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Have you run out of ideas for your outpatient with resistant bipolar depression? You might consider the results of 

 about the use of bright fluorescent light.

There have been a fair number of previous studies on light therapy for bipolar disorder. Some studies with this modality of treatment, when compared with likely inactive controls, have not shown efficacy for patients whose disease does not have a seasonal component. Other reports suggested a high rate of switching to mania in patients with bipolar disorder when they received early morning light (the usual timing for light treatment targeting nonbipolar depression). Fortunately, 2 studies showed good results for chronotherapy; in these studies, patients were kept up all night and then administered 

 However, midday light might be safer and/or more efficacious based on some theoretical considerations, and more acceptable compared with requiring sleep deprivation.

In a small study of midday light, 46 patients with moderate bipolar depression were randomized to 1 hour of bright white light at noon (7000 lux, which is less than the 10,000 lux usually administered for unipolar depression) or 50 lux dim red placebo light for 6 weeks.

 Patients exhibiting mixed features, as well as those with a history of rapid cycling in the past year, were excluded from the study. Patients with active suicidal ideation, those with any substance use disorder in the past 6 months, and those on melatonin, stimulants, or nonsteroidal anti-inflammatory drugs were also excluded. Thus, at best, the study results apply to a very limited number of patients in comparison with usual practice patients.

The light dose was titrated slowly as a precaution against inducing mania. Participants started with a 15-minute treatment, which increased by 15 minutes weekly until reaching 1 hour at week 4. Most other light treatment protocols start with the full dose, so this was another novel aspect of the approach (in addition to the timing of the light).

The results demonstrated that remission (defined as a score of 8 or less on the primary depression rating scale) was seen by week 6 in 68% of the bright light group vs 22% of the control group. There were no mood polarity switches. Quite notably, there was no difference between the active and placebo groups in the first 3 weeks. Remission in other light therapy studies tend to cluster at week 5, so the time frame for improvement was similar to other protocols despite the ramping up of dose over the first 4 weeks. However, based on the improvement difference seen between active and placebo groups in weeks 4 to 6, it seemed likely that more treatment time could have resulted in further remissions for the treatment group. The findings were 

, which is a term rarely encountered for studies of bipolar depression (except, perhaps, for electroconvulsive therapy).

Effort was made to prevent bias among patients regarding their expectations of the bright light compared with the dim red light. Recorded baseline levels of expectations were equal in the 2 groups and did not change when repeated at study completion. Nevertheless, one cannot be extremely confident that the blind was successful when the treatments looked so different.

Nothing is known about what strategies to employ with midmorning light for maintenance of the therapeutic effects.

The caveat should be offered that new treatments often do well in early studies, but then those results are harder to replicate in subsequent and larger studies. Examples of such include 

is associate professor of psychiatry, Harvard Medical School, and co-lead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. He also serves as a member of the Editorial Board of 

. Dr Osser has no financial disclosures regarding this article.

1. Sit DK, McGowan J, Wiltrout C, et al. Adjunctive bright light therapy for bipolar depression: a randomized double-blind placebo-controlled trial. 

2. Benedetti F, Riccaboni R, Locatelli C, et al. Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drug-resistant bipolar depression. 

3. Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression. 

4. Osser DN. Valproic acid: overused in bipolar disorder? 

5. Osser DN. Comorbid PTSD: update on the role of prazosin. 

A rare robust finding from a study on bipolar depression. 

Shining a Spotlight on Bright Light for Acute Bipolar Depression

The US Food and Drug Administration announced their approval of Alkermes’ LYBALVI, a combination of olanzapine and samidorphan, for the treatment of adults with schizophrenia and/or bipolar I disorder. LYBALVI is a once-daily, atypical antipsychotic that works as a maintenance monotherapy for the acute treatment of manic or mixed episodes, or as an adjunct to lithium or valproate.

“LYBALVI represents an important new treatment option for adults with schizophrenia or bipolar I disorder, their clinicians and caregivers, and reflects Alkermes’ commitment to developing new therapies that support patient-centered care,” Richard Pops, Chairman and Chief Executive Officer at Alkermes, said to the press. “We share this accomplishment with our employees and the many researchers, advocates, clinicians and patients who have been essential to the LYBALVI development program since its inception.”

In the ENLIGHTEN clinical development program, the novel antipsychotic demonstrated efficacy, safety, and tolerability. Most notably, patients taking LYBALVI experienced statistically significant less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study. The ENLIGHTEN program’s results, including the pivotal 

, are published in peer-reviewed journals.

“Schizophrenia and bipolar I disorder are complex, chronic diseases and there remains a persistent need for new medications with proven efficacy and safety. Olanzapine, a highly-efficacious atypical antipsychotic, is associated with significant side effects, including weight gain, that may impact patients’ treatment experiences and limit its use,” said René S. Kahn, MD, PhD, Esther and Joseph Klingenstein Professor & Chair, Department of Psychiatry and Behavioral Health System at the Icahn School of Medicine at Mount Sinai. “With the efficacy of olanzapine and evidence of less weight gain in patients with schizophrenia, LYBALVI brings a welcome new addition to our medication arsenal.”

This approval comes under the 505(b)(2) regulatory pathway and is based upon data from 27 clinical studies, including 18 studies evaluating LYBALVI and 9 studies evaluating samidorphan alone, as well as the FDA’s findings of safety and effectiveness of olanzapine in the treatment of bipolar I disorder and schizophrenia. According to the data, olanzapine-associated weight gain may be disease independent.

“People living with schizophrenia or bipolar I disorder must evaluate both efficacy and tolerability when making treatment decisions,” said Paul Gionfriddo, President and CEO of Mental Health America. “We are grateful that companies like Alkermes are driven to continue developing new treatment options in psychiatry that seek to address unmet needs of our community and we applaud the FDA for considering the experiences of individuals living with these conditions.”

Alkermes hopes to make LYBALVI available for patients in the fourth quarter of 2021.

1. Alkermes. Alkermes announces FDA approval of LYBALVI™ for the treatment of schizophrenia and bipolar I disorder. News release. June 1, 2021. 

https://investor.alkermes.com/news-releases/news-release-details/alkermes-announces-fda-approval-lybalvitm-treatment

2. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. 

3. Correll CU, Newcomer JW, Silverman BL, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: A 24-week phase 3 study. 

4. Zyprexa US Prescribing Information. Eli Lilly and Company. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020592s074,021086s048,021253s061lbl.pdf

This combination treatment of olanzapine and samidorphan caused significantly less weight gain in patients with schizophrenia and bipolar I disorder. 

FDA Approves a New Atypical Antipsychotic With Less Adverse Effects

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 

Schizoaffective disorder includes both psychotic and affective symptoms (

), with separate bipolar and depressive subtypes.

 ICD-11 aims to improve the diagnostic accuracy and differential diagnosis of schizoaffective disorder.

 There is debate whether schizoaffective disorder is a separate illness or is part of the continuum of schizophrenia and mood disorder spectrum.

Pharmacotherapy recommendations for schizoaffective disorder are generally derived from studies on schizophrenia and bipolar disorder; thus, symptoms are most commonly treated with antipsychotics, mood stabilizers, and/or antidepressants. Only paliperidone has an approved treatment indication specifically for schizoaffective disorder.

To explore the efficacy of pharmacotherapies for schizoaffective disorder, 

 looked at 2 nationwide cohorts. Treatments included oral and long-acting injectable (LAI) antipsychotics, mood stabilizers, antidepressants, and benzodiazepines and nonbenzodiazepines together (zopiclone, zolpidem, and zaleplon, also known as Z-drugs).

 2 cohorts from nationwide Finnish and Swedish registers. The Finnish cohort included 7655 patients treated for schizoaffective disorder, based on inpatient care as recorded in the Finnish Hospital Discharge Register. The Swedish cohort included 7525 individuals aged 16 to 64 years with schizoaffective disorder who were identified based on inpatient registers, specialized outpatient registers, disability pensions, and a social insurance agency register.

 Cohort members were followed from July 2006 until death, change in diagnosis to schizophrenia, or study end (December 2016 for the Swedish cohort and December 2017 for the Finnish cohort). Sensitivity analyses were performed excluding anyone who received a schizophrenia diagnosis during follow-up.

The main exposure was antipsychotics, based on Anatomical Therapeutic Chemical classification code N05A (except lithium); adjunctive medicine included 

, antidepressants, and benzodiazepines and/or Z-drugs. Psychotropic medication use periods were based on the PRE2DUP methodThe primary outcome measure was hospitalization due to psychosis. The authors also analyzed a composite measure of treatment failure, which included psychiatric hospitalization, change in medication, and death.

Analyses were conducted in each cohort separately using within-individual design and Cox regression models (hazard ratios [HRs] and 95% CIs), with P values adjusted for multiple comparisons. For antipsychotic effectiveness, the reference was antipsychotic nonuse. Nonantipsychotic medications were considered as adjunctive therapies, with antipsychotic use without adjunctive use as the reference (eg, olanzapine monotherapy was the reference for comparisons with olanzapine–mood stabilizer analyses). Data on 16 most commonly used antipsychotics were reported. Five oral antipsychotics (clozapine, olanzapine, quetiapine, risperidone, and aripiprazole) and LAIs (as a single category) were analyzed in combinations with adjunctive pharmacotherapies.

In both cohorts, 60% of the study subjects were female. Mean age was 45 to 47 years. During follow-up, 13% of the Finnish cohort and 22% of the Swedish cohort were censored because of a change in diagnosis to schizophrenia. The median follow-up was 8 years in the Swedish cohort and 11 years in the Finnish cohort. During the follow-up, about half of the participants had a hospitalization for 

. Approximately 90% of individuals used antipsychotics during the follow-up; first-generation agents were more common in Sweden, and clozapine and antipsychotic polypharmacy were more common in Finland. About half of the patients had concurrent antipsychotic and antidepressant use, whereas mood stabilizers were used in 41% of the Swedish and 47% of the Finnish cohort. Benzodiazepines/Z-drugs were used in 72% of the Swedish and 61% of the Finnish cohort.

In both groups, use of clozapine (HR, 0.49-0.50), LAIs, and polypharmacy (HR, 0.51-0.57) were consistently associated with a decreased risk of inpatient hospitalization versus antipsychotic nonuse 

). Notably, quetiapine use was not associated with a decreased risk of psychosis hospitalization in either country. In sensitivity analyses, the pattern of findings was similar.

Antipsychotics plus mood stabilizers were associated with a 16% to 24% decreased risk of a psychosis hospitalization (HR, 0.76-0.84). Antidepressant use was associated with a 10% decreased risk of inpatient hospitalization in the Swedish cohort (HR, 0.90), but not in the Finnish cohort (HR, 1.00). By contrast, Z-drug use was associated with a 7% to 21% increased risk of hospitalization, even after censoring the first 30 days of use. The overall pattern of findings remained similar with the broader outcome of any psychiatric hospitalization (instead of hospitalization for 

The authors found that exposure to antipsychotics was associated with a decreased risk for inpatient hospitalization in patients with schizoaffective disorder. Furthermore, the combination of antipsychotics and adjunctive mood stabilizers (versus antipsychotic monotherapy) was also associated with lower risk of psychosis hospitalization. The evidence was much less robust for adjunctive antidepressants. Adjunctive use of benzodiazepines/Z-drugs was associated with an increased risk of hospitalization.

Study strengths include the use of 2 large nationwide cohorts with multiple years of follow-up and use of the within-individual model, which inherently controls for time-invariant covariates. Study limitations include the lack of availability of some clinically relevant factors and the potential diagnostic uncertainty of register-based data.

The use of antipsychotics, particularly clozapine and LAIs, and adjunctive mood stabilizers was associated with a decreased risk of hospitalization for psychosis among individuals with schizoaffective disorder in 2 nationwide cohorts. In contrast, benzodiazepines/Z-drugs were associated with an increased risk of psychosis-related hospitalization. Future studies of adjunctive treatments should consider the bipolar and depressive subtypes of schizoaffective disorder separately.

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 & Behavior Research Foundation, and the Stanley Medical Research Institute

1. Murru A, Pacchiarotti I, Nivoli AM, et al. What we know and what we don’t know about the treatment of schizoaffective disorder. 

2. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th revision. World Health Organization; 1992.

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013.

4. Peterson DL, Webb CA, Keeley JW, et al. The reliability and clinical utility of ICD-11 schizoaffective disorder: a field trial. 

5. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al. Does schizoaffective disorder really exist? A systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders. 

6. Lintunen J, Taipale H, Tanskanen A, et al. 

Long-term real-world effectiveness of pharmacotherapies for schizoaffective disorder

There is debate whether schizoaffective disorder is a separate illness or is part of the continuum of schizophrenia and mood disorder spectrum. 

Which Pharmacotherapies Are Most Effective for Schizoaffective Disorder?

The US Food and Drug Administration (FDA) has accepted for filing BioXcel Therapeutics’s New Drug Application (NDA) for BXCL501 for the treatment of agitation associated with schizophrenia and bipolar disorders I and II.

“The filing of our NDA marks an important milestone toward our goal to provide a new treatment option for the millions of patients with schizophrenia and bipolar disorders struggling with acute agitation,” said Vimal Mehta, PhD, Chief Executive Officer of BioXcel. “We believe that BXCL501, if approved, would represent a significant improvement in the care and management of agitation in these patients, potentially easing the burden for physicians and allied caregivers.”

BXCL501 is an orally dissolving, thin film formulation of dexmedetomidine, a selective alpha-2a receptor agonist for the treatment of agitation and opioid withdrawal symptoms.

The application is supported by data from 2 randomized, double-blinded, placebo-controlled, parallel group phase 3 studies, SERENITY I & SERENITY II. SERENITY I studied, agitation associated with schizophrenia, while SERENITY II sought to understand agitation associated with bipolar disorders I and II. In both trials, BXCL501 was well-tolerated and met the primary and secondary endpoints at the 120 mcg and 180 mcg doses. Both trials also demonstrated statistically significant, rapid improvements from baseline versus placebo across multiple agitation scales.

“While the FDA reviews our application, we will continue to execute on our comprehensive commercial strategy to ensure we are well positioned for potentially bringing BXCL501 – which is designed to address an important unmet need – to both patients and health care providers across the US,” said Mehta.

The FDA has assigned a Prescription Drug User Fee Act target action date of January 5, 2022. At this time, the FDA is not planning to hold an advisory committee meeting to discuss the application.

1. BioXcel Therapeutics. BioXcel Therapeutics announces FDA acceptance for filing of NDA for BXCL501 for the acute treatment of agitation associated with schizophrenia and bipolar disorders I and II. May 19, 2021. 

https://www.biospace.com/article/releases/bioxcel-therapeutics-announces-fda-acceptance-for-filing-of-nda-for-bxcl501-for-the-acute-treatment-of-agitation-associated-with-schizophrenia-and-bipolar-disorders-i-and-ii/

This treatment for agitation associated with schizophrenia and bipolar disorder is moving up the FDA ladder… 

Drug for the Treatment of Agitation Moves Closer to Reality

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.

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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.

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

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