Dr. Aiken has no financial relationships with companies related to this material.

Getting your Trinity Audio player ready...

Mania is a psychiatric emergency. From job loss to arrest, it can destroy a person’s life in a few days. It calls for rapid treatment, but poor tolerability and low insight often stand in the way of adherence. In this article, I’ll look at how to make first-line treatments more tolerable and suggest options when FDA-approved treatments aren’t feasible.

First-line agents: How to maximize tolerability
The most effective agents for treating mania are lithium, carbamazepine, valproate, and the antipsychotics. Here are some ways to make them more tolerable:

Start with the lowest possible dose and raise slowly. For lithium, that may mean 150 mg, or even lower with the liquid form.
Use controlled-release versions. Carbamazepine XR is better tolerated than ER. With valproate, the ER is the better tolerated formulation.
Give the entire dose at night. With lithium, this also protects the kidneys.
Select an agent based on which side effects you most want to avoid (see the table “Tolerability of Anti-Manic Medications” below).
Pretreat for side effects (see the table “Pretreatment for Mood Stabilizer Side Effects” below).

Tolerability of Anti-Manic Medications
Less sedation	Lithium, cariprazine, aripiprazole, risperidone
Less weight gain	Lithium, carbamazepine, ziprasidone
Less akathisia	Non-antipsychotics or quetiapine, olanzapine, iloperidone, asenapine

From the Clinical Update
“Helping Patients Tolerate Anti-Manic Treatments”
by Chris Aiken, MD
The Carlat Psychiatry Report, Volume 24, Issue 5
May 2026
www.thecarlatreport.com

Pretreatment for Mood Stabilizer Side Effects
Nausea	Ondansetron 4 mg PRN Ginger capsules 1,000–2,000 mg every 12 hours PRN Lorazepam 0.5–1 mg every 8 hours PRN Olanzapine 5 mg every 12 hours PRN
Akathisia	Propranolol 80–240 mg/day Lorazepam 1–3 mg/day divided BID or TID Vitamin B6 150–300 mg BID (as pyridoxal 5′-phosphate)*
Weight gain	Metformin ER 500–1,000 mg/day with food Melatonin 3–5 mg HS Probiotics 1 capsule/day

*Vitamin B6 treats akathisia, extrapyramidal symptoms, prolactinemia, and possibly tardive dyskinesia on antipsychotics, as well as tremor on lithium. The standard form (pyridoxine) carries a risk of neuropathy, while the active form (pyridoxal 5′-phosphate) appears free of this risk (Hadtstein F and Vrolijk M, Adv Nutr 2021;12(5):1911–1929).

From the Clinical Update
“Helping Patients Tolerate Anti-Manic Treatments”
by Chris Aiken, MD
The Carlat Psychiatry Report, Volume 24, Issue 5
May 2026
www.thecarlatreport.com

Benzodiazepine augmentation can rapidly reduce agitation, insomnia, and anxiety during mania, while alleviating mood stabilizer side effects like nausea and akathisia (eg, clonazepam 0.5–2 mg every 12 hours or lorazepam 1–2 mg every 8–12 hours). This strategy works best in the inpatient setting where misuse can be monitored and is best kept short term. Long-term benzodiazepine use is associated with worse functional outcomes in bipolar disorder (Cañada Y et al, Aust N Z J Psychiatry 2021;55(10):1005–1016).

Off-label options for mania
When the FDA-approved routes don’t work or aren’t tolerated, off-label medications are worth considering. Although the evidence supporting them is weaker, they are generally better tolerated than traditional mood stabilizers, allowing them to be used as augmentation without burdensome side effects. Nonpharmacologic approaches also have a role here. Dark therapy is a behavioral strategy with potent anti-manic effects that fit well in any treatment regimen (see sidebar below).

Dark Therapy

Dark therapy is a behavioral approach that was developed at the National Institute of Mental Health for insomnia and bipolar disorder. The original strategy required patients to stay in a pitch-dark room all night long, but we’ve since learned that eliminating just the blue wavelength of light has a similar stabilizing effect on circadian rhythms. In this virtual dark therapy, patients wear blue-light blocking glasses or are in a pitch-dark room from 6:00 PM to 8:00 AM.

Virtual dark therapy was tested in a small, randomized trial of inpatient mania, where it improved symptoms within a week with a large effect size (1.05–1.86; Henricksen TE et al, Bipolar Disord 2016;18(3):221–232). Three tips are critical to its success:

Most blue-light glasses don’t block enough to work, so use a brand that has been tested clinically (eg, Uvex Skyper S1933X, Noir Insight ARG, or pairs available at https://lowbluelights.com).
Likewise, patients need 100% darkness when not wearing the glasses. Strategies include blackout curtains, electrical tape over LED lights, towels over door cracks, or sleeping in the basement. For patients who are afraid of the dark, lowbluelights.com makes nightlights that don’t emit blue light.
Sleep is not the goal. Some patients give up on dark therapy because it doesn’t help them fall asleep. In the research, it improves sleep quality and regularity but is not directly sedating.

As patients improve with dark therapy, they can ease the protocol, gradually moving the start time up by an hour every two to five days until they are donning the glasses one or two hours before bed to maintain stability. Dark therapy can be added to any anti-manic treatment, and many patients appreciate the opportunity to take a more active role in their recovery.

Clonidine
This alpha-2 agonist is FDA approved in ADHD and hypertension. Small trials have explored it in mania since the 1990s, but more solid evidence arrived only recently when it successfully augmented lithium in an RCT (Ahmadpanah M et al, J Psychiatr Res 2022;146:163–171).

Clonidine is well tolerated, and patients often appreciate its sedative qualities during mania. Orthostatic falls are the main risk and improve with extended-release forms.

Levetiracetam
Levetiracetam (Keppra) is an anticonvulsant that can normalize the overly excited calcium signaling seen in manic patients—an ability it shares with lithium and carbamazepine. It is one of the better-studied off-label agents for mania, with support from five randomized trials involving 240 patients. All but one of those trials were positive, and the negative trial also had the most limited design (small, open label). Levetiracetam was used as augmentation, with doses ranging from 250 to 3000 mg (Kishi T et al, Bipolar Disord 2022;24(8):834–835; Mirzazadeh H et al, J Affect Disord 2025;387:119526).

Most patients tolerate levetiracetam. It is weight neutral but can cause sedation, dizziness, and dyscoordination. The XR form is better tolerated and available generic. It may also improve executive function, cognition, and tardive dyskinesia (Lin CY et al, CNS Drugs 2024;38(1):1–14; Woods SW et al, J Clin Psychiatry 2008;69(4):546–554). However, it can cause rare psychiatric side effects, including aggression, suicidality, and psychosis.

Allopurinol
Allopurinol is FDA approved in gout. In five placebo-controlled trials involving 425 patients, it augmented mood stabilizers with a small effect size (Bartoli F et al, Br J Psychiatry 2017;210(1):10–15). Among those trials, allopurinol worked when added to lithium, but not to antipsychotics, raising the untested possibility that its synergy depends on lithium or is blocked by antipsychotics.

Allopurinol is well tolerated with rare joint pain or edema. The main risk is an allergic rash (1:2,500) that—like lamotrigine—requires immediate discontinuation of the drug.

Natural therapies
Palmitoylethanolamide (PEA) is a natural fatty acid with neuroprotective and anti-inflammatory effects. It has been used successfully for pain since the 1970s. In psychiatry, the trials are new and small. So far it has shown promise as augmentation in unipolar depression and bipolar mania, based on results from small, placebo-controlled trials (Abedini T et al, Psychiatry Clin Neurosci 2022;76:505–511).

PEA has no significant side effects or risks. It occurs naturally in peanuts, eggs, and soybeans, but there is no cross-allergy with these.

Another fatty acid, omega-3s (fish oil), is also useful in bipolar disorder, but not for acute mania. Omega-3s may prevent new episodes and treat acute bipolar depression (dose 1,000–3,000 mg/day with an EPA:DHA ratio of at least 2:1).

Off-Label Options for Mania
Treatment	Dose
Allopurinol	Start 100 mg/day, raise by 100 mg every 3–7 days toward 300–600 mg/day (divided BID)
Clonidine	Start 0.1 mg QHS, raise by 0.1 mg every 3 days (target 0.1–0.6 mg QHS)
Levetiracetam	Start XR 500 mg QHS, raise by 500 mg every 5–7 days toward 1000–3000 mg QHS
Palmitoylethanolamide	600 mg BID

From the Clinical Update
“Helping Patients Tolerate Anti-Manic Treatments”
by Chris Aiken, MD
The Carlat Psychiatry Report, Volume 24, Issue 5
May 2026
www.thecarlatreport.com

Not recommended
Other off-label anticonvulsants are unlikely to work. Most have failed in large trials of mania, including lamotrigine, topiramate, and gabapentin. Among them, oxcarbazepine is most likely to work, but its trials trend toward the negative and it is not a reliable mood stabilizer.

Calcium channel antagonists are a promising but unproven strategy. They include the antihypertensives amlodipine, nimodipine, isradipine, and verapamil. Only verapamil has controlled trials, where it largely failed against placebo (Cipriani A et al, Mol Psychiatry 2016;21(10):1324–1332). The others have only observational studies, which show potential benefits in patients with ultra-rapid cycling (where mood episodes change every week or two).

CARLAT VERDICT
Off-label options for mania shine on tolerability, but rest on less solid evidence. Consider them for augmentation or for mild manic symptoms that don’t pose a danger. Otherwise, stick with FDA-approved agents for this dangerous state of mind.

General Psychiatry