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Existing treatments for posttraumatic stress disorder (PTSD) are few in number and, too often, ineffective. Although still classified as a Schedule I drug, methylenedioxymethamphetamine (MDMA) has improved symptoms PTSD in 

In this Mental Health Minute, Tiago Reis Marques, MD, PhD, shares the results of 

, in which the MDMA-assisted arm of the study outperformed the placebo by 35%. He revisits the history of MDMA and looks to the future, when this Schedule I drug may be approved as a legal treatment.

is a senior clinical fellow on the Faculty of Medicine at Imperial College London, an instructor at the Institute of Psychiatry in King’s College, and the CEO of Pasithea Therapeutics.

Would you prescribe a psychedelic like MDMA? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

The latest trial results for MDMA-assisted therapy are in—and they are eye-catching.  

New Hope for PTSD Treatment?

To minimize renal side effects, lithium is best administered 

 at night, and one should routinely use the regular-release (24-hour half-life) preparation.

 It comes in tablets or capsules. Capsules are sometimes better tolerated because they do not have the salty taste that can contribute to nausea. They also are available in 150-mg doses, which is a convenient size for some patients on doses like 450 or 750 mg daily. Plasma levels during acute treatment should not be allowed to go higher than 1.0 mEq/L for a lower risk of 

The regular-release formulation is preferred over the sustained release version (

; now available as a generic) because it provides superior pharmacokinetics for sparing the kidney of potential harm. Studies have shown that once-a-day lithium at night, compared with multiple daily doses, 

 and other symptoms of the lithium-induced diabetes insipidus-like syndrome.

 After the patient reaches the 12-hour postdose level following their evening dose (eg, 0.7 mEq/L), the patient’s level continues to drop during the day, reaching a low point just before the next once-daily dose. This low level is thought to give the kidneys an opportunity to have relatively little lithium coursing through them, which aids recovery from dysfunction, such as increased urine volume. When using a longer-acting preparation, further lowering the level during the second half of the day is minimal and, hence, the protective effect should be lower.

Trials examining renal biopsy results also found that multiple daily doses were associated with more pathological changes to the kidneys.

 Why doesn’t the higher peak lithium level associated with a large once-daily dose harm the kidneys? We can only say, based on the studies, that this effect must be less harmful than the absence of the daily low trough level. 

 in effectiveness has been noted in any of the trials of once-daily lithium.

Another possible advantage of giving the whole dose at night is that the 

 filter lithium more slowly at night. The net effect is that you only need 80% of the daily divided doses when changing patients to a once-nightly regimen. For instance, if someone was on 1500 mg daily in divided doses, they would usually need 1200 mg at night to get the same 12-hour postdose level. The once-daily dose at night reduces the total exposure and need to excrete lithium as compared with the divided doses. It is also possible that tremors will be less bothersome with the once-daily dose: the worst of the tremors will occur in the middle of the night when the patient is (hopefully) sleeping, and the lowest level of severity will be in late afternoon and evening.

The optimal level for maintenance treatment with lithium is 0.6 mEq/L to 0.8 mEq/L, according to a recent 

 Higher maintenance levels are associated with a 

 of long-term kidney harm and (surprisingly) more frequent depressive episodes.

 If patients are having breakthrough manias or hypomanias despite optimal maintenance levels of lithium and are also prone to serious depressions, it is better to add another antimanic agent instead of increasing lithium. Most patients with bipolar disorder experience more time in depressive states than manic states, so this will be a very common situation. If there are breakthrough depressions, 

 adding lamotrigine, lurasidone, quetiapine, or cariprazine.

is associate professor of psychiatry at Harvard Medical School and colead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

An updated review of the optimal lithium dosage regimen for renal protection.

2. Kirkham E, Skinner J, Anderson T, et al. 

One lithium level >1.0 mmol/L causes an acute decline in eGFR: findings from a retrospective analysis of a monitoring database

Less frequent lithium administration and lower urine volume

What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium

5. Severus WE, Kleindienst N, Seemüller F, et al. 

What is the optimal serum level in the long-term treatment of bipolar disorder? A review

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on bipolar depression

Higher lithium levels are associated with a greater risk of long-term kidney harm and more frequent depressive episodes. This bipolar update reviews ways to minimize renal side effects.

Tips for Lithium Dosing for Optimal Renal Safety 

1. Kane JM, Smith JM. Tardive Dyskinesia Prevalence and Risk Factors, 1959 to 1979. 

2. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis.

3 Solmi M, Pigato G, Kane JM, et al. Clinical risk factors for the development of tardive dyskinesia. 

4 Tenback DE, van Harten PN, van Os J. Non-therapeutic risk factors for onset of tardive dyskinesia in schizophrenia: a meta-analysis. 

5 Zai CC, Maes MS, Tiwari AK, et al. Genetics of tardive dyskinesia: Promising leads and ways forward.

6 Zai CC, Lee FH, Tiwari AK, et al. Investigation of the HSPG2 Gene in Tardive Dyskinesia – New Data and Meta-Analysis.

7. Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2, and MnSOD genes: a meta-analysis of pharmacogenetic interactions. 

8. Patsopoulos NA, Ntzani EE, Zintzaras E, et al. CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. 

9. The American Psychiatric Association Practice Guideline for The Treatment of Patients With Schizophrenia, Third Edition. 2021. https://doi.org/10.1176/appi.books.9780890424841

10. Bergman H, Bhoopathi PS, Soares-Weiser K. Anticholinergic medication for antipsychotic-induced tardive dyskinesia. 

11. El-Sayeh HG, Rathbone J, Soares-Weiser K, Bergman H. 

Non-antipsychotic catecholaminergic drugs for antipsychotic-induced tardive dyskinesia.

12. Soares-Weiser K, Maayan N, Bergman H. 

Vitamin E for antipsychotic-induced tardive dyskinesia.

13. Soares-Weiser K, Rathbone J, Ogawa Y, et al. Miscellaneous treatments for antipsychotic-induced tardive dyskinesia. 

14. Ad1elufosi AO, Abayomi O, Ojo TM. Pyridoxal 5 phosphate for neuroleptic-induced tardive dyskinesia. 

15. Kane JM, Smith JM. Tardive dyskinesia prevalence and risk factors, 1959 to 1979. 

16. Caroff SN, Leong SH, Roberts C, et al. Cumulative Burden of Illness in Veterans With Tardive Dyskinesia and Serious Mental Disorders. 

17. Carroll B, Irwin DE. Health Care Resource Utilization and Costs for Patients with Tardive Dyskinesia. 

18. Guy W. ECDEU assessment manual for psychopharmacology: revised. DHEW Publication No. ADM 76-338. Rockville, MD: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976: 534-537.

19. Chouinard G, Ross-Chouinard A, Annable L, Jones B. The extrapyramidal symptom rating scale. 

20. Kalachnik JE, Sprague RL. The dyskinesia Identification System Condensed User Scale (DISCUS): reliability, validity, and a total score cut-off for mentally ill and mentally retarded populations.

21. Casey DE. Tardive dyskinesia: pathophysiology and animal models. 

22. Margolese HC, Chouinard G, Kolivakis TT, et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction. 

23. Blanchet PJ, Parent M-T, Rompre PH, Levesque D. Relevance of animal models to human tardive dyskinesia. 

What do we know about TD? What is on the horizon? Take the quiz to learn more.

Tardive Dyskinesia: 8-Question Quiz on What We Know

“Ms T” is a 25-year-old African American female with an 8-year history of chronic schizophrenia. The onset of her illness was at age 17, and symptoms included auditory hallucinations of demonic figures, visual hallucinations of dead people, delusions of reference that the television is talking about her and thought broadcasting. She was stabilized on antipsychotic medication and has never required psychiatric hospitalization.

On routine metabolic monitoring at age 19, the patient was found to have elevated total (212 mg/dL) and LDL (160 mg/dL) cholesterol, low HDL cholesterol (37 mg/dL), and normal triglycerides (78 mg/dL). A decision was made to start her on adjunctive simvastatin. Subsequently, over the next year her lipid panel normalized except for persistent low HDL (37-40 mg/dL). However, there were no clinically appreciable changes in her symptoms or cognitive function during that time period.

Many patients with schizophrenia-spectrum disorders (SSDs) 

 illness remission using approved treatments.

 Therefore, clinicians should explore novel therapeutic strategies. One potential mechanistic lead is immune dysregulation, given 

 for increased inflammation in schizophrenia.

 Several previous studies have targeted inflammation in schizophrenia, with heterogeneous results.

 Statin drugs reduce cholesterol, metabolic syndrome, and cardiovascular mortality—which is prevalent in schizophrenia—and also cross the blood-brain barrier.

 Several small studies have shown potential benefits of adjunctive statins in SSDs.

 outlines clinical trials of adjunctive statins in the treatment of schizophrenia.

 performed a 12-month, double-blind, randomized placebo-controlled, multicenter trial of simvastatin 40 mg/day to patients with SSDs. Drawn from Dutch inpatient and outpatient settings between November 2013 and February 2019, eligible participants had a DSM-IV diagnosis of SSD (295.x or 298.9) within the past 3 years. Participants were randomized 1:1 to simvastatin or placebo, using block-randomization with stratification for study site and sex. Participants visited the research center 8 times over 2 years, and they were excluded if blood cholesterol was > 8 mmol/L at any visit. Raters were blinded to cholesterol results.

Primary outcomes were symptom severity as measured by the Positive and Negative Syndrome Scale (PANSS) and neurocognitive functioning as assessed by the Brief Assessment of Cognition in Schizophrenia (BACS) at the end of 12 months of treatment. Secondary outcomes included PANSS subscale scores, global assessment of functioning, extrapyramidal symptoms, akathisia, depressive symptoms, and the metabolic syndrome. Data were analyzed using linear mixed models for repeated measurements.

, and 90 completed 12 months of treatment. The follow-up 1 year after the end of treatment was completed by 70 participants. There was no main effect of simvastatin treatment on PANSS total score after 12 months. However, the treatment by time interaction effect was significant, indicating that group differences in symptom severity differed over time. The simvastatin group had significantly lower PANSS total scores at 6 months (mean difference -4.8 points) and 24 months (mean difference 4.7 points) post-baseline. There was no effect on simvastatin on cognitive performance (BACS composite and subtask scores) after 12 months.

There was a significant treatment by time interaction effect, with higher general functioning (GAF) in the simvastatin group at 24 months (mean 4.9 points). There was also a significant decrease in total cholesterol, LDL cholesterol, and non-HDL cholesterol in the simvastatin group over time compared to placebo. Serious adverse events were more common the placebo group (19% versus 7%). There were no significant differences in adverse events between participant groups, including those particularly relevant to treatment with statins, namely dark-colored urine and myalgias.

 that, although well-tolerated, simvastatin augmentation is not an effective treatment for symptom severity or cognition early-phase SSDs. Treatment adherence, particularly given the long duration of the trial, may have contributed to negative findings and is a notable study limitation. Another possibility is that only a subset of patients—namely those who are enriched for inflammation—may show improvement in symptoms and cognition with treatment with simvastatin. The authors note that the early-phase SSD population may have been suboptimal, given that metabolic syndrome was (largely) absent in these patients.

Antiinflammatory augmentation may not be beneficial for symptom severity and cognition in schizophrenia, although this does not preclude the possibility that a subset of patients may benefit from this approach. Future studies—especially in patients with evidence of inflammation—are warranted.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Levi L, Bar Haim M, Burshtein S, et al. 

Duration of untreated psychosis and response to treatment: an analysis of response in the OPTiMiSE cohort

2. Çakici N, van Beveren NJM, Judge-Hundal G, et al. 

An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis

3. Miller BJ, Goldsmith DR. Evaluating the hypothesis that schizophrenia is an inflammatory disorder. 

4. Castilla Guerra L, del Carmen Fernández Moreno M, López Chozas JM, Jiménez Hernández MD. Statins in stroke prevention: what an internist should know. 

5. Sommer IE, Gangadin SS, de Witte LD, et al. 

Simvastatin augmentation for patients with early-phase schizophrenia-spectrum disorders: a double-blind, randomized placebo-controlled trial

6. Chaudhry IB, Husain N, Drake R, et al. Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: pilot study. 

7. Ghanizadeh A, Rezaee Z, Dehbozorgi S, et al. Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial.

8. Sayya M, Boostani H, Ashrafpoori M, et al. Effects of atorvastatin on negative sign in chronic schizophrenia: a double blind clinical trial

9. Tajik-Esmaeeli S, Moazen-Zadeh E, Abbasi N, et al. Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial. 

10. Vincenzi B, Stock S, Borba CP, et al. A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: effect on inflammation, psychopathology, cognition and lipid metabolism. 

Because schizophrenia is associated with increased inflammation, studies on the effects of anti-inflammatory statins are warranted.









Adjunctive Simvastatin in Early Schizophrenia

I have an unhealthy fear of certain medications. Tricyclics, MAOIs, and lithium. All of these have a reputation for adverse effects that is – perhaps – unearned. In practice, I’m constantly surprised by how well-tolerated they turn out to be. In the case of lithium, that surprise has been confirmed both in medical research and patient surveys. When it comes to the side effects that matter most to patients – sedation,

 ­­– lithium’s tolerability ranks right behind lamotrigine if we look at the clinical research. For example, the 

 is only 1 in 16 to 1 in 27 on lithium, compared to 1 in 5 for many other mood stabilizers.

But let’s look beyond the clinical research. A few years ago a Google company called CureTogether posted 

 asking people with bipolar disorder what they found most helpful in their recovery. Over 3000 responded, and only 2 medications made their top 10 list: Lamotrigine and lithium. The rest of the top 10 were behavioral tools.

Most of the lithium’s adverse effects are manageable, and in this podcast we’ll show you how to do it. To start with, titrate lithium slowly. Lithium’s main benefits are in long-term prevention, so there’s usually no reason to rush it (unless you are trying to help a manic patient stay out of the hospital). Start with 300 mg at night and raise it by 300 mg every 5-7 days. Cut those numbers in half if the patient is frail, elderly, or is taking a medication like a thiazide diuretic that can raise lithium.

The main reason people stop lithium in the early phase is nausea. A slow release version will reduce that risk, as will taking the lithium after a meal or with a glass of milk. Most other adverse effects improve with slow release as well – it cuts their overall rate by about 50% - except one: diarrhea. 4 Patients with diarrhea on lithium due better with instant release lithium that gets in and out of their system faster.

Common remedies for nausea (eg, ondansetron, promethazine, ginger capsules) or diarrhea (eg, loperamide, milk of magnesia) are safe to take with lithium.

Another way to improve side effects is to lower the dose. For most patients, the optimal blood level for long-term prevention is 0.6, or somewhere in the range of 0.4-0.8. The same blood level is ideal for treating depression – whether bipolar depression or unipolar. The only place where you’ll need a high dose is in acute mania, where serum levels of 0.8-1.2 are usually necessary.

 need the same blood levels as adults, but the elderly are different. Aim for a serum level that’s 30% below the usual in patients over age 60, and then further personalize that dose based on their response.

 The blood-brain barrier becomes more permeable as we age, so more lithium gets into the older brain at lower serum levels. Conservative dosing in the elderly has another benefit: These patients are much more sensitive to lithium’s side effects, particularly imbalance and tremor.

Tremor is one of the most common side effects with lithium, and it is very sensitive to the dose. The first step is to lower caffeine and – if possible – other tremor-promoting medications like bupropion (Wellbutrin) or atypical antipsychotics. Beta-blockers help lithium tremor, and although propranolol is the most commonly used, there is research supporting other beta blockers like atenolol, metoprolol, and nadolol for lithium tremor.

 The average dose of propranolol is around 120 mg/day. Usually we start with instant release propranolol and then change to the extended release after figuring out how much they need.

You may read that beta-blockers interact with lithium, and this is true, but the interaction is minor. They usually raise its levels by about 20%.

Another option with dual-benefits for lithium tremor is nimodipine. This calcium-channel blocker has good research for essential tremor, and is used third-line for mania and mania and rapid cycling.

 It’s well tolerated, and a typical target dose is 120mg a day. If your patient doesn’t want to add another medication in and prefers natural remedies, there’s high-dose vitamin B6. In doses from 900-1200 mg/day vitamin B6 improved lithium-related tremor, and it may reduce adverse effects on antipsychotics as well. B6 has open-label data for akathisia and tardive dyskinesia.

 Although natural, high-dose B6 is not risk free and can rarely cause neuropathy which usually resolves with discontinuation of the vitamin. It is hard to find B6 in a dose that high, so I keep a list of products on my 

Weight gain is a side effect on most patient’s minds when considering lithium, but the risk of significant weight gain is much lower than most patients expect. I start with some reassuring data: In a large meta-analysis, patients actually lost weight on lithium during the acute phase of treatment.

 Over the long-term, however, weight gain is possible. About 1 in 3 patients will gain 4-10 lbs on lithium, and most of that weight gain occurs in the first few years of treatment.

But the most important part of this education is to let your patient know that there is something they can do about it. Lithium will make them thirsty, so if they stick with water and avoid caloric beverages they can lower that risk – and that includes avoiding diet soft drinks which actually cause weight gain through indirect metabolic effects even though they have no calories of their own. 

Another way to reduce weight gain is to optimize thyroid function on lithium. Beyond that, any reasonable approaches for weight loss can be used, such as diet, exercise, or medications like topiramate 50-100 mg/day.

Like most psychiatric medications, lithium can cause sexual dysfunction. We know of one evidence-based remedy for this: Aspirin, at least for men. In a randomized, double-blind trial of men with sexual dysfunction on lithium aspirin 240 mg/day improved the problem.

Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) can also be used.

Now we get to the most serious risk with lithium: Renal insufficiency. Here is what I tell patients. As you age, the kidneys tend to slow down, and lithium can make them slow down even more in some patients who take it long term. We will monitor the kidneys and may need to lower or stop it if we see this happening, because if we don’t catch it it could – very rarely – go on to kidney failure.

There are at least 3 ways to protect against renal problems on lithium.

First, give the entire dose at night. This strategy improved renal function in a few long term comparison studies.

Next, avoid toxic levels. High levels of lithium can kill kidney cells, and that may be why one large study found a direct correlation between number of toxic episodes on lithium and renal problems. It also looked like the kidneys were spared in that study if the lithium levels were kept at or below 0.8.

Watch out for extreme polyuria and polydipsia. These are signs of nephrogenic diabetes insipidus, which is both an adverse effect on lithium and a risk factor for renal insufficiency. A laboratory test will reveal elevated sodium in the blood and very dilute urine; check for urine osmolality, urine sodium, basic metabolic panel. Nephrogenic diabetes insipidus is a risk factor for future renal insufficiency, and there is some evidence that treating the syndrome can reduce that risk by preventing fibrotic changes in the kidneys, such as with amiloride.

If the serum creatinine starts to rise, lower the lithium to the lowest effective dose and check it more often. Consult a nephrologist if the serum creatinine rises to 1.5 mg/dl.

Another medical risk with lithium is hypothyroidism. This is usually treatable with a thyroid supplement, and you don’t need to stop lithium because the thyroid function goes down. If you do come off lithium, the hypothyroidism usually resolves – but not always – so you can gingerly try to come off the thyroid medication while checking levels. 

Hypothyroidism may be worth addressing on lithium even when it is subclinical. A controlled study from the Mayo Clinic found that patients prescribed lithium were less likely to relapse into depression if their TSH was close to 2.4 microIU/ml.

Lithium has several dermatologic risks. It can cause acne and psoriasis, and some patients report thinner, brittle hair on it although overt hair loss is rare.

Any standard treatments for acne can be used with lithium,10 but one to consider is minocycline. This antibiotic has neuroprotective and antiinflammatory effects, and it may treat depression, according to a handful of small-to-medium size controlled trials in bipolar and unipolar depression (the dose of minocycline for depression is 200 mg/day;

 lower doses are used for acne, eg, 1 mg/kg/day).

 along with their antibiotic to avoid problems in the gut microbiome. Probiotics also have a growing evidence base in depression, anxiety, and bipolar, and there’s some evidence that probiotics help acne. Psoriasis – those scaly, dry patches of skin that worsen in the winter and tend to show up on the elbows, knees, palms, face, or back - is a relative contraindication with lithium. For this I will refer to a dermatologist, but I may suggest 2 CAM treatments that can help bipolar and psoriasis. In a few small trials, psoriasis improved with 

 – both of which are fairly risk free and have small studies in bipolar depression.

Although lithium is a first-line treatment that ranks high on the list of patient’s favorites, it has fallen out of general use, particularly in the United States.

 When drugs meet that fate, they are often reserved for the most refractory patients, such as patients with severe mania who require high doses, which doesn’t help lithium’s reputation. Adverse effects should not stand in the way of its usage – when they are managed carefully and I have found that surprisingly tolerable.

But still, about 1 in 10 patients don’t tolerate it and have to stop the medication.

About 1 in 3 patients with bipolar disorder respond very well to lithium – and these tend to be the patients with classic, “textbook case” bipolar – with euphoric manias that are cleanly separated from depressions, and low rates of rapid cycling, mixed states, and major psychiatric comorbidities. These need not be patients with bipolar I though – patients with bipolar II can have classic hypomanias, and in one study lithium worked better for bipolar II than bipolar I.

When lithium works well, its benefits tend to last. It is among the top medications that prevent hospitalization.

 Its preventative effects have outshined other mood stabilizers, like valproate, in head-to-head trials, and it has added benefits that are relevant to bipolar disorder. Lithium prevents suicide, dementia, and some new evidence suggests it may lower the stroke risk and aid cardiac remodeling after a heart attack – that’s good news if it holds up, because stroke is the #1 cause of death in bipolar disorder, and cardiovascular disease tends to start 20 years earlier in patients with bipolar disorder than it does in the general population.

I hope you will join us again for more practical updates on PsychPearls, and you can also catch us every Monday on the 

is the Mood Disorders Section Editor for 

 He has written several books on mood disorders, most recently 

 with his cohost Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

 and is also a practicing Psychiatric Mental Health Nurse Practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.

Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects.

Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium.

Effects of lithium on cognitive performance: a meta-analysis.

4. Girardi P, Brugnoli R, Manfredi G, et al. 

Lithium in bipolar disorder: optimizing therapy using prolonged-release formulations.

5. Severus WE, Kleindienst N, Seemüller F. 

What is the optimal serum lithium level in the long-term treatment of bipolar disorder--a review?

Lithium in late-life mania: a systematic review.

Lithium tremor revisited: pathophysiology and treatment.

Lithium side effects and toxicity: prevalence and management strategies.

9. AprahamIan I, TeIxeIra de SouSa R, da CoSTa L et al

. Lithium safety and tolerability in mood disorders: a critical review.

10. Murru A, Popovic D, Pacchiarotti I, et al. 

Management of adverse effects of mood stabilizers.

11. Kalita-DE Croft P, Bedford JJ, Leader JP, et al. 

Amiloride modifies the progression of lithium-induced renal interstitial fibrosis.

12. Frye MA, Yatham L, Ketter TA, et al. 

Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies.

13. Rosenblat JD, Kakar R, Berk M, et al. 

Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.

14. Zaenglein AL, Pathy AL, Schlosser BJ, et al. 

Guidelines of care for the management of acne vulgaris.

Lithium-associated psoriasis and omega-3 fatty acids.

Treatment of bipolar disorder in a lifetime perspective: is lithium still the best choice?

The new news about lithium: An underutilized treatment in the United States.

Suicidal behavior in mood disorders: response to pharmacological treatment.

 Pharmacological treatment and risk of psychiatric hospital admission in bipolar disorder.

Although lithium is a first-line treatment that ranks high on the list of patient’s favorites, it has fallen out of general use, particularly in the United States. When lithium works well, its benefits tend to last. It is among the top medications that prevent hospitalization. More in this podcast.

Dosing Tips for Lithium: How to Improve Tolerability

The FDA is reviewing 3 controlled trials of lumateperone (Caplyta) in bipolar depression. The results have not been published, but their bare bones have been presented at conferences. Here is what we know so far.

All 3 were large, randomized, placebo controlled, quadruple-blind trials in bipolar I and bipolar II depression. The first trial was negative, but lumateperone worked in the next 2 with a small to medium effect size (0.27-0.56). As with other atypicals in bipolar depression, lumateperone’s efficacy was evident as early as week 1 (

Negative trials are a common problem in multicenter studies like this one, which involved 58 centers. When each enter takes care of only a small number of patients, they tend to give those patients more time and attention. This inflates the placebo response, which in this case was 1.7 times greater than the placebo response in the positive trial.

 Negative results did not hold back the approval of other atypicals like cariprazine in bipolar depression, but lumateperone may not cross the finish line if the FDA finds flaws with its 2 positive studies.

The trials bring needed attention to bipolar II disorder, which was included along with bipolar I in each of the trials. Of the 4 atypicals approved in bipolar depression (cariprazine, lurasidone, quetiapine, and olanzapine-fluoxetine combo), only quetiapine and cariprazine were extensively studied in bipolar II depression, and 

 lists 5 atypical antipsychotics in bipolar depression.

Lumateperone’s favorable trials remained positive when broken down into bipolar I and bipolar II subgroups. A fourth trial is underway that will test the drug in a third group: unipolar depression with mixed features. Currently, only lurasidone (Latuda) has 

Lumateperone is a serotonin 5-HT2A antagonist, a mechanism it shares with asenapine, clozapine, olanzapine, risperidone, and quetiapine, as well as mirtazapine and trazodone. Unlike other antipsychotics, it has low affinity for the dopamine D2 receptor. Its occupancy there is 39%. In contrast, the next lowest is 60% occupance for clozapine and quetiapine, and most other antipsychotics 

 So far, this has translated to a lower rate of akathisia and extrapyramidal side effects in schizophrenia, and that benefit extended to the bipolar trials as well.

This profile resembles that of pimavanserin (Nuplazid), an antipsychotic with low dopamine occupancy that is an inverse agonist at serotonin 5-HT2A (“inverse agonists” do not block the receptor, but they cause it to act in ways opposite to an agonist). Pimavanserin is FDA-approved in psychosis due to Parkinson disease, and it has also 

 in depression in a large, randomized, placebo-controlled augmentation trial.

Lumateperone has a few drawbacks in bipolar disorder. It is costly, has never been teste din mania, and is only FDA-approved in schizophrenia. If approved, its main advantage over other atypical antipsychotics is likely to be tolerability. Lumateperone had low rates of akathisia, weight gain, metabolic disturbances, and prolactinemia in the short-term bipolar depression studies, as well as in the schizophrenia studies which lasted up to one year. Its main side effects are somnolence, nausea, dry mouth, and dizziness. The starting dose is the same as the target dose, and the same as the schizophrenia dose: 42 mg at night.

If approved, lumateperone will bring at least 2 qualities that are needed in the bipolar armamentarium: Efficacy in bipolar II depression and reasonable tolerability. Pending that, it is worth considering in patients with moderate to severe bipolar depression who have not responded to other options.

 with his co-host Kellie Newsome, PMH-NP.

The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

1. Durgam S, Satlin A, Vanover KE, et al. Lumateperone in the treatment of bipolar depression: Efficacy across symptoms. Poster presentation, International Society for Bipolar Disorders Annual Conference, June 2020.

. Intra-cellular therapies announces positive topline results from study 402 evaluating lumateperone as adjunctive therapy in patients with bipolar depression

Clinical Trial Evaluating ITI-007 (Lumateperone) as a Monotherapy for the Treatment of Bipolar Depression,

Clinical trial evaluating iti-007 as an adjunctive therapy to lithium or valproate for the treatment of bipolar depression

Clinical trial evaluating lumateperone monotherapy in the treatment of bipolar depression or major depressive disorder

 Lumateperone monotherapy for the treatment of bipolar depression conducted globally,

Evaluation of cariprazine in the treatment of bipolar I and II depression: a randomized, double-blind, placebo-controlled, phase 2 trial.

A preview of 3 pivotal trials suggests promising results, but there are reasons to wait before jumping in with this antipsychotic.

Psychopharmacology

New Hope for PTSD Treatment?

Tips for Lithium Dosing for Optimal Renal Safety

Tardive Dyskinesia: 8-Question Quiz on What We Know

Adjunctive Simvastatin in Early Schizophrenia

Dosing Tips for Lithium: How to Improve Tolerability

A New Option for Bipolar Depression

Sex, Drugs, and Psychosis: Reviewing Psychiatric Medications’ Taboo Side Effect

Sedation: The Ups and Downs of a Side Effect

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