Chris Aiken, MD

 had a problem, and the medications weren’t solving it. “I've taken a lot of Prozac, Paxil, Wellbutrin, Effexor, Ritalin, Focalin. I’ve also studied deeply in the philosophies of the religions, but cheerfulness kept breaking through.”

The “cheerfulness” Cohen complained of was a wry euphemism for something darker. The poet, novelist, and songwriter had “dealt with depression ever since my adolescence. . . Moving into some periods, which were debilitating, when I found it hard to get off the couch, to periods when I was fully operative, but the background noise of anguish still prevailed.”

By his mid-60s Cohen had been through several hospitalizations and tried tricyclics, MAOIs, second generation antidepressants, and anticonvulsants without success. Despite releasing one of the most successful albums of his career, The Future, he found himself “really, really low, on many medications . . . I pulled my car over to the side of the road. I took out all the medication and threw it out the window.”

A few years later the depression lifted, and, by Cohen’s report, it did not return. Depression is overdetermined, to borrow Freud’s phrase, and its resolution is equally mysterious. But a new study sheds light on some of the forces that may have been at play in Cohen’s recovery.

Cohen’s depression had reached “a certain unendurable point” in 1994. He retreated from public life and joined a 

, where he was later ordained as a monk. There he learned to shift his focus away from the “loyalty and the tyranny” of his inner thoughts-the self-focused, ruminative kind that come with depression.

Rumination is a repetitive pattern of thought that plagues many patients with depression. It is also a strong predictor of depressive relapse. Rumination is problem solving gone awry, brooding over unresolvable conflicts and questions that can’t be answered. “Why am I such a loser . . . When will this end . . . What do people really think of me . . . What is the point?” Rumination arises from the brain’s default mode network, which engages in thoughts about the self, the future, and the social world.

 The default mode is activated when we’re bored, uncomfortable, or lonely. For people who are prone to depression, the slightest trigger will turn it on.

Yet there is a brighter side to the dark imaginations of the default mode. When not conjuring foreboding possibilities, it can dream up creative solutions and inspire great art. That might explain why so many creative thinkers have strong ruminative tendencies.

 That dogged style of thought also lends itself to the persistence that is necessary to create great works. As Cohen described it, songwriting was an act of drudgery where “you’re not doing anything else but trying to find the rhyme for ‘orange.’ It doesn’t exist. Some people say it’s ‘door hinge,’ but that’s not right.”

Buddhism did not answer Cohen’s ruminative questions. In his words, it simply “dissolved them.” Psychologists call this metacognitive awareness. It is the ability to see one’s thoughts objectively, with some detachment, and it is a strong predictor of sustained remission from depression.

 It is also a key ingredient in mindfulness, which is derived from the kind of Buddhist practice that Cohen pursued.

Twenty years after Cohen’s recovery, a remarkable study came out of 

, the same Indian city where Cohen broke free from his depression.

 It was a controlled trial of Buddhist meditation for bipolar II depression. By psychotherapy standards, the study was huge, with 622 patients. Half were randomized to cognitive behavioral therapy, and the other half underwent training in meditation. The study lasted 2 years, during which the meditation group was advised to follow a simple 30-minute practice once a week (see 

). That is correct-only 30 minutes per week. The teaching was also low intensity: 5 to 10 two-hour sessions interspersed throughout the 2-year study.

 (CBT) group with a large effect size (0.7). How did this mild intervention outperform cognitive behavioral therapy with such a large effect?

The secret may lie in the 2-year duration. That is how long it took Leonard Cohen’s mood to lift “by imperceptible degrees” while he studied meditation in Mumbai. Other behavior changes, like exercise and social rhythm therapy, also show more robust effects when allowed to build for 6 to 12 months. The challenge is to help patients stay motivated through those imperceptible degrees of progress.

This article was originally posted on March 26, 2020, and has since been updated. -Ed

is the Mood Disorders Section Editor for 

, and the Director of the Mood Treatment Center. He has written several books on mood disorders, most recently 

 podcast with his co-host Kellie Newsome, PMH-NP. Dr Aiken does not accept honoraria from pharmaceutical companies but receives royalties from PESI for T

The default mode network and social understanding of others: what do brain connectivity studies tell us

. 2014;8:74.
	2. Perkins AM, Arnone D, Smallwood J, Mobbs D. 

Thinking too much: self-generated thought as the engine of neuroticism

. 2015;19:492-498.
	3. Teasdale JD, Moore RG, Hayhurst H, et al. 

Metacognitive awareness and prevention of relapse in depression: empirical evidence

Meditation for treating adults with bipolar disorder II: a multi-city study

Articles

A recent study shows that meditative practice is surprisingly effective for bipolar depression. The late poet helps explain why.

What Leonard Cohen Can Teach Us About Depression

Slideshows

These mood stabilizers cover a lot of ground, but it is important to know how to use them.

Dosing Secrets for the Top Mood Stabilizers

I’ve been pouring over textbooks and treatment guidelines, and these four mood stabilizers keep rising to the top.

 None of them are perfect, but each has a unique role in bipolar disorder:

Lithium and quetiapine top the lists for all three phases of the illness: mania, depression, and the maintenance phase. Lurasidone and lamotrigine are either untested (lurasidone) or ineffective (lamotrigine) in mania, but they are essential tools for bipolar depression.

Lithium stands out for its preventative effects in bipolar disorder, but it also has important benefits outside of the manic-depressive symptom lists. It is the only mood stabilizer that significantly reduces the risk of suicide, and it reduces mortality in other ways as well. Although lithium is often avoided out of concerns of toxicity, it actually lowers the risk of cancer, heart disease, stroke, and viral illnesses.

 All of those occur at higher frequency in bipolar disorder. Vascular disease is the leading cause of death in bipolar disorder,

 and viral illnesses are both a consequence (ie, STDs) and cause (ie. inflammatory effects) of bipolar symptoms.

 bipolar disorder tend to respond best to lithium. They are characterized by full remission between episodes, predominance of manic over depressive symptoms, illness onset in late teens, and a family history of bipolar disorder. They also tend to lack significant mixed states, rapid cycling, and psychiatric comorbidities, although a recent study found that comorbid panic disorder predicted lithium response.

Quetiapine covers ground that lithium does not. It is more effective against mixed manias, while lithium is preferred for the purer, euphoric highs. It also works better in acute depressive episodes. Quetiapine cannot claim the medical benefits that lithium does, but it does assist with two symptoms that patients find particularly troubling: anxiety and insomnia.

 Although its long-term adverse effects give me pause, it did provide the best protection against both poles of the illness in Terrence Ketter’s analysis of the numbers needed to treat (NNT) for long-term maintenance.

Lurasidone (Latuda) and Lamotrigine (Lamictal)

Both of these occupy a unique niche in bipolar depression. Lurasidone is the more effective of the two, with a number needed to treat (NNT) of 5 compared to lamotrigine’s 12.

 But lamotrigine is the better tolerated option, with few of the adverse effects that matter most to patients: weight gain, fatigue, sexual dysfunction, and long-term medical risks. Lamotrigine is better at preventing depression than it is at treating it.

There is some evidence that lamotrigine works better in bipolar II disorder, where frequent cycles of depression predominate, than bipolar I.

 Some experts favor it for the rapid mood fluctuations of cyclothymic disorder, and I’ve found it useful there as well.

 The main risk of lamotrigine is during the first three months of treatment, when Stevens-Johnson syndrome and other life threatening allergic reactions can occur at a rate of about 1:3000.

Long-term tolerability is not the strong suit of atypical antipsychotics like lurasidone, but these medicines can work quickly to get patients out of severe episodes. The ones that 

 are cariprazine (Vraylar), lurasidone (Latuda), olanzapine-fluoxetine combo (Symbyax), and quetiapine (Seroquel). Among them, lurasidone offers a good balance of efficacy and tolerability. Lurasidone’s main problems â nausea, akathisia, cost, and lack of evidence in mania â are less likely to occur with quetiapine, so patients who cannot tolerate one will often tolerate the other.

Matching the mood stabilizer to the patient is a matter of balancing competing goals. Each stands out in its own way, whether for tolerability, treatment of comorbidities, or benefits in depression, mania, or the maintenance phase. Together, these four treatments cover lot of ground, but you also need to know how to use them. That is covered in the next installment.

 His 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 

1. Parker GB, Graham RK, Tavella G. Is there consensus across international evidence-based guidelines for the management of bipolar disorder? 

2. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. 

3. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. 

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

5. Mohammad O, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for acute mania. Harv Rev Psychiatry. 2014;22(5):274â294.

Advances in Treatment of Bipolar Disorders,

 1st Edition. American Psychiatric Publishing, Washington, DC.

7. Post RM. The new news about lithium: An underutilized treatment in the united states. 

8. Weiner M, Warren L, Fiedorowicz JG. Cardiovascular morbidity and mortality in bipolar disorder. 

9. Tucker JD, Bertke AS. Assessment of cognitive impairment in HSV-1 positive schizophrenia and bipolar patients: Systematic review and meta-analysis. 

10. Scott J, Bellivier F, Manchia M, et al. Can network analysis shed light on predictors of lithium response in bipolar I disorder?

11. Pompili M, Rihmer Z, Gonda X, Serafini G, Sher L, Girardi P. Early onset of action and sleep-improving effect are crucial in decreasing suicide risk: the role of quetiapine XR in the treatment of unipolar and bipolar depression. 

12. Wang Z, Kemp DE, Chan PK, et al. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. 

13. Terao T, Ishida A, Kimura T, Yarita M, Hara T. Preventive effects of lamotrigine in bipolar II versus bipolar I disorder. 

14. Manning JS, Haykal RF, Connor PD, Cunningham PD, Jackson WC, Long S. Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament. 

None of them are perfect, but a few rise to the top, according to recent guidelines.

Top Mood Stabilizers for Bipolar Disorder

Recovery from depression is a process, and patients need steady, realistic guidance to move through each stage. Insights here.

5 Things to Say to Patients With Depression

For the accompanying podcast to this piece, see 

Psychiatric medications have been fighting infections for decades. The MAOIs were originally used to treat tuberculosis. Thioridazine has been rediscovered as a treatment for antibiotic-resistant infections,

 and lithium doubles as an antiviral agent.

, I speak with Janusz Rybakowski, MD, PhD, a pioneer in lithium research who helped discover its antiviral properties.

The first inklings of lithium’s antiviral effects came from observations that patients were less likely to catch the common cold, or rhinovirus, while on the medicine. Lithium improves immune function, increasing neutrophil count as well as lymphocytes, leukocytes, and natural killer cells. But lithium’s antiviral properties extend beyond that. It directly impedes viral replication in animal and 

This was first discovered in the 1980s with the herpes family of viruses. Lithium treated and prevented labile herpes, whether taken orally or as a topical ointment. Since then, lithium has demonstrated antiviral activity against over a dozen viruses, both DNA and RNA types. These include HIV, cytomegalovirus, Epstein-Barr virus, pseudorabies virus, vaccinia, adenovirus, gastroenteritis virus, measles, coxsackievirus, multiple herpetic viruses, and four strands in the coronavirus family.

Lithium has never been tested against the current coronavirus, officially known as 

severe acute respiratory syndrome coronavirus 2

. Janusz Rybakowski, MD, PhD, who conducted some of the early studies of lithium’s antiherpetic viral effects, sees potential in lithium and plans to organize an international study comparing COVID-19 outcomes in lithium-treated vs. non-lithium treated patients with mood disorders.

Lithium shares a common mechanism with chloroquine, the antimalarial drug that is being explored as a treatment for COVID-19. Both inhibit glycogen synthase kinase 3 (GSK3), a mechanism that is implicated in other antiviral therapies.

 There is an important difference between chloroquine and lithium, however. Chloroquine is associated with numerous adverse psychiatric effects, particularly psychosis, mania, and emotional lability.

We are a long way from knowing whether lithium treats the novel coronavirus and whether its risks will outweigh its benefits there. In the meantime, it is reassuring for patients who are taking lithium to know that lithium has pro-immune and antiviral properties. We warn patients about the medical risks of lithiumâhypothyroidism, renal insufficiency, cardiac arrhythmia, and drug toxicityâbut we need to inform them of its medical benefits as well. Besides its antiviral effects, lithium lowers the risks of stroke, heart disease, cancer, and neurologic illnesses, particularly dementia. In mood disorders, lithium lowers the all-cause mortality rate as well as the rate of 

Viral illnesses also put patients at risk for lithium toxicity, and they should be advised of these preventative steps (see 

Avoid NSAIDs like naproxen and ibuprofen, as these can raise lithium levels. Instead, use acetaminophen for fever control.

If severe vomiting or diarrhea ensues, physicians should hold lithium until the problem resolves.

1. Lagadinou M, Onisor MO, Rigas A, et al. Antimicrobial properties on non-antibiotic drugs in the era of increased bacterial resistance. 

2. Rybakowski JK. Antiviral and immunomodulatory effect of lithium. 

3. Puertas MC, Salgado M, MorÃ³n-LÃ³pez S, et al. Effect of lithium on HIV-1 expression and proviral reservoir size in the CD4+ T cells of antiretroviral therapy suppressed patients. 

4. Nowalk JK and Walkowiak J. Lithium and coronaviral infections. A scoping review. [version 2; peer review: 1 approved, 1 approved with reservations]. 

 2020, 9:93 (https://doi.org/10.12688/f1000research.22299.2)

5. Post RM. The new news about lithium: an underutilized treatment in the united states. 

6. Chen PH, Chao TF, Kao YH, Chen YJ. Lithium interacts with cardiac remodeling: the fundamental value in the pharmacotherapy of bipolar disorder. Prog Neuropsychopharmacol 

Lithium may have antiviral properties, but it also carries unique risks during a viral infection.

Lithium in a Time of Coronavirus

In this podcast, I speak with Janusz Rybakowski, PhD, MD, a pioneer in lithium research who helped discover its antiviral properties.

Lithium has successfully deterred over a dozen viruses, but how will it affect the novel coronavirus? In this podcast, Chris Aiken, MD, speaks with Janusz Rybakowski, PhD, MD, a pioneer in lithium research who helped discover its antiviral properties.

The Antiviral Side of Lithium

Sleep deprivation increases the risk of viral infections and even mania. Here is the evidence.

Can Good Sleep Prevent a Virus?

Chris Aiken, MD, provides practical tips to help clinicians get started or to hone their skills in telepsychiatry.

Practical tips to help clinicians get started or to hone skills in telepsychiatry.

Telepsychiatry Comes of Age, Reluctantly

It is not unusual to exhaust the FDA-approved therapies for bipolar depression. That is when we find ourselves in the half-tested world of off-label therapies. I have tried most of them, from anti-inflammatories to melatonin agonists, and the one that I have seen the biggest difference with is the dopamine agonist pramipexole.

 dopamine receptors in the nucleus accumbens, also known as the “pleasure center.” What that suggests is that it is uniquely suited to address two cardinal symptoms of depression: low motivation and anhedonia. In two small, randomized controlled trials, pramipexole treated bipolar depression when added to a mood stabilizer, and the effect size was large (0.77-1.1).

Pramipexole also worked in controlled trials of unipolar depression, so it is a good choice when the patient’s diagnosis is unclear, such as those who don’t have full hypomania but have a family history of bipolar disorder and moods that seem to worsen with antidepressants.

Tolerability is one of pramipexole’s strong suits. It does not tend to cause weight gain, sexual dysfunction, or cognitive problems. The main adverse effects are nausea, which usually improves with time, and fatigue, which rarely lasts into the morning.

Medically, pramipexole is less risky than most conventional choices for bipolar depression. There is a possible risk of congestive heart failure, and though the studies are mixed on that it is concerning enough to warrant caution in those with heart disease.

 Edema can be seen in those of advanced age or compromised vascular function, and its appearance should prompt a consultation with the primary care provider and a reduction or cessation of the medication.

 Orthostatic hypotension is another cardiovascular risk to watch out for on pramipexole.

The two psychiatric risks to worry about on pramipexole are hallucinations and compulsive behavior.

Pramipexole does not seem to cause overt psychosis but can cause hallucinations, particularly visual ones. Patients see shadows or small creatures, usually with good insight and little distress about it. This adverse effect is rare in the mood disorder population (< 1%) and there are no reports of delusions on the drug. Nor has pramipexole exacerbated psychosis in schizophrenia, where it has been studied for negative symptoms, extrapyramidal symptoms, and hyperprolactinemia.

In contrast, it is patients with Parkinson disease (PD) who have the greatest risk of hallucinations on pramipexole, where it is often used with FDA approval to relieve motoric symptoms. Problems with compulsivity, such as pathological gambling, are also more common in the PD population.

Pramipexole’s ability to increase hedonic drive is a blessing and a curse. On the one hand, it can make a patient more active and motivated. Rarely, that can morph into benign compulsivity. Bookshelves are sorted alphabetically, closets compartmentalized into tidy bins, and garages turn spick and span. Patients are more often amused than bothered by these tendencies, which they prefer hands-down over their recent depression. Taken too far, however, and problems start to happen. Pathological gambling is the most notorious, but more often it crops up as overspending on Amazon and eBay, excessive masturbation, or binge eating.

The neurologic term for this syndrome is hedonistic homeostatic dysregulation (HDD). It is seen with other D

 agonists, such as aripiprazole which carries a warning about “uncontrollable urges to gamble, binge eat, shop, and have sex.” HDD is distinct from mania, and there are no reports of HDD in the 504 subjects who participated in the mood disorder studies.

 Though rare, it is worth asking about in practice as it can lead to severe problems and patients may not associate it with the drug. The cases I have seen were not associated with manic features and improved with dose reduction or complete cessation of the treatment.

Pramipexole works as monotherapy in unipolar depression, but in bipolar disorder it should be taken in concert with a mood stabilizer. That could be lithium, valproate, or, in bipolar II patients, lamotrigine. It can also be taken with an antipsychotic, as most of these antagonize a different dopamine receptor (D

). Some, particularly haloperidol, are inverse agonists at the pramipexole site, D

 (ie, they have the opposite effect there), but pramipexole has been studied in haloperidol-treated patients with good effect. A few antipsychotics might synergize D

effects of pramipexole, such as aripiprazole, brexpiprazole, cariprazine, and lumateperone, which are partial D

The ideal candidate for pramipexole is a patient with full bipolar depression who lacks mixed or psychotic features and has not recovered on FDA-approved options. Dosing is best at night, although a few find it “activating” and do better with morning dosing. Start with 0.125 mg to 0.25 mg qhs and raise by 0.25 mg every 5 to 7 days. Nausea is the most common reason for discontinuation, and effective antidotes include ondansetron (4 mg q8 hr prn), a proton-pump inhibitor like pantoprazole (40 mg qd), or 

Use a rating scale to monitor progress and follow up when the daily dose reaches 0.75 mg. A few are fully recovered at that point, but most are only 25% better and benefit from further titration. The usual dose is 1.5 mg qhs, though some go higher into the 2 mg to 3 mg range.

Pramipexole is not a mood stabilizer, and its long-term effects are largely untested. Open-label studies lasting up to 1.5 years in mood disorders offer some reassurance,

 and in my own experience the theoretical risks of tolerance, manic cycling, or psychosis have not occurred in patients who have remained on it for 10 to 15 years. The decision to discontinue pramipexole medication is a collaborative one, but I would wait 6 to 12 months after recovery before attempting to taper it off, which can be done over 1 to 2 months.

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

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

1. Zarate CA Jr, Payne JL, Singh J, et al. 

Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.

Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression.

Pramipexole in psychiatry: a systematic review of the literature.

4. Tundo A, de Filippis R, De Crescenzo F. 

Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis.

5. Perez-Lloret S, Rey MV, Crispo J, et al. 

Risk of heart failure following treatment with dopamine agonists in Parkinson's disease patients.

6. Montastruc F, Moulis F, Araujo M, Chebane L, Rascol O, Montastruc JL. 

Ergot and non-ergot dopamine agonists and heart failure in patients with Parkinson's disease.

Risk factors for the development of pedal edema in patients using pramipexole.

A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.

Assessing efficacy/effectiveness and safety/tolerability profiles of adjunctive pramipexole in bipolar depression: acute versus long-term data.

When we find ourselves in the half-tested world of off-label therapies, what’s a psychiatrist to do?

An Underutilized Option for Bipolar Depression

Novel Approaches to Bipolar: What Worked, and What Did Not, in 2019

The treatment of bipolar disorder changed in ways big and small in 2019. At the regulatory level, cariprazine (Vraylar) joined a select group of atypical antipsychotics with FDA-approval in bipolar depression, and lithium’s FDA-approval was broadened from age 12 and older to age 7 and older. Besides the official decrees, over a dozen randomized controlled trials were released.

Cariprazine (Vraylar) has been studied for bipolar depression since 2009. Most of the results have been positive for the 1.5 mg daily dose but raising the dose to 3 mg daily has not raised the efficacy. There was a new trial in 2019 with results that are consistent with earlier findings.

Compared with other atypical antipsychotics, cariprazine’s advantage lies in its tolerability profile and its proven efficacy in both mania and depression. The only other atypical with FDA-approval in both poles is quetiapine. However, cariprazine’s positive trials are limited to bipolar I depression (not bipolar II), and its effect size in bipolar I depression is small (0.3), both in this study and in a 

Antipsychotic augmentation after mania: 6 months may be enough

When risperidone was used to augment a mood stabilizer in mania, the antipsychotic continued to prevent manic relapses for up to 6 months, but not beyond that. Longer use (1 year) only lead to more weight gain without further mood benefits, according to a post-hoc analysis of a 2016 study that arrived at the same conclusion (the original study lumped patients on risperidone and olanzapine augmentation together).

 This puts a different spin on the maintenance story, as earlier studies stopped the antipsychotic after 2 to 3 months. That design proved that early discontinuation was riskier than ongoing treatment, but it didn’t tell us whether the medication could be safely stopped at a later point. Discontinuation at 6 months is now feasible, but I would taper slowly, lowering the dose every 2 weeks, and make sure to keep the original mood stabilizer in place.

Lithium’s long-lasting benefits in children

In contrast to risperidone, lithium keeps working to prevent episodes after the 6 month-mark. That was the conclusion of this randomized, placebo-controlled trial of children aged 7 to 12 years. The result is not exactly surprising, as these patients had responded to lithium after a manic or mixed episode, and only 40% were taking another mood stabilizer. What’s impressive is that-by chance-there were 3-times as many patients on a back-up mood stabilizer in the placebo group. Despite that unfair advantage, the placebo group was 

 as the lithium group to have mood and related problems in the 7-month trial (86% vs 35%).

Separately, lithium performed well in a large uncontrolled study from 2019 that followed youth with bipolar disorder for an average of 10 years. Compared with other mood stabilizers, those on lithium had half as many suicide attempts, better functioning, and less depression and aggression.

Carbamazepine and valproate and have long been used to augment lithium, but the two strategies were never compared head-to-head until this year. The number of study subjects was small but the duration was long, which can be just as informative as a large, short-term trial. Both anticonvulsants performed similarly on measures of mania and depression, but carbamazepine was better tolerated, with lower rates of weight gain, fatigue, and sexual dysfunction.

The carbamazepine-lithium combination gained popularity in the 1980s after reports of patients who did not respond to either drug alone but recovered when both were used together. The two medications also cancel out some of each other’s adverse effects. Lithium reverses some of the neutropenia with carbamazepine, and the two have opposite effects on water retention, which partially balances out when they are combined.

Intuition may work for understanding people, but it’s a poor guide for psychopharmacology. Supraphysiologic thyroid does not sound like a good idea for anxious patients, but in this 2019 study it did not worsen anxiety, and anxiety symptoms did not predict its antidepressant effects. The study was a post hoc analysis of a 2014 trial that found that levothyroxine was effective in bipolar depression.

TMS does not harm, and might even help cognition

Bipolar depression responds to both electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), but ECT is limited by its cognitive effects. A study in 2018 of TMS in bipolar disorder concluded that the treatment did not cause cognitive deficits, and in 2019 a small, sham-controlled study in euthymic bipolar patients found that TMS improved cognitive measures.

Two medications for dementia-rivastigmine and memantine-underwent trials in bipolar mania.

 The results were either not significant, or not clinically significant, so I’ll pass on those interventions until there are more data. Next month I’ll review the 2019 trials of anti-inflammatories (celoxib, aspirin, atorvastatin, and pioglitazone), nutraceuticals (N-Acetylcysteine), and five types of psychotherapy in bipolar disorder. The tension will be high; half of the treatments on that list did not work.

 is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. As the Editor in Chief of The Carlat Psychiatry Report, he hosts a weekly podcast with Kellie Newsome on psychiatric practice. He is the coauthor with Jim Phelps, MD, of 

. He does not accept honoraria from pharmaceutical companies.

Editor's note: This article was originally posted on January 9, 2020, and has since been updated.

1. Earley WR, Burgess MV, Khan B, et al. Efficacy and safety of cariprazine in bipolar I depression: a double-blind, placebo-controlled phase 3 study. 

Cariprazine in the treatment of bipolar disorder: a systematic review and meta-analysis

3. Valdes M, Bertolin S, Qian H, et al. Risperidone adjunctive therapy duration in the maintenance treatment of bipolar I disorder: a post hoc analysis

4. Findling RL, McNamara NK, Pavuluri M, et al. 

Lithium for the maintenance treatment of bipolar i disorder: a double-blind, placebo-controlled discontinuation study

5. Hafeman DM, Rooks B, Merranko J, et al. Lithium versus other mood stabilizing medications in a longitudinal study of bipolar youth. 

6. Missio G, Moreno DH, Demetrio FN, et al. A randomized controlled trial comparing lithium plus valproic acid versus lithium plus carbamazepine in young patients with type 1 bipolar disorder: the LICAVAL study. 

7. Aziz R, Aiken C. Harnessing beneficial drug interactions. 

8. Pilhatsch M, J Stamm T, Stahl P, et al. Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms. 

9. Yang LL, Zhao D, Kong LL, et al. High-frequency repetitive transcranial magnetic stimulation (rTMS) improves neurocognitive function in bipolar disorder. 

10. Keshavrzi A, Rezaei H, Haghighi M, Jahangard L. Effect of rivastigmine (acetyl cholinesterase inhibitor) versus placebo on manic episodes in patients with bipolar disorders: results from a double blind, randomized, placebo-controlled clinical trial

11. Omranifard V, Tarrahi MJ, Sharifi S, Karahmadi M. Evaluation of the effect of memantine supplementation in the treatment of acute phase of mania in bipolar disorder of elderly patients: a double-blind randomized controlled trial. 

The treatment of bipolar disorder changed in ways big and small in 2019. More in this summary.

Author | Chris Aiken, MD