Carlos A. Zarate, Jr, MD

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Consider novel, promising strategies for treatment-resistant depression in order to help guide discussions with patients about appropriate treatments.

1. Understand novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

2. Understand currently available and promising neurostimulation treatment options for treatment-resistant depression.

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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Treatment-resistant depression (TRD), which is broadly defined as “the failure to achieve and sustain euthymia with adequate antidepressant treatment,”

 remains a commonly encountered clinical challenge. Treatment response in depression has been characterized by a response curve that demonstrates diminished improvement of symptoms over successive adequate courses of treatment (

 Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study confirm what we know from clinical practice—namely that the chances of adequate symptom resolution are very low (single digits) after 2 initial unsuccessful treatment trials. Approximately one-third of patients do not achieve remission after trials with 4 different conventional treatments. In this context, one definition of TRD is nonresponse to 2 or more antidepressant trials, reflecting this sharp drop-off in response after the second treatment.

A number of organizations (eg, the Canadian Network for Mood and Anxiety Treatments, the National Institute of Health and Care Excellence, and the American Psychiatric Association) have put forth clinical algorithms for the treatment of 

. Current standard treatment options across these guidelines include conventional antidepressant medications (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs]), other antidepressant drugs (eg, 

, mirtazapine, vilazodone, and vortioxetine), combining antidepressants (eg, bupropion [Wellbutrin, Forfivo] or mirtazapine [Remeron] added to an SSRI or SNRI, augmentation strategies that target associated symptoms such as sleep or anxiety (eg, second-generation antipsychotics, 

, lamotrigine [Lamictal], buspirone [Buspar], and thyroid hormone), and psychotherapy. Furthermore, new and developing advances in depression therapeutics now offer the prospect of significant improvement when administered in conjunction with, or as alternatives to, standard treatments. These promising therapies include rapid-acting novel antidepressant drugs as well as neurostimulation interventions.

, a glutamatergic modulator, has antidepressant properties has led to a mechanistically new treatment option for individuals with TRD.

 Furthermore, its rapid antidepressant effects manifest within hours compared with weeks for conventional antidepressants. Currently, intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as 

, available off-label) and intranasal esketamine (FDA approved with a required risk evaluation and mitigation strategy [REMS] monitoring protocol) are the only routes of administration that have sufficient evidence to support their use. The initial controlled trials of IV ketamine (a single infusion of 0.5 mg/kg over 40 minutes) for TRD found that ketamine exerted rapid (typically within hours) antidepressant effects that peaked at 24 hours, with about 70% of patients demonstrating response.

 Response typically lasted 3 to 7 days postinfusion. Ketamine appears to have broad therapeutic properties, demonstrating particular effectiveness for anxious depression, depression with anhedonic features, and suicidal ideation.

Preliminary evidence also suggests its usefulness in treating other disorders comorbid with major depressive disorder (MDD), including obsessive-compulsive disorder (OCD), posttraumatic stress disorder, social anxiety disorder, and 

 Notably, ketamine has also proven effective for difficult-to-treat atypical features.

 Adverse events associated with subanesthetic-dose ketamine (0.5 mg/kg) are typically transient (eg, somnolence/sedation, hypertension, nausea, dissociation), although risk of abuse and/or dependence have not been sufficiently studied. One key limitation is the short duration of antidepressant effects in response to a single administration, which has prompted use of repeat doses of IV ketamine. Such repeat infusions are typically administered twice per week, and treatments are tapered when maximal response has been reached, which appears to maintain remission.

Esketamine is the S-enantiomer of ketamine and demonstrates greater potency at the glutamate NMDA receptor than the R-enantiomer. In clinical trials, intranasal esketamine (twice weekly, 56 or 84 mg) added to conventional antidepressant therapy significantly improved symptoms compared with placebo.

 Intranasal esketamine (Spravato) received FDA approval for the treatment of adults with TRD in March 2019 and for the treatment of adults with MDD with acute suicidal ideation or behavior in August 2020. Given concerns about adverse events, the FDA approved 

 under a REMS, requiring administration and observation in a medically supervised setting. In terms of adverse effects, reports to the FDA through 2020 noted that esketamine was significantly associated with increased risk of dissociation, sedation, and “feeling drunk.”

 Unexpectedly, a small percentage (2.81%) of patients reported onset of suicidal ideation after starting esketamine treatment. Compared with data for venlafaxine, signals remained for suicidal and self-injurious ideation but not for suicide attempt or completed suicide. Despite the difficulty in attributing causality in the population of patients with TRD who receive esketamine, this safety signal warrants further investigation.

A recent systematic review and meta-analysis that conducted a head-to-head comparison of IV ketamine and esketamine found that IV ketamine may hold a slight edge in efficacy in treating both MDD and bipolar depression, despite intranasal esketamine’s FDA approval.

In terms of risks, a few studies have reported relatively minor adverse events associated with IV ketamine. However, given the lack of a REMS protocol with IV ketamine, and a REMS report following each dose of 

, it is likely that the adverse events of esketamine are extensively reported, whereas they are likely underreported for IV ketamine. There is a need for ongoing vigilant adverse events reporting for both treatments.

While consensus on where ketamine should reside in the depression treatment algorithm is still developing, a recent overview suggests that IV ketamine and intranasal esketamine have both demonstrated efficacy for this patient population.

 Both agents may be more efficacious than second-generation antipsychotic drugs, although their relative efficacy compared with electroconvulsive therapy (ECT) has not been established. In selecting next-step and/or adjunctive treatments, important issues to consider include patient preference, adverse event profile, and accessibility (ie, cost, insurance coverage, and availability).

On the investigational side, interest in the use of arketamine (the R-enantiomer of ketamine) for TRD has also grown. Animal models suggest that arketamine may have more potential antidepressant-like effects than esketamine, and human trials have just begun. The ketamine metabolite (2

)-hydroxynorketamine has also generated significant interest as a treatment for TRD that potentially lacks dissociative adverse events and abuse potential. It is currently being studied in phase 1 human trials.

Another newly developed treatment for depression has a novel mechanism of action. Brexanolone (Zulresso), a neurosteroid and injectable form of allopregnanolone (a GABA

 positive allosteric modulator), was developed as a treatment for 

. Levels of allopregnanolone, which gradually rise throughout pregnancy, fall precipitously post pregnancy. Slowed downregulation of GABA

 receptors is thought to contribute to postpartum depression. Significant improvement in depressive symptoms was noted within 24 hours of brexanolone infusion, which is administered as a 60-hour IV infusion during inpatient care; this antidepressant response lasted up to 30 days.

 Brexanolone received FDA approval for postpartum depression in March 2020. An orally administered allopregnanolone analogue, Zuranolone, is currently in phase 3 clinical trials for both MDD and postpartum depression.

The success of ketamine has revived interest in the use of psychedelic agents, particularly psilocybin, for the treatment of depression. Controlled trials of psilocybin offer some evidence of efficacy for MDD patients, although further studies are needed.

 Psychedelic-assisted psychotherapy—that is, the use of 

 as an adjunctive treatment to psychotherapy—is in the early stages of investigation. In addition to concerns about prompting illicit use, it should be noted that psilocybin may increase the risk of seizures when coadministered with lithium.

In addition to new pharmacological treatments for TRD, several viable neurostimulation options currently exist or are emerging. ECT remains the most established treatment for severe TRD, and the FDA reaffirmed ECT’s importance as a treatment option when it reclassified ECT devices in December 2018 as a Class II (moderate risk) device for the indication of major depressive episodes associated with MDD or bipolar depression.

 With response rates greater than 50% by the first week of treatment, ECT should be a serious consideration for patients who have not responded to conventional treatment.

 Patients with psychotic depression and catatonic depression, as well as elderly patients, may particularly benefit from ECT.

However, ECT use remains limited by 2 main issues: the short duration of its effects and the cooccurrence of cognitive adverse events. After a successful course of ECT, relapse rates are quite high without effective relapse prevention strategies. To decrease the chance of relapse after a course of ECT, patients are often given maintenance medication or ECT therapy. The Prolonging Remission in Depressed Elderly study demonstrated that relapse rates can be dramatically reduced by introducing a Symptom-Titrated Algorithm-Based ECT (STABLE) approach that combines pharmacotherapy with continued ECT on a schedule adjusted to individual patient response.

 The STABLE intervention reduced relapse rates more effectively than medications alone and achieved these benefits without substantially worsening cognitive function.

The most concerning cognitive adverse events of ECT involve short-term and long-term memory. While studies confirm that short-term memory effects usually resolve within weeks of a treatment course, long-term memory deficits may be prolonged. Mitigation strategies used to minimize risk of memory loss include right unilateral electrode placement, ultrabrief pulse width, square wave electrical stimulation, and increasing the length of time between treatments. In addition, new technologies such as magnetic seizure therapy (MST) are under investigation as an alternative method to initiate seizures (which are thought to be the essential aspect of the therapy).

 By shaping the magnetically induced electric field that initiates the seizure to minimize the effect on brain areas related to memory function, MST may ultimately be associated with significantly fewer cognitive adverse events. Published study results suggest that MST leads to fewer cognitive adverse events than ECT while preserving efficacy.

Repetitive Transcranial Magnetic Stimulation

Another neurostimulation modality for TRD is 

repetitive transcranial magnetic stimulation

 (rTMS), which was cleared by the FDA for TRD in 2008. It has an excellent safety profile, with the primary significant adverse event being the rare occurrence of seizures. It was initially unclear whether rTMS demonstrated the speed of response and high degree of effectiveness needed for patients with severe depression or TRD. However, recent work to optimize the dosage of rTMS (including neuronavigated individualized spatial targeting and accelerated delivery of multiple treatment sessions) have improved treatment outcomes. Intermittent theta-burst stimulation (iTBS)—a form of rTMS—was recently cleared by the FDA for use in TRD. iTBS, which cuts treatment session times from 50 minutes to 3 minutes, was cleared based on studies demonstrating comparable results with standard 10 Hz rTMS.

 In addition, further refinements to the treatment (ie, functional-connectivity-guided targeting) may lead to even greater rates of effectiveness.

 Another recently reported approach couples iTBS with individualized circuit-based neuronavigation and an accelerated treatment schedule called the SNT protocol. A randomized controlled trial of SNT found a 52.5% drop in depression scores with active SNT compared with an 11.1% drop with sham.

Vagus nerve stimulation (VNS), which initially received FDA approval for epilepsy, was later discovered to have antidepressant effects; it received FDA approval for TRD in 2005 as an adjunctive treatment for depression that has failed to respond to at least 4 adequately dosed antidepressant treatments. Although the pivotal randomized controlled trial failed to find definitive evidence of efficacy, a 1-year, nonrandomized comparison of open-label VNS versus treatment as usual found a significant advantage in the VNS group.

 A new randomized controlled trial is currently underway to provide more definitive evidence (NCT03887715).

A final consideration for severe and refractory TRD patients is deep brain stimulation (DBS). DBS is not FDA approved for depression but is on the US market to treat Parkinson disease, epilepsy, essential tremor, dystonia, and OCD. For TRD, DBS may be accessible in the context of research studies. DBS treatment consists of electrode placement and electrical stimulation of the ventral capsule/ventral striatum or subgenual cingulate cortex. In smaller investigations and case studies, DBS appeared to demonstrate immediate and striking improvements in 

. However, 2 phase 3 trials were terminated early after interim analyses of the results, and further large-scale trials have not yet been undertaken. Research on DBS has continued, but in a different direction (including identification of novel targets, predictors of response, and novel stimulation approaches). One promising strategy has been the development of closed-loop systems, pairing chronic deep-brain sensing to individualize stimulation programs for patients with TRD.

 Newer Treatments Approved or Under Investigation for TRD

In summary, a number of viable new options offer the possibility of optimizing care for patients with TRD. The 

 summarizes the currently available, developing, and promising new treatments previously described. Given the field’s relative lack of clinical experience with these treatments, these treatments should be considered cautiously after a comprehensive assessment of benefits and risks. However, given the risks of inadequately treated depression, they deserve consideration. In addition, these mechanistically novel treatments may further our collective understanding of depression and serve to further transform depression therapeutics.

Funding for this work was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002927).

is the medical director of the clinical research unit in the experimental therapeutics and pathophysiology branch at the National Institute of Mental Health.

is director of the NIMH’s Division of Translational Research and director of the Noninvasive Neuromodulation Unit in the NIMH Intramural Research Program; she is also JP Gibbons Professor Emeritus in the Duke University School of Medicine’s Department of Psychiatry and Behavioral Sciences.

is an NIH Distinguished Investigator as well as chief, Section on Neurobiology and Treatment of Mood and Anxiety Disorders, of NIMH’s Experimental Therapeutics and Pathophysiology Branch. He is also clinical professor of psychiatry and behavioral sciences at George Washington University.

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Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial.

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Efficacy of ketamine in the treatment of substance use disorders: a systematic review.

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Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.

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Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports.

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Articles

In this CME, review novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

Promising Strategies for Treatment-Resistant Depression

Bipolar disorder (BP) is a chronic, debilitating illness that affects 0.4% to 4% of the US population.

 The first nosological efforts describing BP appeared in the early 2nd century ad and culminated in Kraepelin’s eloquent description of its phenomenology in his 1921 textbook on manic-depressive insanity.

 Nevertheless, the course and underlying pathophysiology of BP remain elusive.

The disorder is frequently unrecognized, misdiagnosed, and not optimally managed. Moreover, no agent has been specifically developed on the basis of an understanding of the pathophysiology of the illness or mechanism of action of effective treatments.

The current gold standard treatment for BP is lithium, whose mood-stabilizing effects are believed to occur via distinct cellular signaling pathways/targets, such as glycogen synthase kinase 3 inhibition (considered to regulate cellular apoptosis), and other potential downstream cellular mechanisms. In addition to lithium, valproate, and carbamazepine, several atypical antipsychotics (including asenapine) are FDA-approved for the treatment of acute bipolar mania (

While these drugs have certainly provided relief for many individuals with BP, significant issues with tolerability and efficacy remain. For instance, clinicians may find themselves in situations in which better-tolerated agents are less effective, and vice versa. In addition, balancing efficacy with adverse effects that affect adherence, such as sedation and weight gain, underscore the urgent need to develop novel and more effective treatments.

Findings from a meta-analysis indicate that the following agents were more effective than placebo for mania: aripiprazole, asenapine, carba­mazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone).

 Limited data suggest large effect sizes for carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen.

Another large meta-analysis evaluated the comparative efficacy of aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone at therapeutic doses for treatment of acute mania.

 The study concluded that antipsychotic drugs were significantly more effective than mood stabilizers; olanzapine, risperidone, and quetiapine were better tolerated than haloperidol. Risperidone, olanza­pine, and haloperidol were particularly efficacious. Most of the trials were short (typically 3 weeks), and therefore caution is needed when extrapolating the results to clinical practice. It is also important to note that because of informed consent and general enrollment issues with manic patients, more severe cases were invariably excluded.

Because strong evidence exists for the use of lithium-and to a somewhat lesser extent, lamotrigine and valproate-as a maintenance treatment for BP, antipsychotics may be increasingly used to treat the acute manic phase of the disorder and mood stabilizers (particularly lithium) may be used for long-term treatment. Nivoli and colleagues

 reviewed the major guidelines for the treatment of manic/hypomanic and mixed episodes and found that all guidelines agreed that concurrent antidepressants should be stopped during a manic/mixed episode.

Improved pharmacological strategies with pronounced and sustained effects would have an enormous impact on public health, particularly given the high mortality associated with BP. A variety of compounds are now being tested that offer mechanistically different approaches for the treatment of BP. Some of the drugs we will discuss target partic­ular pathways specific to lithium, while others focus on more novel targets, such as 

-methyl-D-aspartate (NMDA) and opiate receptors. Evidence also suggests that older agents used to treat other diseases can be “re-purposed” if they show promise in reducing manic activity.

 While the focus of these compounds is on the treatment of mania, some may also be beneficial during the depressed phase of the illness.

Tamoxifen is a protein kinase C (PKC) inhibitor and antiestrogenic drug that crosses the blood-brain barrier and is relatively well tolerated (up to 200 mg/d). Lithium is thought to regulate the PKC signaling cascade, and findings suggest that PKC activation enhances the release of dopamine, a neurotransmitter implicated in mania.

 A recent genome-wide association study also implicated diacylglycerol kinase eta (DGKH) in the pathogensis of BP; DGKH is a key protein in the lithium-sensitive phosphatidylinositol pathway and a precursor to PKC.

A number of studies evaluated the effects of adjunctive tamoxifen treatment for mania, with encouraging results. The most recent of these was a double-blind, randomized, placebo-controlled, 6-week study (N = 40) that evaluated the efficacy and safety of tamoxifen with adjunctive lithium in the treatment of acute bipolar mania.

 Combined tamoxifen/lithium therapy was superior to lithium alone for rapidly reducing manic symptoms; results were apparent as early as day 7. In that study, all psychotropic medications except benzodiazepines were discontinued at least 48 hours before randomization.

Lorazepam (1 to 2 mg/d) was stopped after the initial 10 days and was not dispensed within 8 hours of the administration of the mania rating scale. The starting dosage of tamoxifen was 20 mg twice daily (40 mg/d). Daily doses were subsequently increased by 10 mg to achieve 80 mg/d in twice-daily divided doses. This dosage of tamoxifen was well tolerated, and no clinically significant adverse effects except fatigue were observed. Despite these clinically encouraging results, long-term safety data are limited, and tamoxifen is associated with increased risk of endometrial carcinoma and uterine sarcoma.

 This selective NMDA glutamate receptor antagonist is approved for the treatment of moderate to severe Alzheimer disease. Preclinical studies found that memantine was associated with antimanic-like properties, such as decreased locomotor hyperactivity.

 
FDA-approved treatment for bipolar disorder in adults 

In an open-label, multisite, pilot study (N = 33), 20 to 50 mg/d of memantine as monotherapy was well tolerated, and patients with acute mania responded by day 21.

 The study evaluated 3 cohorts who received either 20 to 30 mg/d, 30 to 40 mg/d, or 40 to 50 mg/d, with an allowed increase or decrease of 10 mg/d based on tolerability and response. The greatest response occurred in the group that received 20 to 30 mg/d. The most frequently reported adverse effects were nausea, headache, and constipation.

Unfortunately, no randomized placebo-controlled trials to date have demonstrated the antimanic efficacy of memantine in either manic or mixed-state patients. However, it is interesting to note that a recent 8-week, double-blind, randomized, placebo-controlled, proof-of-concept trial found that memantine augmentation (20 mg/d) of lamotrigine conferred no statistically significant benefit to patients with bipolar depression. Nevertheless, post hoc results suggest that depressive symptoms did improve in these patients during initial titration (5 mg/wk) and for the first 4 weeks but that no sustained effects were evident at 8 weeks.

 Valproic acid is widely used to treat BP; however, its teratogenicity limits its use in women of childbearing potential. Valnoctamide is an analogue of valproic acid, but it does not undergo biotransformation to the corresponding free acid. It also lacks key structural groups (eg, free carboxylic groups) implicated in valproic acid’s teratogenicity. In preclinical studies, valnoctamide was markedly less teratogenic than valproic acid, with no significant changes regarding embryolethality.

 The drug has anticonvulsant properties similar to those of valproate and has been marketed as an anxiolytic and sedative in several European countries.

A recent double-blind, 5-week, add-on (with risperidone up to 6 mg/d), controlled trial (N = 32) of valnoctamide was conducted to measure its efficacy in treating mania.

 Patients were given valnoctamide 600 mg/d, increased to 1200 mg/d after 4 days, or placebo. Valnoctamide was significantly more effective than placebo across all efficacy measures beginning at week 3 through week 5. Adverse events included abnormal liver function test results (less than 3 times normal) in 1 patient; the test results normalized after the patient was switched back to valproate.

No other clinical trials with valnoctamide have been conducted to date, nor are any such trials currently pending. Nevertheless, valnoctamide may be a promising alternative to valproate for treating mania in women of childbearing age. Additional surveillance data in humans are required to make definitive claims regarding this agent.

 Opiates that primarily target μ-opiate receptors have been given in the past to patients with BP

; however, specific κ-opiate receptor (KOR) agonists have not been tested in patients with mania. In animal studies, direct activation of KORs caused depressogenic or dysphoric effects, while blockade of the same receptors produced antidepressant-like effects.

 Although no specific KOR agonist is currently approved for human use, the analgesic agent pentazocine functions as a partial KOR agonist, with weaker affinity for μ- and σ-opiate receptors.

In a recent proof-of-concept, open-label, add-on, 3-day, acute-dose study, 10 inpatients with BP-I who were hospitalized for mania received two 50-mg doses of pentazocine 2 hours apart.

 Manic symptoms were reduced 1 hour after each dose (44% after the first dose, and 41% after the second dose). Participants initially received standard treatment for BP. Efficacy measures used in the 3-day trial included the Young Mania Rating Scale (YMRS) and the Mania Acute Change Scale7-scored at hourly intervals for 6 hours.

No psychotomimetic, dysphoric, or adverse events occurred. Patients’ vital signs were stable throughout the study, and light-headedness and sedation were noted to be minimal. Limitations included the design and small number of patients in the study and questions as to whether the effects of this agent were sustained or transient. Nevertheless, these promising initial results may provide the impetus to conduct larger trials. An ongoing study is currently evaluating the effects of pentazocine versus those of lorazepam or placebo on manic symptoms.

 Kraepelin was the first to associate manic symptoms with hyperuricemia, uric acid excretion, and gout. (Machado-Vieira and colleagues

 provide a thorough review of purinergic dysfunction in mania.) Allopurinol is a xanthine oxidase inhibitor approved for the treatment of gout. Results from initial add-on studies with allopurinol in refractory mania were positive; however, sample sizes were small and allopurinol was used in conjunction with a variety of medications, including antipsychotics.

A recent 4-week, randomized, placebo-controlled, double-blind study (N = 180) evaluated the efficacy of allopurinol (600 mg/d) or dipyridamole (a nucleoside inhibitor; 200 mg/d) in combination with lithium.

 A linear model analysis found that allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (

 = .003) compared with placebo. Remission rates were also more favorable for persons who received allopurinol than for those who received dipyridamole or placebo (

 = .008). Furthermore, decreased plasma uric acid levels were significantly positively associated with antimanic effects in the allopur­inol group. Overall, allopurinol was well tolerated; the most common adverse effects were dizziness and di­arrhea. An ongoing clinical trial is evaluating allopurinol as a maintenance strategy for mania in BP.

 L-type calcium channels affect several organ systems and are widely expressed in the CNS, thus influencing neuroplasticity and neuronal excitability. Lithium is known to act on calcium signaling pathways, and recent genome-wide association studies support an association between a common variation on the α 1C subunit of the L-type voltage-gated calcium channel gene and BP.

In 2007, Memory Pharmaceuticals Corporation conducted a phase 2a study of MEM 1003, a novel L-type calcium channel antagonist, for acute mania in BP. Study participants (N = 84) were randomized to receive either MEM 1003 or placebo for 3 weeks. Despite positive tolerability and safety data, both primary and secondary outcome measures showed that MEM 1003 was ineffective in treating bipolar mania.

 These results, unfortunately, are in line with earlier failed studies that investigated calcium channel antagonists in the treatment of BP.

 While it is beyond the scope of this article to offer an intensive review of all agents, we do wish to briefly mention NAC, which affects the glutathione antioxidant system. In patients with BP, a subgroup analysis found that NAC led to remission of manic symptoms.

 Most studies, however, suggest that NAC has more robust effects on depressive symptoms.

 The expression “nutraceutical” was coined in 1989 and was defined as “a food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease.”

 Nutraceuticals differ from dietary supplements because they are intended to not only supplement the diet but also to prevent and/or treat a particular disease or disorder. Many patients with BP (60%) who adhere to pharmacological treatment continue to experience recurring manic or depressive mood episodes while taking medications at recommended therapeutic doses. Thus, adjunctive neutraceuticals can act as agents with either super-additive or multi-target biologic effects or as agents with the potential to minimize adverse effects by reducing the necessary dose of conventional drugs.

Note that despite active research, no substantive evidence exists to support these notions. However, Sarris and colleagues

 recently conducted a systematic review of human clinical trials of nutraceuticals used adjunctively with standard pharmacotherapy in BP. Inclusion criteria (eg, open label, controlled, sample size greater than 10) narrowed 1710 studies to 18 that evaluated ω-3, NAC, inositol, and vitamins and minerals in combination with standard medications to treat BP (either mania or depression). Several nutraceuticals were found to improve bipolar mania, including a chelated mineral formula, l-tryptophan, magnesium, folic acid, and branched-chain amino acids (eg, leucine, isoleucine, and valine).

In contrast, the evidence did not support the adjunctive use of ω-3 in bipolar mania, although it may be useful in bipolar depression. Given that many of the trials involved small sample sizes and did not account for baseline dietary patterns, these positive results should be interpreted with caution. Likewise, significant heterogeneity between studies also prevented a meta-analysis of the findings.

While challenges in treating mania persist, the future discovery of novel therapeutic agents will likely expand our understanding of this devastating illness and provide key insights into future drug development.

-The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and thank the 7SE Research Unit of the NIMH-NIH for their support.

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Carlos A. Zarate, Jr, MD

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