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 covered a wide variety of psychiatric issues and industry updates, from assessment and management of older age bipolar disorder to the relationship between antidepressants and emotional numbing. Here are some highlights from the week.

Assessment of Individuals With Older Age Bipolar Disorder

The DSM-5 describes bipolar disorder (BD) as a condition that is characterized by recurrent and/or cyclical episodes of mania or hypomania and depression. In the DSM-5, there are 2 subtypes of BD: bipolar I disorder (BD-I) and bipolar II disorder (BD-II). A diagnosis of BD-I is established if an individual experiences at least 1 manic episode with additional major depressive and/or hypomanic episodes. Individuals are diagnosed with BD-II if they experience at least 1 hypomanic episode and at least 1 major depressive episode without any manic episodes. Although BD is not as common among older adults as it is among younger adults, available evidence indicates that the total number of older adults with BD is expected to increase significantly over the next few decades. It has been observed that between 1980 and 1998, the relative frequency of late-onset bipolar disorder increased from 1% to 11%. 

Antidepressants Do Not Work by Numbing Emotions

Recent evidence from randomized, placebo controlled trials (1979 to 2016) has shown that, in about 15% of patients with depression, antidepressant treatment is robustly superior to placebo—contrary to the often-repeated claim that antidepressants are “not much better than a sugar pill.” It is not yet clear what clinical or biological features make this subgroup so antidepressant-responsive, although differences between drug and placebo increased significantly (P<0.001) with greater baseline severity of depression. 

Considering National and Personal Character in Russia’s Invasion of Ukraine

I caught a brief interchange of the September 27th “Late Show” when Stephen Colbert was interviewing the well-known foreign war correspondent Clarissa Ward. She seemed to be concluding that Russia has an unusual propensity to tolerate suffering, so that a long war would not be all that psychologically difficult for the country as a whole.

Her comment reminded me of how long Russia was able to hold out, starvation common by the end, to the siege of Leningrad by the German Nazis in World War II. They ultimately shifted the whole tide of the war. 

The Strength and Value of Organized Psychiatry

Is organized medicine really on the decline? As more nursing and other allied organizations are growing and becoming more politically active, what is happening to membership in physician organizations? Given the increasing stressors of the COVID-19 pandemic, gun violence, physician wellbeing, rising health care costs, the scope of practice issues, and government intrusion on medical decision making, this is a time when physicians, the field, and our patients need help more than ever. Is there still strength in numbers? 

. And be sure to stay up-to-date by subscribing to the 

Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

From older age bipolar disorder to the relationship between antidepressants and emotional numbing, here are highlights from the week in Psychiatric Times.

The Week in Review: September 26-30

Recent evidence from randomized, placebo controlled trials (1979 to 2016) has shown that, in about 15% of patients with depression, antidepressant treatment is robustly superior to placebo—contrary to the often-repeated claim that 

 are “not much better than a sugar pill.”

 It is not yet clear what clinical or biological features make this subgroup so antidepressant-responsive, although differences between drug and placebo increased significantly (P<0.001) with greater baseline severity of depression.

Perhaps if we had a better understanding of antidepressants’ mechanisms of action—and how these mechanisms interact with this drug-responsive subgroup—we would be better able to predict which patients are likely to do well on antidepressants. Unfortunately, the matter is further complicated by the marked heterogeneity of 

 (MDD), which almost certainly contains several biological subtypes.

Critics of antidepressant treatment sometimes argue that antidepressants work—to the extent that critics acknowledge they work—by “numbing” or “blunting” emotions. Thus, Moncrieff has hypothesized that “Antidepressant-induced emotional numbness may directly reduce the intensity of people’s feelings of depression.”

 Similarly, Moncrieff and Horowitz have argued that

“…antidepressants appear to have a generalized emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it…[but] if antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.”

A recent review provided a much more nuanced picture, concluding that

“Emotional blunting has been reported by many patients diagnosed with MDD, but its neuropsychological basis remains indefinite. Most patients specifically attribute this symptom to their antidepressant medication; however, some psychologists believe that emotional blunting is also a residual symptom of depression due to incomplete treatment.”

In this article, we examine 3 independent studies of antidepressant treatment in major depression and its effects on emotional numbing or blunting. The key difference between 2 of these studies and much of the critical writing about antidepressants is their use of the 

Oxford Questionnaire on the Emotional Side-effects of Antidepressants

 (OQESA or OQuESA)—arguably the “gold standard” of assessment in this area.

 (This scale is now called the Oxford Depression Questionnaire, or ODQ.)

We shall see that none of the studies support the claim that antidepressants act to reduce depression through a process of emotional blunting or “numbing.” This is not to deny the clinical importance of assessing emotional blunting in the course of antidepressant treatment, nor is it to discount in any way the patient’s felt experience during treatment.

A Randomized-Controlled Study from France

Corruble and colleagues carried out a randomized, controlled, double-blind study comparing agomelatine (25-50 mg/d, n=164) and the SSRI, escitalopram (10-20 mg/d, n=160).

 Agomelatine is an atypical antidepressant that acts as an agonist to the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. It is not approved for use in the United States. [

https://www.psychiatryadvisor.com/home/depression-advisor/unique-attributes-of-agomelatine-might-renew-interest/]

The trial involved 12 weeks of active treatment, then a 12-week double-blind extension. The effects of these drugs on emotional experiences were compared in patients who completed the OQESA (agomelatine: n= 25; escitalopram: n= 20). Agomelatine and escitalopram similarly improved depressive symptoms, but emotional blunting was reported by 60% of patients taking escitalopram, versus 28% of those taking agomelatine.

At baseline before antidepressant treatment, the emotional experiences probed were extremely common and the same in both treatment groups. Of 20 OQESA items, 8 were more common in the escitalopram group and 12 in the agomelatine group. The occurrence of blunting items was associated with the depressed state measured by the Hamilton Depression Scale (HAMD) and Clinical Global Impression (CGI). Emotional blunting was significantly less prominent after 2 weeks, 12 weeks, and 24 weeks of treatment. At 24 weeks, emotional blunting was endorsed more frequently in the escitalopram group than in the agomelatine group, despite similar depression ratings in the 2 groups.

The authors concluded that “emotional blunting is prominent among patients with MDD at baseline” and hypothesized that emotional blunting “…behaves overall like a correlate of depressive symptoms.”

“The simplest explanation for our present findings is that emotional blunting is a symptom of depression not measured in conventional scales, which is incompletely treated with SSRIs as compared with agomelatine.” 

In short, the study findings provide no support for the claim that antidepressants act by a generalized emotion-numbing effect.

Two More Studies Reach Similar Conclusions

In a 16-week study of 98 patients diagnosed with MDD, Aşçibaşi et al analyzed the effects of antidepressant treatment (SSRI, n = 41; SNRI, n=40, other, n=13) on Montgomery-Åsberg Depression Rating Scale (MADRS) and OQESA scores.

 The OQESA scale was used at the 8- and 16-week visits. In brief, the study found that 

as the rate of remitted patients is increased, OQESA scores get decreased; 

and furthermore, the OQESA score of the remitted group was statistically low when compared with that of the nonremitted group at the 8- and 16-week visits. OQESA and MADRS scores were significantly correlated in all assessments. The authors opined that “…during the treatment of depression, depression-related emotional blunting symptoms and antidepressant-related emotional adverse effects may coexist”; however, “…as the severity of [the] depressive syndrome decreases, the severity of emotional adverse effects due to the antidepressants also decreases.”

These findings are not consistent with the claim that 

 reduce depressive symptoms via an emotion-numbing effect.

Finally, Peters et al analyzed data from adult outpatients with acute MDD who participated in 3 8-week randomized controlled trials.

 Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383), and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the “inability to feel” item from the MADRS. The study found that emotional responsiveness 

, on average, in all treatment groups, and that fewer than 6% of participants experienced more emotional blunting after antidepressant treatment. The authors acknowledged that this was a short-term study that cannot speak to the long-term effects of antidepressant treatment. Nonetheless, they concluded that, “The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response.” Rather—and consistent with the previous 2 studies—the authors hypothesized that “In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.”

Some Important Caveats and Study Limitations

 highlight the methodological advantages and limitations of the research discussed in this article. The Peters et al study has the highest-quality evidence, using completed controlled clinical trials, with a substantial number of research participants in each arm, including the placebo group.

 The study also uses the most neutral screen for emotional blunting, in that there is no suggestion of what might be the cause.

 both use the OQESA/ODQ, which was designed to measure more than emotional blunting and has a separate section to determine if the patient endorses emotional blunting to be caused by antidepressant treatment. The wording of the questions—and the fact that no other possible etiology for emotional blunting is suggested in the remainder of the questionnaire—is a potential source of bias. In this case, the participants are forced to choose antidepressants as an etiology. In effect, this is a “leading question,” and research participants may be able to guess that antidepressant induced emotional blunting is a focus of the research.

 In contrast, MADRS Item 8 captures emotional blunting but does not suggest a specific cause.

Emotional numbing or blunting is a fairly common complaint among patients taking serotonergic antidepressants and appears less common with noradrenergic/dopaminergic agents like 

 It is important to inform and educate patients about this problem and to inquire about it periodically, since emotional blunting is both distressing and associated with poor adherence to antidepressant treatment.

 However, it should not be assumed that the patient’s antidepressant is necessarily 

 of the patient’s complaint, since emotional blunting or numbing is frequently reported at baseline (prior to treatment).

Indeed, the studies reviewed here show that antidepressants did 

 significantly decrease emotional responsiveness, and that treatment response was 

 mediated by emotional blunting. More likely, emotional numbing, in most cases, is a residuum of the original depression.

How, then, do antidepressants work? Their precise mechanism of action is not fully understood, although recent studies point to the role of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which is now regarded as “… a key player in antidepressant action.”

 Antidepressants may also have anti-inflammatory effects—potentially important, since major depression is associated with elevated biomarkers of inflammation.

 During the past 4 years, 2 antidepressants modulating the glutamate system have been approved by the US Food and Drug Administration (FDA) for the treatment of major depression.

 Evidence supporting a role for stress, GABAergic dysfunction, altered neurosteroid signaling, and HPA axis dysregulation in 

 may suggest a role, in the near future, for neuroactive steroids in the treatment of depression.

In summary, there is no credible, scientific basis for telling patients that antidepressants are acting by means of generalized emotional numbing. On the contrary, our review shows that several antidepressants are actually associated with 

 of emotional numbing during the course of treatment. That said, if emotional blunting is convincingly related to use of a serotonergic antidepressant, changing to a noradrenergic/dopaminergic agent is a viable option for many patients.

 is recently retired from clinical practice and is a freelance writer and researcher on psychiatric topics. He writes the Real Psychiatry Blog. 

 is professor emeritus of psychiatry and a lecturer on bioethics and humanities at SUNY Upstate Medical University in Syracuse, New York; a clinical professor of psychiatry at Tufts University School of Medicine in Boston, Massachusetts; and editor in chief emeritus of 

(2007-2010). He is the author of several books. A collection of his works can be found on Amazon.

Dr Pies would like to thank Dr Marc Stone, Dr Randall Moore, and Prof Cathryn Lewis for their helpful email comments on aspects of this article. Thanks to Dr John J. Miller for suggestions re: mechanism of action. The views presented here are solely those of the authors. 

1. Stone MB, Yaseen ZS, Miller BJ, et al. 

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis.

Unpacking major depressive disorder: from classification to treatment selection.

Against the stream: antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants.

4. Moncrieff J, Horowitz M. Depression is probably not caused by a chemical imbalance in the brain – new study. 

. July 20, 2022. Accessed September 22, 2022. 

https://theconversation.com/depression-is-probably-not-caused-by-a-chemical-imbalance-in-the-brain-new-study-186672

Emotional blunting in patients with major depressive disorder: a brief non-systematic review of current research.

The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): development, validity, reliability and sensitivity to change.

7. Corruble E, de Bodinat C, Belaïdi C, Goodwin GM; agomelatine study group. 

Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial.

8. Aşçibaşi K, Çökmüş FP, Dikici DS, et al. 

Evaluation of emotional adverse effects of antidepressants: a follow-up study.

Emotional blunting with bupropion and serotonin reuptake inhibitors in three randomized controlled trials for acute major depressive disorder.

11. Goodwin GM, Price J, De Bodinat C, Laredo J. 

Emotional blunting with antidepressant treatments: a survey among depressed patients.

BDNF - a key transducer of antidepressant effects.

13. Tynan RJ, Weidenhofer J, Hinwood M, et al. 

A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia.

The effect of glutamatergic modulators on extracellular glutamate: how does this information contribute to the discovery of novel antidepressants?

The novel rapid-acting neurosteroid-based antidepressant generation.

A new depression scale designed to be sensitive to change.

As patients improve with antidepressant treatment, emotional numbing decreases.

Partial or inadequate response to antidepressants—whose mechanisms primarily involve monoamine pathways—are common.

 Multiple lines of evidence suggest that the glutamatergic system is also involved in the pathophysiology of 

. Dextromethorpahn is a N-methyl-D-aspartate receptor antagonist and a sigma-1 receptor agonist, both of which modulate glutamate neurotransmission. The clinical utility of dextromethorphan is limited by extensive CYP2D6 metabolism.

 AXS-05, an oral tablet that combines dextromethorphan and bupropion, is formulated to increase the bioavailability and half-life of dextromethorphan through inhibition of its metabolism by bupropion, and is under development for the treatment of 

 performed a phase 2, 6-week randomized double-blind active-controlled trial of AXS-05 in MDD at 4 sites in the US. They specifically used confirmation of disease severity through independent assessment and comprehensive blinding of trial sites to address factors that may contribute to poor signal detection in clinical trials.

 They included patients aged 18-65 with DSM-5 MDD and a current moderate or severe major depressive episode. Subjects had a score ≥ 25 on the Montgomery-Åsberg DepressionRating Scale (MADRS) and a score ≥ 4 on the ClinicalGlobal Impressions severity scale (CGI-S). Exclusion criteria were bipolar disorder, panic disorder, OCD, treatment-resistant depression (≥ 2 failed antidepressant trials in the current episode), substance use disorder in the past year, lifetime history of psychotic disorder, clinically significant suicide risk, and history of seizure disorder. Participants were randomized 1:1 to either dextromethorphan-bupropion (45 mg/105 mg) or bupropion (105 mg) once daily for 3 days then twice daily thereafter.

The primary efficacy variable was the change from baseline to week 6 in the MADRS total score. Secondary endpoints were clinical response (≥ 50% reduction in MADRS total score) or remission (MADRS total score ≤ 10), CGI-S and CGI-Improvement scores, scores in the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and MADRS-6 score. Study patients also tracked their mood daily with a visual analogue mood scale. The study safety population included all patients who received at least 1 dose of study medication. The efficacy population included all patients with illness severity confirmed by the independent assessor who were randomized, received at least 1 dose of study medication, and had at least 1 postbaseline assessment. Efficacy variables assessing a change from baseline were analyzed using mixed models with repeated measures. Those efficacy variables related to percentages were analyzed by chi-square tests.

The authors randomized 97 patients, of whom the independent assessment failed to confirm diagnosis or severity for 17 patients, resulting in 80 patients. Seventy-four of the 80 patients completed the trial. Mean treatment adherence was > 90% in both groups based on tablet counts. There were nonsignificantly more women, Black or African American, and Hispanic or Latino patients in the bupropion group (p > 0.15 for each). Dextromethorphan-bupropion was associated with significantly greater reduction in MADRS scores versus bupropion (-13.7 versus -8.8 points, effect size = 1.2), with statistically significant differences beginning at week 2. Response (60.5% versus 40.5%) and remission (46.5% versus 15.2%) at week 6 was significantly more likely in the dextromethorphan-bupropion group. Dextromethorphan-bupropion was also associated with significantly greater improvement on the CGI-S scale (-1.6 versus -1.0). The prevalence of any adverse events was 73% in the dextromethorphan-bupropion group and 65% in the bupropion group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, dry mouth, decreased appetite, and 

. There were no serious adverse events in the trial. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, sexual dysfunction, increased suicidality, or significant changes in laboratory parameters and vital signs.

The authors concluded that AXS-05 showed rapid, substantial, and statistically significant antidepressant efficacy compared to the active comparator on multiple clinician- and patient-reported measures of depression severity. A primary strength was the use of bupropion (at an identical dose to AXS-05) as the active comparator. Study limitations include exclusion of patients with lower levels of symptom severity and other psychiatric or medical comorbidities. Thus, findings from efficacy trials may not be mirrored in general practice. Another limitation is the short duration of the trial (6 weeks).

This study demonstrates that dextromethorphan-bupropion significantly improves depressive symptoms compared to bupropion and was generally well tolerated. This combination represents a novel pharmacologic approach to the treatment of MDD.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

1. Machado-Vieira R, Henter ID, Zarate CA Jr. 

New targets for rapid antidepressant action.

Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers.

4. Tabuteau H, Jones A, Anderson A, et al. 

Effect of AXS-05 (Dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial.

5. Freeman MP, Pooley J, Flynn MJ, et al. 

Guarding the gate: remote structured assessments to enhance enrollment precision in depression trials.

A new—cough, cough—combination treatment for depression. Researchers performed an RCT of dextromethorphan-bupropion in major depressive disorder.

Dextromethorphan-Bupropion in Depression

 covered a wide variety of psychiatric issues and industry updates, from historic USPSTF draft screening recommendations to the need for novel treatments for bipolar depression. Here are some highlights from the week.

USPSTF Makes Historic Anxiety and Depression Draft Screening Recommendations

The US Preventive Services Task Force (USPSTF) just released a draft recommendation stating that adults under the age of 65 should be screened for anxiety. The USPSTF draft recommendation is not final; it will now enter a public comment period.

The USPSTF draft “concludes with moderate certainty that screening for anxiety in adults, including pregnant and postpartum persons, has a moderate net benefit,” although the evidence for older adults (65 and older) is insufficient. The USPSTF has not previously made a recommendation on this topic. 

In the spring, while the year was still young, 

 published a 7000-word essay entitled “Doctors Gave Her Antipsychotics. She Decided to Live With Her Voices.” Some of it recounted the tragic but ultimately heroic story of Caroline Mazel-Carlton, a woman with a long experience of auditory hallucinations who, after much trauma, has become a powerful advocate for humane support and acceptance of those with similar experiences. The story, in the hands of author Daniel Bergner, is not hers alone, but rather the centerpiece of a quasi-editorial calling for a sea-change in psychiatric practice—a “fundamental paradigm shift” in our treatment of mental health. 

The Need for Novel Treatments for Bipolar Depression

Bipolar depression is a condition that proves difficult to treat for many patients. When patients with bipolar disorder (BD) go through a depressive episode, medication adjustment is often the first intervention that clinicians consider. Evidence for standard pharmacologic treatments for bipolar depression shows the strongest support for several dopamine-blocking agents, as well as for lithium and lamotrigine (Lamictal). Recently published treatment guidelines are reflective of this evidence. Pharmaceutical industry support for research on dopamine-blocking medications has contributed to their dominance in the marketplace. Older generic medications are less likely to be included in research trials and thus may not be adopted widely due to a perceived or real lack of evidence. 

Nutritional Treatments: The Next Frontier in Psychiatry

Over the last decade, we have seen an exponential increase in research relating diet quality to mental health. The typical Western diet of ultra-processed foods does not adequately meet the brain’s nutritional requirements and is a proven risk factor for the subsequent emergence of mental disorders in both adults and children. Given the strength of the data supporting the role of optimal nutrition for good mental health, psychiatrists are well positioned to introduce their patients to the topic of diet for mental health and the possible benefit of nutrient supplements for psychiatric conditions. 

From historic USPSTF draft screening recommendations to the need for novel treatments for bipolar depression, here are highlights from the week in Psychiatric Times.

The Week in Review: September 19-23

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to help readers conceptualize the difference between the use of standard and novel treatment approaches when treating patients with bipolar depression.

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(This is the first part of a 2-part article discussing novel treatments for bipolar depression. Part 2 will appear in subsequent issue and will discuss specific options and treatment strategies. –Ed.)

Bipolar depression is a condition that proves difficult to treat for many patients. When patients with bipolar disorder (BD) go through a depressive episode, medication adjustment is often the first intervention that clinicians consider. Evidence for standard pharmacologic treatments for bipolar depression shows the strongest support for several dopamine-blocking agents, as well as for 

 and lamotrigine (Lamictal). Recently published treatment guidelines are reflective of this evidence. Pharmaceutical industry support for research on dopamine-blocking medications has contributed to their dominance in the marketplace. Older generic medications are less likely to be included in research trials and thus may not be adopted widely due to a perceived or real lack of evidence.

A number of novel pharmacologic treatments have been studied for bipolar depression, and clinicians will be well served by becoming familiar with them. When standard treatments fail or cause intolerable adverse effects, having another set of options in your arsenal can be invaluable. In addition, utilizing nonpharmacologic treatments that have been shown to be effective for managing 

 is another important component of a comprehensive treatment plan.

Case Study “Sam” is a nonbinary person assigned female at birth, aged 22 years, who is diagnosed with BD II. They have a personal history of depressive episodes, anxiety symptoms, and hypomanic symptoms, as well as a strong family history of BD. They were originally diagnosed with major depressive disorder and generalized anxiety disorder in high school and, at that time, tried escitalopram, 

, and gabapentin. After the initial diagnosis of BD at age 21 years, Sam tried lamotrigine with poor results. They were started on lithium, which kept their mood stable for about a year until they began to experience a depressive episode that included hypersomnia, depressed mood, poor energy and motivation, poor appetite, and suicidal thoughts. Sam’s lithium level was 0.8 mmol/L, and they did not tolerate higher doses due to adverse effects. They tried several dopamine-blocking medications but were unable to tolerate any of them due to adverse effects, primarily sedation. Sam also tried a serotonin reuptake inhibitor in conjunction with lithium without effect on mood.

Standard pharmacologic treatments for bipolar depression are covered in various published treatment guidelines (

). There are currently 4 guidelines that are less than 10 years old, and they include recommendations for treating acute 

 The organizations that have released these guidelines are the British Association for Psychopharmacology, the Canadian Network for Mood and Anxiety Treatments and the International Society for Bipolar Disorders (CANMAT/ISBD), the National Institute for Health and Care Excellence, and the Royal Australian and New Zealand College of Psychiatrists. Each of these guidelines emphasizes the importance of nonpharmacologic interventions such as psychotherapy, family engagement, and addressing 

. Although these are important interventions, a detailed discussion of them is beyond the scope of this article.

The guidelines also include recommendations for pharmacologic treatments for acute bipolar depression. The CANMAT/ISBD guidelines include many of the novel treatments (which will be discussed here and in Part 2) as third-line recommendations.

 Guidelines also promote the engagement of the patient/service user in the treatment-planning process, and they highlight the importance of selecting interventions that are agreeable and likely to be followed. Clinicians may have the best of intentions in selecting treatments that are reflected in treatment guidelines, but if the patient is not on board due to concerns about adverse effects or difficulty achieving the recommendation (eg, 

 is not possible due to physical limitations, patient is unable to access psychotherapy due to lack of insurance coverage, etc), the treatment plan needs to go in a different direction.

If first-line, FDA-approved treatments have been trialed without success, it becomes necessary to use treatments that lack official FDA approval. Whatever is chosen, treatment options should be evidence based. All of the medications and interventions discussed have varying degrees of evidence. Clinicians should understand what the levels of evidence signify and should have reasonable expectations for the 

 of the drug or therapeutic intervention used.

Nassir Ghaemi, MD, MPH, an expert in this field, provides a concise and useful overview of evidence levels; he ranks them as levels 1 through 5, with the strongest evidence at level 1 and the weakest at level 5.

 Level 1 includes blinded randomized controlled trials (RCTs); level 2, open-label RCTs; level 3, large observational studies; level 4, small observational studies; and level 5, expert opinions and case studies. However, as Ghaemi has noted, level 4 or 5 evidence—although weaker—is not necessarily without value. Rather, the designation simply means that the evidence is not as strong. In a perfect world, treatment choices would be guided by evidence at levels 1 and 2. In the real world, however, conducting blinded RCTs on every treatment option is not always feasible or possible.

When patients struggle for relief from debilitating symptoms, it is often necessary to push forward with options that have a weaker evidence base. As clinicians progress down the levels of evidence, they should have realistic expectations of outcomes. When using third- and fourth-line treatments, the expected result may only be some degree of symptom relief and not complete remission. Fortunately, when patients present with severe symptoms, even a slight degree of improvement is usually welcome and acceptable to the patient. Additionally, patients may be interested in trying nonpharmacologic approaches as well as different pharmacologic options. The treatments to be discussed in this article have been listed according to their levels of evidence in 

. Part 2 will explore the use of these treatments, which address different targets based on a current understanding of the pathophysiology of psychiatric illness.

A growing body of research supports the role of 

 in the pathology of BD as well as in unipolar depression. The results of numerous studies have shown elevated proinflammatory cytokine levels in patients with BD.

 C-reactive protein was found to be significantly elevated in patients with BD during mania and more moderately so in depressive episodes.

 These findings can direct clinicians toward new treatment paths for patients who struggle with difficult-to-treat bipolar depression. Choosing treatments that target inflammation may improve the efficacy of current drug regimens and may also boost patients’ overall health. Many of the interventions discussed in this article are thought to target inflammation. These include probiotics, exercise, sleep, diet, and actual anti-inflammatory agents such as celecoxib.

Within the context of the inflammatory hypothesis are the roles of the microbiome and the gut-brain axis, which comprises several somatic components, including the gut microbiome, enteric nervous system, vagus nerve, neuroendocrine system, and central nervous system.

 The relationship between inflammation and the microbiome is currently not well understood, but it is known that the gut microbiome impacts immune system functioning through its relationship with cytokine modulation.

 In addition, gut microbiota modulate the production of neurotransmitters, and have been shown to be altered in individuals with BD, although findings have been mixed.

 External factors that may influence the biodiversity of the gut microbiome include diet, alcohol and other substances, medication, environment, genetics, and mode of birth (vaginal versus Cesarean).

 Evidence points toward a possible causal relationship between gut-brain axis alterations and the development of BD and other psychiatric disorders, mediated by epigenetic changes.

 Current knowledge of the relationship among the gut-brain axis, immune system activity, inflammation, and psychiatric symptoms has not yet yielded strong evidence for specific treatment interventions, but emerging evidence provides some support for the use of modalities such as anti-inflammatory diets and medications.

Clinical Decision-Making With Novel Approaches

When standard treatments have not worked, an important first step is to rework the diagnosis using evidence-based assessment tools. Some indispensable tools include the Mini International Neuropsychiatric Interview (MINI) and the Harvard Bipolarity Index (HBI). The MINI has been validated and is often more accurate than clinician opinion alone.

 The HBI is also key in helping clinicians to refine a diagnosis and to distinguish between BD and other psychiatric conditions.

The HBI considers 5 clinical domains: signs and symptoms, age of onset, course of illness, response to treatment, and family history. A score of 50 or more highly suggests a BD diagnosis. Additionally, screening for the presence of trauma may be helpful, as a comorbid trauma diagnosis makes treating most psychiatric conditions more difficult. A tool such as the Adverse Childhood Experiences Questionnaire can also be useful,

 although some critics say that this tool may not be substantive enough to fully assess the impacts of childhood 

 Use of the Clinician- Administered PTSD [posttraumatic stress disorder] Scale for DSM-5 is also advised.

 All of these tools are relatively easy to use and will increase the likelihood of an accurate diagnosis.

After confirming or altering the diagnosis, clinicians can then move on to selecting appropriate treatment options. If a diagnosis of bipolar depression is confirmed, and standard treatments have been unsuccessful, clinicians can begin to explore the treatments that will be discussed further in Part 2. Although using treatments that are not FDA approved may be a new experience for some clinicians, the evidence hierarchy can guide clinical decision-making. There is no evidence that trying more and more medications with the same mechanism of action is likely to be effective. Indeed, selecting pharmacologic interventions with different mechanisms of action that have evidence of efficacy in the treatment of 

 is a sensible strategy. Patients may require a combined strategy of nonpharmacologic and pharmacologic interventions. Because many of the nonpharmacologic interventions are conducive to overall health and well-being and have minimal to no adverse effects, there is little harm in trying them alongside pharmacologic interventions.

Evaluating patient-specific factors is also important when selecting treatments. Clinicians should already be familiar with this process when using standard FDA-approved medications. For example, if a patient has 

, most clinicians would be less likely to select a dopamine-blocking medication with a high risk for metabolic adverse effects. Similarly, for patients who have comorbid inflammatory conditions, the use of anti-inflammatory agents may be a wise choice. Patients who have accompanying neurocognitive symptoms may benefit from a dopamine agonist medication. For patients with limited resources, light box therapy may not be attainable and would not be a reasonable recommendation. In that case, a recommendation to sit outdoors for 30 minutes every morning would be more realistic. One potential benefit of using older generic medications is that they may be more accessible than newer brand-name drugs. Tailoring treatment selections to the patient’s individual needs and preferences may increase the likelihood of success.

Case Study, Continued After considering Sam’s treatment history, presenting symptoms, and treatment preferences, the treating clinician decided to start pramipexole along with lithium. Pramipexole was titrated over 3 weeks to 1 mg daily with PRN ondansetron for nausea. The clinician also recommended that Sam increase their physical exercise and morning sunlight exposure.

About 3 weeks later, Sam began to notice improvement in motivation and energy, appetite, sleep patterns, and suicidal thoughts. Their depressed mood persisted, however, and Sam’s therapist noted it was likely related to situational factors and past trauma. Sam experiences a great deal of family stress associated with their mother and grief related to their father’s death a few years prior. Sam and their therapist continued to work through these issues, and Sam’s mood slowly improved over the next several months.

is a psychiatric mental health nurse practitioner and clinical assistant professor at the Virginia Commonwealth University School of Nursing in Richmond, VA.

is a psychiatric mental health nurse practitioner at the Mood Treatment Center in Winston-Salem, NC.

1. Treatment guidelines: bipolar disorder. American Association of Psychiatric Pharmacists. Accessed July 19, 2022. 

https://cpnp.org/guideline/external/bipolar

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.

In this CME article, learn more about the rationale for considering novel treatments for patients with bipolar depression.

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