Chris Aiken, MD

Changing a single ingredient in the diet rarely makes a difference in studies of depression. 

, soy, and matcha tea have all been tried without success.

 Instead, nutritional psychiatry research has 

 the best antidepressant effects with a balanced, Mediterranean-style diet.

 But a small trial of almond supplementation in diabetes shows promise.

The study was a small, randomized controlled 

 of 45 Chinese adults with type-II diabetes.

 All of the subjects were counseled to adopt a low-fat diet that was rich in vegetables and protein and low in salt and carbohydrates. The control group was allowed a daily serving (300 grams) of a carbohydrate-rich food (in China, this was typically rice or noodles), while the intervention group cut that carb dish in half and replaced it with 56 grams of almonds (about half a cup).

After 3 months, those in the almond group had a significant reduction in depression on the self-reported PROMIS scale, while the average mood of the control group did not budge. The effect size was large (0.94 using Hedges’ correction for small sample sizes), although the statistical spread on that effect was wide (+/- 0.62). Importantly, the investigators did not require a diagnosis of depression to enter the trial. On average, their scores (49) fell just below the 55-point cut-off for mild depression on the 

, although some had moderate or severe depression (up to 81 on the PROMIS).

Metabolic parameters (weight and glycated hemoglobin (HbA1c)) improved significantly with both diets, although the reduction in HbA1c was larger (by 1 point) in the almond group (p < 0.01). Next, the investigators looked at changes in the gut microbiome to clarify the mechanism behind this antidepressant effect.

A diverse microbiome in the GI tract is associated with both metabolic and mental health. The gut bacteria 

 with the brain through multiple pathways, including the vagus nerve, inflammatory signaling, and short-chain fatty acids.

 microbiome diversity improved in both groups, but the almond group had a significant increase in bacterial species that produce short chain fatty acids (

). This type of bacteria stimulates production of the metabolic hormone glucagon-like peptide-1, which lowers appetite and regulates insulin. Supporting this hypothesis, levels of glucagon-like peptide-1 rose throughout the trial in the almond group.

is the Mood Disorders Section Editor for 

 He has written several books on mood disorders, most recently 

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

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

Effects of walnut consumption on mood in young adults-a randomized controlled trial.

2. Simpson EEA, Furlong ON, Parr HJ, et al. 

The effect of a randomized 12-week soy drink intervention on everyday mood in postmenopausal women.

3. Dietz C, Dekker M, Piqueras-Fiszman B. 

An intervention study on the effect of matcha tea, in drink and snack bar formats, on mood and cognitive performance

A randomised controlled trial of dietary improvement for adults with major depression (the 'SMILES' trial).

An almond-based low carbohydrate diet improves depression and glycometabolism in patients with type 2 diabetes through modulating gut microbiota and glp-1: a randomized controlled trial.

Minimally important differences and severity thresholds are estimated for the PROMIS depression scales from three randomized clinical trials

7. Bastiaanssen TFS, Cowan CSM, Claesson MJ, Dinan TG, Cryan JF. 

Making sense of … the microbiome in psychiatry.

Subba R, Sandhir R, Singh SP, Mallick BN, Mondal AC. 

Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control.

Qian F, Liu G, Hu FB, Bhupathiraju SN, Sun Q. 

Association between plant-based dietary patterns and risk of type 2 diabetes: a systematic review and meta-analysis

Francis HM, Stevenson RJ, Chambers JR, Gupta D, Newey B, Lim CK. 

A brief diet intervention can reduce symptoms of depression in young adults - A randomised controlled trial.

Parletta N, Zarnowiecki D, Cho J, et al. 

A Mediterranean-style dietary intervention supplemented with fish oil improves diet quality and mental health in people with depression: A randomized controlled trial (HELFIMED).

Sánchez-Villegas A, Martínez-González MA, Estruch R, et al. 

Mediterranean dietary pattern and depression: the PREDIMED randomized trial.

Articles

A daily serving of almonds improved depressive symptoms in diabetes, but will it work in non-diabetic depression?

Almonds May Lift Depression in Diabetes

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 

 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.

Podcasts

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.

Table 1. Lumateperone in Bipolar Depression

Table 2. 5 Atypical Antipsychotics in Bipolar Depression

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.

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.

8. Suppes T, Silva R, Cucchiaro J, et al. 

Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo-controlled study.

Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia.

A phase 2, randomized, double-blind, placebo-controlled study of adjunctive pimavanserin in patients with major depressive disorder and an inadequate response to therapy (CLARITY).

11. Chapel S, Chiu YY, Hsu J, Cucchiaro J, Loebel A. 

Lurasidone dose response in bipolar depression: a population dose-response analysis.

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

A New Option for Bipolar Depression

Not long ago, tranquilization was an important goal of psychopharmacology, and sedation was integral to this therapeutic effect. Major tranquilizers (ie, antipsychotics) sedated psychosis and mania, while minor ones (ie, benzodiazepines) calmed the anxious mind. Even antidepressants were thought to 

, in part because insomnia is a symptom of depression, but also because of concerns that patients might act on suicidal impulses if their energy improved before their depression did.

Table 1. Sedative Effects of Psychiatric Medications

Table 2. The Most and Least Sedating Antidepressants Within Each Class 

Table 3. Antipsychotics and Sedation Effects

Those ideas were put to rest in the 1990s, as nonsedating medications proved just as effective as their sedating predecessors. Rather than forewarning suicide, early increases in energy and physical activity are actually a 

 Improved functioning is the goal in psychopharmacology, and sedation usually does not contribute to that goal.

Introduction: Finding Solutions While Managing Problems

Addressing Obesity in Patients Taking Antipsychotics

Sedation: The Ups and Downs of a Side Effect

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


Robert Drury, Brendan King, Caleb Natale, Wayne Hellstrom, MD

Sedation is sometimes desirable and sometimes not. It is desirable when treating 

, as long as the sedative effects do not linger into the morning. It can also be life-saving when treating acute agitation in emergency situations. Increased activity does not foretell a positive outcome, and may even be a risk factor for suicide, when it is due to adverse effects like 

The simplest way to manage unwanted sedation is to choose medications that are less likely to cause it. 

 ranks psychiatric medications by their sedation risk, based on meta-analyses of clinical trials and data from the US Food and Drug Administration (FDA)

 Although these analyses arrived at fairly consistent conclusions, 

 is still only an approximation. The relative rankings apply within each class, but some classes as a whole are more sedating than others, particularly the antipsychotics.

Surprisingly, the traditional mood stabilizers, particularly lithium, are not nearly as sedating as the antipsychotics. Lithium has been reported to cause sedation in about 1 in 16 to 1 in 27 patients, depending on the study. With most second-generation antipsychotics, this rate is 

 While lithium may not cause much drowsiness, it does cause adverse effects that can be mistaken for sedation, like motoric and cognitive slowing, especially in higher concentrations.

There are 2 nonsedating antidepressants that have stimulant-like properties: bupropion and tranylcypromine. Tranylcypromine is a monoamine oxidase inhibitor (MAOI), but it is structurally related to amphetamine and has dopaminergic effects in the brain. Both of these medications are best dosed in the morning. However, their stimulating effects do not necessarily mean that they will disrupt sleep quality, as we will see later in this review. 

 shows the most and least sedating antidepressants within each class.

Sedation is rarely encountered when treating 

 (ADHD) with traditional stimulants, but it can be a problem with the nonstimulant treatment options. Sedation is a well-known side effect of the α2 agonists, particularly clonidine, but new data suggests that atomoxetine may also carry a high risk. In clinical trials of atomoxetine, only 1 in 20 patients reported fatigue.

 However, in the FDA postmarketing reporting system, atomoxetine ranked second for its propensity to prompt reports of somnolence. (The study ranked atomoxetine against 30 antidepressants since it has an antidepressant structure).

 If fatigue was rare in clinical trials of atomoxetine, why did it prompt so many reports of somnolence? The best explanation for this discrepancy is that peak plasma levels of atomoxetine can be 10-fold higher in CYP2D6 poor metabolizers. Therefore, while fatigue may be rare with this drug, it is likely to be quite severe in patients that do experience it.

When it comes to antipsychotics, finding a nonsedating option is like navigating between the fabled 

. Patients tend to experience akathisia when we select the less sedating options like lurasidone, risperidone, cariprazine, and aripiprazole. The more sedating ones, such as clozapine, olanzapine, quetiapine, and ziprasidone, are less likely to cause 

. When patients cannot tolerate either of these side effects, brexpiprazole and iloperidone are good options, with number needed to harm (NNH) above 30 for both sedation and akathisia.

 Lumateperone is also relatively free of akathisia, and its sedative effects are usually manageable with evening dosing.

Some medications are so sedating that this adverse effect limits their use. This is particularly true when they are taken in the morning, as is often the case for the short half-life medications that are given in divided doses. Quetiapine (half-life, 6 hours), ziprasidone (7 hours), clozapine (12 hours), and trazodone (5 to 9 hours) were all recommended for twice daily dosing when they were first released, based on the half-lives of the drugs. However, pragmatic physicians soon began dosing these medications at night without any loss of efficacy. This strategy is supported by about a dozen clinical trials comparing evening dosing to divided dosing in patients with schizophrenia and mood disorders.

 Asenapine could also be added to that list, as it was originally recommended to be given in divided doses but has a 24-hour half-life.

Sedation can be an asset when these short half-life medications are given at night, as their sedative effects are generally limited to the hours of sleep. The major risk with this strategy is orthostasis, particularly in older patients. For quetiapine, the extended-release version reduces this risk by smoothing over the peak levels.

When switching medications is not an option and evening dosing does not relieve sedation, antidotes may help, but are not consistently helpful. Modafinil and armodafinil improved residual fatigue in both bipolar and unipolar depression, but the benefit was small (effect size = 0.15).

 to improve fatigue in studies of patients with schizophrenia, although those trials were probably underpowered to detect the difference.

 Traditional stimulants have even less evidence of benefit and carry more risks. Concerns about tolerance, addiction, psychosis, mania, and cardiovascular risks significantly limit their use.

Psychiatric medications may cause fatigue through direct sedative effects or by worsening sleep quality. When medications make it difficult for a patient to fall asleep, the effect is usually readily apparent to the patient. When they disrupt sleep quality, the cause is less apparent. Poor sleep quality causes a variety of problems, some of which can be mistaken for symptoms of psychiatric disorders (eg, daytime fatigue, trouble concentrating, irritability, slowed reaction time, and poor problem-solving abilities).

Serotonergic antidepressants can cause both initiation insomnia and restless, fragmented sleep.

 The sedative effects of these antidepressants generally parallel their tendency to disrupt sleep, suggesting that poor sleep quality may be part of the reason that patients feel tired on these medications.

On the other hand, some antidepressants (eg, bupropion, levomilnacipran, and vortioxetine) have low rates of both sedation and insomnia.

 Despite its stimulating effects, bupropion actually improves sleep quality, increasing slow-wave sleep and reducing REM 

 Bupropion can cause difficulty falling asleep, but it does so at about the same rate as the selective serotonin reuptake inhibitors (SSRIs).

 Vortioxetine has not been adequately tested in a sleep lab, but it was 

 to normalize sleep architecture in an animal study and, in a post hoc analysis of a clinical study, it improved subjective reports of sleep quality.

If a patient needs a sedative to fall asleep, mirtazapine and trazodone both achieve this effect without worsening sleep quality. These antidepressants increase the slow waves that characterize the deepest stage of sleep.

 Likewise, the sedating antipsychotics usually do not worsen sleep quality, and may, in fact, improve it (

Quetiapine improved sleep quality, increased sleep efficiency, and reduced nocturnal awakenings in patients with bipolar disorder. Olanzapine, risperidone, and ziprasidone also resulted in improvements in sleep quality, beyond their effects on sleep initiation.19 Lumateperone, which shares a serotonin 5-HT2A receptor antagonist effect with trazodone, was originally developed as a hypnotic before gaining approval in schizophrenia. Taken nightly, in low doses (1-10 mg hs), lumateperone improved sleep without causing next-day sedation.

 These sedating options may provide dual benefits when patients require an antipsychotic for schizophrenia or a mood disorder, but antipsychotics have too many risks to justify their use for insomnia alone.

Sedation may not always be desirable, but it is difficult to avoid in psychiatry. Some of the most sedating medications have unique benefits that may justify their use (

 Evening dosing may improve tolerability, as long as adverse effects that are linked to the peak serum level do not get in the way. Orthostasis, for example, can cause a problem when antipsychotics and some antidepressants (eg, trazodone, mirtazapine, tricyclics, MAOIs) reach peak levels.

On the other hand, it is not necessary to jump to a sedating medication just because a patient has trouble sleeping. Some of these medications, like the SSRIs and the serotonin-norepinephrine reuptake inhibitors, worsen sleep quality. In fact, sleep may improve with an activating medication, either because it deepens sleep quality as bupropion does, or because it helps the patient reset their circadian rhythm. Patients tend to sleep better when they rise at regular times and stay active during the day.

is an instructor in clinical psychiatry at the Wake Forest School of Medicine and the director of the Mood Treatment Center in Winston-Salem, North Carolina. He is editor-in-chief of 

and coeditor of the Bipolar Disorder Section for 

Sedation may not always be desirable, but it is difficult to avoid in psychiatry. Some of the most sedating medications are discussed.

Chris Aiken, MD

Articles

Almonds May Lift Depression in Diabetes

Dosing Tips for Lithium: How to Improve Tolerability

A New Option for Bipolar Depression

Sedation: The Ups and Downs of a Side Effect

The Mighty Blueberry

How to Treat Anxiety in Bipolar Disorder

Adult-Onset ADHD Raises Questions

How to Switch Stimulants: A Dosing Guide for ADHD

5 Types of Anxious Bipolar Disorder

Can Food Treat Depression?