Thinking Beyond the Guidelines: Evidence-Based Novel Therapies for Bipolar Depression

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CATEGORY 1 CME

Premiere Date: November 20, 2022

Expiration Date: May 20, 2024

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1. Physicians (CME)

2. Other

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PART TWO ACTIVITY GOAL

The goal of this activity is to help readers understand and apply novel treatment approaches for patients with bipolar depression.

PART TWO LEARNING OBJECTIVES

1. Evaluate nonpharmacologic and pharmacologic treatments for bipolar depression.

2. Distinguish evidence-based novel treatments for bipolar depression.

TARGET AUDIENCE

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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(This is the second part of a 2-part article discussing novel treatments for bipolar depression. Part 1 appeared in the September issue and discussed the need for novel treatments for bipolar depression. –Ed.)

Bipolar depression (BD) can be difficult to treat due to several factors, and choosing the most appropriate treatment approaches should be based upon patient-specific factors (eg, comorbidities, preferences). Based on treatment response and these patient-specific issues, there are a variety of nonpharmacologic therapies and novel pharmacologic options that can be considered as part of the treatment plan.

Nonpharmacologic Interventions

Table 1. Nonpharmacologic Treatments for Bipolar Depression

Although many clinicians tend to focus on pharmacologic treatments for BD, nonpharmacologic interventions have been shown to be effective in bipolar depression, many of which contribute to an overall healthy lifestyle and can be recommended in addition to medications (Table 1). Additionally, some of these interventions pose only a low risk, and they may be preferable to the use of medications for select patients. Barriers associated with implementation include cost and accessibility. Clinicians should familiarize themselves with the following interventions and recommend them to patients whenever possible.

Chronotherapeutic treatments. The International Society for Bipolar Disorder recommends the use of chronotherapeutic treatments.¹ Its guidelines recommend the use of bright light therapy and sleep deprivation/wake therapy for BD and dark therapy for mania. Several meta-analyses and systematic reviews found positive results for bright light therapy in BD.^2-4 Although studies are relatively small, bright light has few to no adverse effects and should be considered for patients who have the resources to purchase a light box. In several meta-analyses, the brightness of the light box and length of time utilized varied, depending on the study. In most trials, the light provided ranged from 2500 to 10,000 lux, and the administration time ranged from 7.5 to 60 minutes delivered upon awakening in the morning.^2-4 Participants were maintained on medication regimens during the studies. Clinicians should be aware of the hypothetical risk for affective switching; however, based on available studies, the risk is minimal.

There is limited evidence that sleep deprivation and light therapy conducted together can effectively treat BD. Sikkens et al studied 60 participants with drug-resistant BD who underwent sleep deprivation periods along with daily bright light therapy sessions.⁵ After 1 week of treatment, 44% of patients showed significant improvement. Of this group, 17% remained euthymic at 1 year of follow up. For those interested in this approach, Veale provides an easy-to-follow method (Table 2).⁶ Although the directions are relatively simple, this protocol may be quite challenging for many patients due to the sleep restriction requirements.

Table 2. Light Therapy and Sleep Restriction Guidelines⁶

The use of blue light-blocking sunglasses in the evening reduces depressive and manic symptoms.⁴ If patients have difficulty following the sleep deprivation and light therapy protocols, a middle ground might include wearing blue light–blocking glasses in the evening starting at 7 PM and doing bright light therapy every morning. Blue light–blocking sunglasses can be purchased for about $10, and light boxes with the appropriate specifications can be purchased for $100 to $200. There is some variability in light box specifications in the research; typically, a box measuring 12 ×17 inches is recommended. The brightness should be between 2500 and 10,000 lux, and patients should use the light box for about 30 minutes per day as soon as possible after waking up. The light box should be placed above eye level while in use, and sunglasses should not be worn.

The cost of the light box may be prohibitive for some patients. In those cases, clinicians should adapt suggested interventions to meet the patient’s needs. For example, patients may be able to sit outdoors in bright sunlight for 15 to 30 minutes in the morning.

Physical exercise. Exercise has been shown to reduce inflammatory markers, and physical activity may be beneficial in BD. For example, Paolucci et al studied 61 university students engaged in various levels of exercise intensity.⁷ The investigators found moderate, continuous exercise produced the best results. Participants reported reductions in depression and anxiety, and they had lower levels of inflammatory markers. Of note, high-intensity interval training also improved depression, but it increased the participants’ perception of stress and increased the inflammatory markers TNF-α and interleukin-6.

According to available literature related to the impact of exercise on numerous psychiatric conditions, exercise improves depressive symptoms, reduces stress, decreases inflammatory markers, and promotes the synthesis of monoamine neurotransmitters in patients with bipolar disorder.^8,9 Although exercise alone may not lead to remission, it has clear benefits, and should be recommended at moderate levels. Easily accessible forms of exercise—such as walking—may be easiest for patients to implement. For patients who have mobility issues or who live in areas where walking is not possible, chair exercise or yoga might be good alternatives. Other patients may find it easier to set up an exercise schedule at a gym or with a personal trainer. Generally, an exercise program that the patient is most likely to maintain is the best choice.

Smoking cessation. Data related to cigarette smoking and mental illness show a clear negative impact of smoking on the symptoms of BD.⁸ Indeed, smoking is a risk factor for the development of BD. Cigarette smoking is also well known to negatively affect inflammatory markers.¹⁰

Although there is no evidence that smoking cessation will treat BD successfully, it makes sense to encourage all patients to stop smoking. Several effective pharmacologic and nonpharmacologic treatments are available to assist with this goal. Early evidence suggested that varenicline might worsen mood and increase the risk of suicidal ideation, but more recent analyses have not shown an increase in neuropsychiatric adverse effects with use of varenicline, bupropion, or nicotine replacement therapy.¹¹

There are no concerning drug interactions with varenicline or bupropion and medications typically used to treat BD, but clinicians should be aware that cigarette smoking is a cytochrome P450 inducer. If patients quit smoking, the blood levels of some psychotropics can increase. Because the effect is related to smoking itself, the same interaction does not exist with nicotine replacement therapy.

Dietary interventions. Healthy dietary patterns improve overall health and reduce symptoms of psychiatric illnesses.^8,12-15 Specifically, the results of numerous studies have shown that following an anti-inflammatory diet can improve overall health and, potentially, psychiatric symptoms.

Implementation of the Mediterranean diet and MIND (Mediterranean-Dietary Approaches to Stop Hypertension [DASH] Intervention for Neurodegenerative Delay) diets has anti-inflammatory properties. The Mediterranean diet is rich in antioxidants and flavonoids. It uses liberal amounts of whole grains, fruits, vegetables, nuts, olive oil, and omega-3 fatty acids, primarily through the consumption of fish. The MIND combines the benefits of the DASH, which was developed to prevent cardiovascular disease. It encourages reduced consumption of saturated fat, sodium, and sugar intake and promotes healthy proteins, whole grains, fruits, and vegetables. All of these diets have a variety of health benefits and anti-inflammatory properties that may aid in relieving depressive symptoms. Additionally, they may help combat the metabolic effects of numerous psychiatric medications.

When counseling patients about dietary change, clinicians may find it helpful to focus on a few specific items that patients can add to their current diets. Advising patients to overhaul their entire eating style may be overwhelming and ineffective. For example, patients may be able to focus on adding more vegetables, nuts, and seafood as a first step. In addition, small steps may be the best strategy for patients who consume great amounts of inflammatory foods such as sugar and starchy items. These individuals may find it less overwhelming if they focus on 1 change at a time (eg, switching from soda to water or flavored water) and then adopt other changes. Motivational interviewing approaches are useful when encouraging lifestyle change. Ideally, clinicians should check in with patients at every visit to monitor their progress in implementing lifestyle changes.

Supplements and nutraceuticals. The results of several studies have noted that use of various dietary supplements may benefit patients diagnosed with BD and unipolar depression. Inflammatory state alterations reflective of microbiota alterations in the gastrointestinal (GI) system are present in many psychiatric conditions, including BD.¹⁶ Probiotics modulate stress hormones, increase brain-derived neurotrophic factor (BDNF) and serotonin levels, and reduce inflammation.¹⁷ The brain-gut axis involves pathways including the parasympathetic nervous system, the immune system, the gut neuroendocrine system, and neurotransmitters produced in the gut.¹⁷ For example, a large portion of endogenous serotonin is manufactured in the GI tract. Serotonin modulates the blood-brain barrier and vagal nerve activity.¹⁷

Currently, evidence in humans on this topic is limited to observational studies. Probiotic supplementation may have a role in improving BD; current research, however, is limited by small trials and methodologic variability.^15,18,19 Omega-3 fatty acids have anti-inflammatory properties, and may be effective in supporting treatment of BD.^13,20,21 In a systematic review, Sarris et al found a positive effect for omega-3 fatty acids in depression.²² Additionally, several studies have shown positive effects for omega-3 fatty acids in patients diagnosed with BD.²⁰ If using fish oil supplements, patients should ensure that the eicosapentaenoic acid (EPA) content is 1.5 times the amount of docosahexaenoic acid (DHA). In addition, patients should take between 1000 to 3000 mg per day.²³ Most people are unlikely to obtain this amount of EPA and DHA in their diet, unless they have a high intake of fish rich in omega-3 fatty acids.

Other supplements that have been studied in managing BD and unipolar depression include coenzyme Q10, inositol, and several vitamins and minerals.^13,21 However, the evidence on these agents is very limited and has shown mixed findings. At this point, treatment recommendations cannot be made based on the research.

Use of L-methylfolate also may be considered as an adjunctive treatment.^24,25 When folate and lamotrigine were combined in 1 study, lamotrigine became clinically ineffective; however, this finding has not been replicated.²⁶ There are no other known drug interactions with these supplements.

Brain stimulation. Transcranial magnetic stimulation (TMS) can be considered when standard treatments fail.²⁷ Clinicians should be aware of a risk for psychomotor agitation in patients with BD who are treated with TMS. Currently, several FDA-approved devices are being used in patients with BD, and TMS is being used more commonly in this patient population.

Deep brain stimulation (DBS) has been studied for BD, and has shown promising results.²⁸ Several small studies showed that DBS provided significant improvement in depressive symptoms among patients with BD.²⁸ Among the studies, there was no consistent brain area of focus for the DBS treatment; in TMS, on the other hand, the left dorsolateral prefrontal cortex was targeted. A risk for affective switching was seen in 1 patient among these trials, but adjustment of stimulation parameters mitigated the symptoms. DBS is not commonly used; however, it is surgically invasive and costly, and the device must be removed if treatment is not successful.

Electroconvulsive therapy (ECT) remains one of the most potent interventions for depressive disorders, including BD.²⁹ The duration of the current episode is a significant predictor of therapeutic response, and some recommendations indicate that ECT should be considered earlier in the course of treatment. Unfortunately, many clinicians consider it a treatment of last resort. This stance may prolong the duration of a course of BD and reduce the likelihood of response.

Magnetic seizure therapy also is a promising treatment option.³⁰ It delivers high-intensity magnetic field impulses through a coil to induce seizure activity in the brain. Currently, however, this treatment is not widely available.

Novel Pharmacologic Interventions

Table 3. Potential and Emerging Novel Pharmacologic Agents

There is evidence supporting the use of various off-label pharmacologic treatments in BD (Table 3). Off-label medications typically are not included in published treatment guidelines, partially because research is less frequently conducted with older generic medications. Studies of off-label medications may show inconsistent findings due to smaller sample sizes and methodological variation. In addition, the majority of the systematic reviews and meta-analyses of these studies do not include information about the dosing ranges used, which limits their generalizability and clinical utility. When considering these novel medications, clinicians should consider them to be second-, third-, or fourth-line options, at best. Most importantly, clinicians should consider patient-specific factors that may influence treatment selection.

Dopaminergic agents. The use of dopaminergic agents (eg, dopamine antagonists, dopamine reuptake inhibitors) to treat depressive disorders is well established; indeed, dopamine antagonists are a mainstay of treatment according to published treatment guidelines. Other agents with varying mechanisms of action also have been studied. Amantadine and memantine are similar drugs that are believed to be dopamine agonists and NMDA-receptor antagonists.³¹ Typically, these drugs are used for Parkinson disease, dyskinesias, and neurocognitive impairment.

Although a small meta-analysis did not find a benefit for memantine over placebo to treat depression,³² another review found several studies that demonstrated positive effects.³³ In addition, a case series demonstrated benefit with amantadine given for BD.³⁴ Research on these agents remains limited, although they may be an option for patients with BD, particularly if affected patients have accompanying neurocognitive symptoms. In most studies, these drugs were used adjunctively with mood stabilizers.^32-34

Dopamine agonists and amphetamines have been studied for use in BD. Their efficacy has been demonstrated in RCTs, open label trials, and case report series.³⁵ However, they run a risk of inducing manic and/or psychotic symptoms; therefore, clinicians should monitor patients closely for the emergence of such manifestations.

Modafinil and armodafinil typically are used to treat narcolepsy and sleep-wake cycle disorder. The results of 5 RCTs in a meta-analysis demonstrated that augmentation with modafinil/armodafinil was associated with significantly greater rates of treatment response in patients with BD.³⁶

The dopamine agonists pramipexole and ropinirole are indicated to treat Parkinson disease and restless leg syndrome. A systematic review and meta-analysis involving 5 RCTs and 8 open-label or observational studies showed positive outcomes when pramipexole was used in patients with unipolar depression or BD.³⁷ Two small studies found positive effects when ropinirole was used to treat BD or unipolar depression.^38,39 Nausea is a common adverse effect associated with use of pramipexole; prophylactic use of an antinauseant may be advisable when treatment with the drug is initiated. On a positive note, pramipexole has not increased the risk of mood switching.³⁷

Anti-inflammatory agents. As discussed previously, chronic and acute inflammation may be related to depressive symptoms. There is preliminary evidence that biomarkers (eg, CRP, other inflammatory cytokines) may be elevated in people with bipolar disorder and other conditions affecting mood.⁴⁰ A meta-analysis of 4 studies using infliximab, a TNF inhibitor, did not find positive effects when the drug was given to patients treatment-resistant unipolar depression.⁴¹ However, the use of other anti-inflammatory agents in the treatment of BD has some research support. For example, several studies have shown positive outcomes for celecoxib, a COX-2 inhibitor, when used adjunctively with standard treatments.^42-44 Importantly, a concurrent proton-pump inhibitor to protect the GI system should be prescribed when using celecoxib.

Minocycline is a tetracycline derivative antibiotic that also has anti-inflammatory properties. A small RCT showed positive effects for its use in patients with unipolar depression.⁴³ A systematic review found positive effects in treating schizophrenia but not BD or unipolar depression; 16 RCTs were included, although only 1 focused on BD, and 3 focused on unipolar depression.⁴⁵ In addition, there was a wide dosing range among studies (50-300 mg) and some methodological variation, making generalities difficult.

N-acetylcysteine (NAC) is another anti-inflammatory agent that has been studied to treat BD. This drug primarily has been used to treat acute liver injury, but it is also available as an over-the-counter supplement. It has anti-inflammatory effects believed to be related to modulation of cytokine production and glutathione, an antioxidant that modulates NMDA receptors that may be related to the therapeutic effect of NAC. Several reviews included trials demonstrating the efficacy of NAC in treating BD.^20,42,43

Statin drugs used to treat hypercholesteremia exert anti-inflammatory effects, as well. Research on using these agents to treat psychiatric disorders is very limited; however, there are some potentially promising findings involving schizophrenia, unipolar depression, and dementia.²⁶

Glutamatergic inhibitors and NMDA receptor antagonists. Riluzole is believed to function as a glutamate inhibitor and an NMDA receptor antagonist. It is indicated as a treatment for amyotrophic lateral sclerosis. Lamotrigine, also a glutamate inhibitor, is more commonly used in psychiatry. A literature review provided preliminary evidence supporting riluzole use in patients with depression or several other psychiatric disorders.⁴⁶ Similarly, a small, open-label study of glutamatergic neurotransmission and depressive symptoms in BD showed an improvement in depressive symptoms with the use of riluzole.⁴⁷

Dextromethorphan is another glutamate modulator and NMDA receptor antagonist. There is evidence supporting its adjunctive use with standard medication treatments in mood disorders.^48,49 Dextromethorphan has been studied as a combination therapy with quinidine and as a monotherapy.

Ketamine and esketamine are believed to act as NMDA receptor antagonists and to increase synaptic plasticity. These drugs also have glutamatergic activity. Although much of the research on these agents focuses on unipolar depression, there is also evidence that they can be used effectively to treat BD.^50,51 Unfortunately, ketamine research remains a challenge due to funding and recruitment issues. Esketamine is currently FDA-approved for the treatment of unipolar depression; research has not focused on its use in BD.

Antiglucocorticoid agents. Antiglucocorticoid drugs that have been investigated for use in mood disorders include metyrapone, ketoconazole, and mifepristone.⁴⁹ In a meta-analysis, individuals with depressive symptoms associated with unipolar depression and higher cortisol levels at baseline responded to metyrapone and ketoconazole.⁵² Also discussed in this meta-analysis was the use of mifepristone for patients with psychotic depression or bipolar disorder.⁵² Evidence on mifepristone in BD is limited, but use of this drug in affected patients has produced promising results—baseline cortisol levels were similar among responders and nonresponders. Again, these small studies had methodological variability.

Miscellaneous agents. Other miscellaneous agents that have been studied for BD include pioglitazone (an antidiabetic agent), pindolol (a β-blocker that also blocks 5-hydroxytryptamine 1A receptors and possibly exerts antidepressant effects through that mechanism), and liothyronine sodium (T₃) and levothyroxine sodium (T₄) hormone supplementation. The results for these agents have been mixed. For example, although an RCT found positive effects of pioglitazone, another failed to show benefit.^53,54 Pindolol has been studied as an adjunct to dark therapy) and has significantly improved the antidepressant effects of sleep deprivation.^1,55 In addition, there is evidence to support the use of T₃ and T₄ as an augmentation strategy.^56,57 The use of thyroid hormone augmentation in unipolar depression is well established; however, research in BD is more limited. In practice, T₄ is often preferred due to cost and availability, but there is evidence that T₃ may be more effective.⁵⁸

Concluding Thoughts

Although there are a number of FDA-approved medications and published treatment guidelines related to the treatment of BD, the established medications are often ineffective or intolerable due to adverse effects in many cases. Fortunately, there are a variety of emerging nonpharmacologic and pharmacologic options to treat BD when standard treatments have failed. The majority of nonpharmacologic treatments have minimal to no adverse effects and they contribute to an overall healthy lifestyle. Physical exercise, light box therapy, or an anti-inflammatory diet can be excellent therapeutic options for some patients. Medications with mechanisms of action other than those of standard pharmacologic treatments may be sensible third- or fourth-line therapeutic options. Psychiatric clinicians would be well-served by familiarizing themselves with novel treatment choices for BD and applying an individualized approach to enhance patient outcomes.

NP Hardy is a psychiatric mental health nurse practitioner and clinical assistant professor at the Virginia Commonwealth University School of Nursing. Mr McCarthy is a psychiatric mental health nurse practitioner at the Mood Treatment Center in Winston-Salem, North Carolina.

References

1. Gottlieb JF, Benedetti F, Geoffroy PA, et al. The chronotherapeutic treatment of bipolar disorders: a systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. Bipolar Disord. 2019;21(8):741-773.

2. Hirakawa H, Terao T, Muronaga M, Ishii N. Adjunctive bright light therapy for treating bipolar depression: a systematic review and meta-analysis of randomized controlled trials. Brain Behav. 2020;10(12):e01876.

3. Lam RW, Teng MY, Jung YE, et al. Light therapy for patients with bipolar depression: systematic review and meta-analysis of randomized controlled trials. Can J Psychiatry. 2020;65(5):290-300.

4. Bisdounis L, Saunders KEA, Farley HJ, et al. Psychological and behavioural interventions in bipolar disorder that target sleep and circadian rhythms: a systematic review of randomized controlled trials. Neurosci Biobehav Rev. 2022;132:378-390.

5. Sikkens D, Riemersma-Van der Lek RF, Meesters Y, et al. Combined sleep deprivation and light therapy: clinical treatment outcomes in patients with complex unipolar and bipolar depression. J Affect Disord. 2019;246:727-730.

6. Veale D. Wake and light therapy. David Veale. 2020. Accessed July 19, 2022. https://www.veale.co.uk/wake-and-light-therapy/#

7. Paolucci EM, Loukov D, Bowdish DME, Heisz JJ. Exercise reduces depression and inflammation but intensity matters. Biol Psychol. 2018;133:79-84.

8. Firth J, Solmi M, Wootton RE, et al. A meta-review of “lifestyle psychiatry”: the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders. World Psychiatry. 2020;19(3):360-380.

9. Sá Filho AS, Cheniaux E, de Paula CC, et al. Exercise is medicine: a new perspective for health promotion in bipolar disorder. Expert Rev Neurother. 2020;20(11):1099-1107.

10. Rom O, Avezov K, Aizenbud D, Reznick AZ. Cigarette smoking and inflammation revisited. Respir Physiol Neurobiol. 2013;187(1):5-10.

11. Evins AE, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with psychotic, anxiety and mood disorders in the EAGLES trial. J Clin Psychopharmacol. 2019;39(2):108-116.

12. Martins LB, Braga Tibães JR, Sanches M, et al. Nutrition-based interventions for mood disorders. Expert Rev Neurother. 2021;21(3):303-315.

13. Marx W, Moseley G, Berk M, Jacka F. Nutritional psychiatry: the present state of the evidence. Proc Nutr Soc. 2017;76(4):427-436.

14. Norwitz NG, Dalai SS, Palmer CM. Ketogenic diet as a metabolic treatment for mental illness. Curr Opin Endocrinol Diabetes Obes. 2020;27(5):269-274.

15. Gabriel FC, Oliveira M, Martella BDM, et al. Nutrition and bipolar disorder: a systematic review. Nutr Neurosci. 2022;73(11):1-15.

16. Mangiola F, Ianiro G, Franceschi F, et al. Gut microbiota in autism and mood disorders. World J Gastroenterol. 2016;22(1):361-368.

17. Alam R, Abdolmaleky HM, Zhou JR. Microbiome, inflammation, epigenetic alterations, and mental diseases. Am J Med Genet Part B Neuropsychiatr Genet. 2017;174(6):651-660.

18. Zhang P, Kong L, Huang H, et al. Gut microbiota – a potential contributor in the pathogenesis of bipolar disorder. Front Neurosci. 2022;16:830748.

19. Borkent J, Ioannou M, Laman JD, et al. Role of the gut microbiome in three major psychiatric disorders. Psychol Med. 2022;52(7):1222-1242.

20. Ayorech Z, Tracy DK, Baumeister D, Giaroli G. Taking the fuel out of the fire: evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders. J Affect Disord. 2015;174:467-478.

21. Ashton MM, Kavanagh BE, Marx W, et al. A systematic review of nutraceuticals for the treatment of bipolar disorder. Can J Psychiatry. 2021;66(3):262-273.

22. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Focus (Am Psychiatr Publ). 2018;16(3):328-340.

23. Ghasemi Fard S, Wang F, Sinclair AJ, et al. How does high DHA fish oil affect health? A systematic review of evidence. Crit Rev Food Sci Nutr. 2019;59(11):1684-1727.

24. Lam NSK, Long XX, Li X, et al. The potential use of folate and its derivatives in treating psychiatric disorders: a systematic review. Biomed Pharmacother. 2022;146:112541.

25. Nierenberg AA, Montana R, Kinrys G, et al. L-methylfolate for bipolar I depressive episodes: an open trial proof-of-concept registry. J Affect Disord. 2017;207:429-433.

26. Kim SW, Kang HJ, Jhon M, et al. Statins and inflammation: new therapeutic opportunities in psychiatry. Front Psychiatry. 2019;10:103.

27. Goldwaser EL, Daddario K, Aaronson ST. A retrospective analysis of bipolar depression treated with transcranial magnetic stimulation. Brain Behav. 2020;10(12):e01805.

28. Gippert SM, Switala C, Bewernick BH, et al. Deep brain stimulation for bipolar disorder - review and outlook. CNS Spectr. 2017;22(3):254-257.

29. Perugi G, Medda P, Toni C, et al. The role of electroconvulsive therapy (ECT) in bipolar disorder: effectiveness in 522 patients with bipolar depression, mixed-state, mania and catatonic features. Curr Neuropharmacol. 2016;15(3):359-371.

30. Diaz AP, Fernandes BS, Quevedo J, et al. Treatment-resistant bipolar depression: concepts and challenges for novel interventions. Braz J Psychiatry. 2022;44(2):178-186.

31. Wilcox MR, Nigam A, Glasgow NG, et al. Inhibition of NMDA receptors through a membrane-to-channel path. Nat Commun. 2022;13(1):4114.

32. Kishi T, Matsunaga S, Iwata N. A meta-analysis of memantine for depression. J Alzheimers Dis. 2017;57(1):113-121.

33. Amidfar M, Réus GZ, Quevedo J, Kim YK. The role of memantine in the treatment of major depressive disorder: clinical efficacy and mechanisms of action. Eur J Pharmacol. 2018;827:103-111.

34. Krzystanek M, Pałasz A. Possibility of a new indication for amantadine in the treatment of bipolar depression—case series study. Pharmaceuticals (Basel). 2020;13(10):326.

35. Perugi G, Vannucchi G, Bedani F, Favaretto E. Use of stimulants in bipolar disorder. Curr Psychiatry Rep. 2017;19(1):7.

36. Nunez NA, Singh B, Romo-Nava F, et al. Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: a meta-analysis of randomized controlled trials. Bipolar Disord. 2020;22(2):109-120.

37. Tundo A, de Filippis R, De Crescenzo F. Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis. Acta Psychiatr Scand. 2019;140(2):116-125.

38. Capote HA, Rainka M, Westphal ES, et al. Ropinirole in bipolar disorder: rate of manic switching and change in disease severity. Perspect Psychiatr Care. 2018;54(2):100-106.

39. Gershon AA, Amiaz R, Shem-David H, Grunhaus L. Ropinirole augmentation for depression: a randomized controlled trial pilot study. J Clin Psychopharmacol. 2019;39(1):78-81.

40. Solmi M, Suresh Sharma M, Osimo EF, et al. Peripheral levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: a meta-analysis of mean differences and variability. Brain Behav Immun. 2021;97:193-203.

41. Bavaresco DV, Uggioni MLR, Ferraz SD, et al. Efficacy of infliximab in treatment-resistant depression: a systematic review and meta-analysis. Pharmacol Biochem Behav. 2020;188:172838.

42. Rosenblat JD, Kakar R, Berk M, et al. Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 2016;18(2):89-101.

43. Husain MI, Strawbridge R, Stokes PRA, Young AH. Anti-inflammatory treatments for mood disorders: systematic review and meta-analysis. J Psychopharmacol. 2017;31(9):1137-1148.

44. Bavaresco DV, Colonetti T, Grande AJ, et al. Efficacy of celecoxib adjunct treatment on bipolar disorder: systematic review and meta-analysis. CNS Neurol Disord Drug Targets. 2019;18(1):19-28.

45. Zheng W, Zhu XM, Zhang QE, et al. Adjunctive minocycline for major mental disorders: a systematic review. J Psychopharmacol. 2019;33(10):1215-1226.

46. de Boer JN, Vingerhoets C, Hirdes M, et al. Efficacy and tolerability of riluzole in psychiatric disorders: a systematic review and preliminary meta-analysis. Psychiatry Res. 2019;278:294-302.

47. Brennan BP, Hudson JI, Jensen JE, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010;35(3):834-846.

48. Henter ID, Park LT, Zarate CA. Novel glutamatergic modulators for the treatment of mood disorders: current status. CNS Drugs. 2021;35(5):527-543.

49. Henter ID, de Sousa RT, Gold PW, et al. Mood therapeutics: novel pharmacological approaches for treating depression. Expert Rev Clin Pharmacol. 2017;10(2):153-166.

50. Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res. 2022;151:693-709.

51. Singh B, Vande Voort JL, Frye MA, Kung S. Can ketamine be a safe option for treatment-resistant bipolar depression? Expert Opin Drug Saf. 2022:1-4.

52. Lombardo G, Enache D, Gianotti L, et al. Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: a meta-analysis. Psychoneuroendocrinology. 2019;110:104420.

53. Zeinoddini A, Sorayani M, Hassanzadeh E, et al. Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: a randomized, double-blind, placebo-controlled trial. Depress Anxiety. 2015;32(3):167-173.

54. Aftab A, Kemp DE, Ganocy SJ, et al. Double-blind, placebo-controlled trial of pioglitazone for bipolar depression. J Affect Disord. 2019;245:957-964.

55. Smeraldi E, Benedetti F, Barbini B, et al. Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial. Neuropsychopharmacology. 1999;20(4):380-385.

56. Stamm TJ, Lewitzka U, Sauer C, et al. Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014;75(2):162-168.

57. Uhl I, Bez JA, Stamm T, et al. Influence of levothyroxine in augmentation therapy for bipolar depression on central serotonergic function. Pharmacopsychiatry. 2014;47(4-5):180-183.

58. Parmentier T, Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression: a review of the literature. J Affect Disord. 2018;229:410-414.