Yedishtra Naidoo, MD

In a scenario common to psychiatrists, patient M presents to the clinic, requesting treatment for “mood swings.”

The clinician’s first reaction may be to take a breath and exhale slowly-and perhaps reach up to massage his or her neck before considering the differentials. Unspecified bipolar disorder? Comorbid borderline personality disorder (BPD)? Is it time to break out the mixed specifier from DSM-5?

A 32-year-old man with thin cut marks on his arms, M describes irritability and changes in mood that last hours or days, reduced sleep, impaired appetite, and distractibility. He is easily provoked, has been having racing thoughts and increased activity. He describes his mood as “depressed” and complains that his work and interpersonal relationships are impaired. He admits to multiple past suicide attempts.

After gathering collateral and nailing down a diagnosis, the next question is management. Given M’s depressive symptoms, is an antidepressant suitable?

Diagnostic criteria for bipolar disorder mixed state in DSM-5 were discussed at APA 2015 by Roger McIntyre, MD. They are defined as:

• Hypomania plus 3 depressive symptoms 

• A full depression plus 3 mania symptoms

The latter criterion applies to patient M. If a major depression is present, one cannot count irritability, insomnia, distractibility, or indecisiveness toward mania. The specifier was previously applied to bipolar I but is now also applied to bipolar II and unipolar depression in DSM-5.

Manic symptoms that characterize mixed manic episodes typically include greater mood lability and irritability. 

 may be defined as rapid oscillations of intense affect, with difficulty regulating these oscillations or their behavioral consequences.

 Nevertheless, it is a common presenting complaint, as was the case with patient M.

Bipolar disorder mood instability tends to last days, rather than minutes or hours as in BPD. Linked to episodic high-energy states rather than interpersonal sensitivity and self-injury, the mood instability is defined more by euphoria than the anger seen in BPD. However, when applied to bipolar disorder, the positive predictive value (PPV) for 

 In other words, when included in a clinical diagnosis, it is accurate only 14% of the time. On the other hand, mood elevation has a PPV of 0.81; reduced need for sleep, 0.62; racing thoughts, 0.64; and increased goal-directed activity, 0.71.

One particularly divisive topic has been the use of antidepressants in bipolar disorder. Should a patient who has bipolar disorder with depressive features be treated with an antidepressant? This question was discussed at length by 

, in his talk at APA 2015. In clinical practice, 55% of physicians were not concerned that their choice of treatment would lead to a manic episode; 5% thought there was no further risk of treatment-emergent mood disorder when giving antidepressants to patients with bipolar I disorder; and 54% would prescribe antidepressants as a monotherapy for depressed patients with risk factors for bipolar I disorder.

 As discussed by Dr Ghaemi, however, antidepressants are often ineffective for bipolar depressive symptoms.

Dr Ghaemi’s group undertook a randomized controlled trial that examined citalopram as a maintenance treatment for bipolar depression. After 12 months, there was no benefit of citalopram over placebo in improving depressive symptoms. In addition to its ineffectiveness, he argued, it can cause a switch to mania-particularly when used with TCAs and SNRIs. This switching can occur in patients treated acutely and in those receiving maintenance therapy. The rate to manic switch is typically highest in bipolar I disorder, followed by mixed states, bipolar II disorder and, finally, unipolar depression.

, quetiapine was found to be effective in acute bipolar depression, as measured by the Montgomery-Asberg Depression Rating Scale response.

 Paroxetine was found to be no better than placebo. In addition to manic switching, some patients with bipolar mixed presentations who received antidepressants experienced an up to 3-fold increase in depressive episodes.

On the basis of the above evidence, it appears that antidepressants should be avoided in most patients with bipolar disorder. As argued by Dr McIntyre, however, clinical wisdom suggests that some patients with a diagnosis of bipolar depression seem to improve with antidepressants. There is also some 

Until there is a biomarker for bipolar disorder, the debate about antidepressants in patients with the disorder will likely continue. In the meantime, clinical features can be used to better predict those patients with bipolar disorder. As always, more research is required to elucidate the etiology of manic, mixed, and depressive episodes to better guide diagnosis and treatment.

This article was originally posted on 6/15/2015 and has since been updated.

Dr Naidoo is a fourth year psychiatry resident in the Department of Psychiatry and Behavioral Neurosciences at Wayne State University in Detroit.

 Marwaha S, He Z, Broome M, et al. How is affective instability defined and measured? A systematic review. 

 Goldberg JF, Garno JL, Callahan AM, et al. Overdiagnosis of bipolar disorder among substance use disorder inpatients with mood instability. 

 Glauser TA, Cerenzia W, Wiley S, et al. Identifying psychiatrists’ practice patterns when managing depression in patients with bipolar I disorder: a descriptive study to inform education needs. 

 Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. 

 Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. 

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Unspecified bipolar disorder? Comorbid borderline personality disorder? Or, in the case presented here, is it time to break out the mixed specifier from DSM-5? 

Bipolar Disorder: Got Antidepressants?

Psychiatrists are faced on a daily basis with depressed patients whose relative inactivity and high BMI are a cause for concern. These patients warrant routine psychoeducation and coordination with primary care physicians who can monitor metabolic indicators, such as lipid profiles. Investment in a good office scale to monitor patient weights is also a good idea.

In his talk on depression and obesity at APA 2015, Julio Licinio, MD, highlighted several important reasons why obesity and depression should be studied:

• Epidemiological studies suggest that depression can cause obesity and vice versa

• Antidepressants can result in weight gain and are the second most sold drug category in the US

• Stress can cause depression and obesity, and both can have negative cardiometabolic effects

• Depression and obesity are expensive: they cost the US government $210 billion and $147 billion a year, respectively

The interaction between obesity and depression is bidirectional, and stress may be a common mediator. Chronic stress may result in both disorders. It is well known that glucocorticoids affect numerous body organs and systems, including the liver, muscles, immune system, and cardiovascular system. However, they also affect the CNS.

Repeated stress or chronically elevated glucocorticoid levels can cause atrophy of apical dendrites in CA3 and reduce production of new granule cells in the dentate gyrus causing 

 This frequently results in cognitive impairments and neuronal loss in limbic regions such as the hippocampus. Stress hormones also affect the immune system. The brain produces its own cytokines that are regulated differently from those in the periphery; this may not imply infection or immune reactivity. These neurokinins contribute to mood, cognition, and behavior.

 as a hormone that signals fullness by binding its receptor in the hypothalamus.

 It has also been suggested that leptin has an important role to play in depression. Animal and human studies have shown that low circulating leptin levels are associated with exposure to chronic stress and with symptoms of depression, such as reduced locomotion and reduced sucrose-seeking in humans.

Findings indicate that antidepressants such as fluoxetine increase neurogenesis via cytokine increase, particularly interleukin (IL)-6 and IL-1Î±.5 

, leptin-deficient mice had reduced brain weight and cortical volume.

 Conversely, other results have shown that neurogenesis in limbic regions was increased in humans and mice treated with leptin.

These findings support the hypothesis that some depressed individuals may lack neurotrophic support because of low levels of circulating leptin, and the presence of chronic stress results in neuronal apoptosis in limbic structures. Replacement of leptin in these individuals may help correct that deficiency. However, financial and regulatory mechanisms have inhibited clinical trials in this area.

Top 5 reasons to monitor obesity in depressed patients

1. The 2 frequently coexist
2. Epidemiological studies suggest that depression can cause obesity and vice versa
3. Antidepressants can result in weight gain and are the second most sold drug category in the US
4. Stress can cause depression and obesity, and both can have negative cardiometabolic effects
5. Depression and obesity are expensive: they cost the US government $210 billion and $147 billion a year, respectively

What is the link to obesity? Since leptin is produced in adipose tissue, shouldn’t overweight individuals have elevated circulating leptin? The answer to the second question is yes. However, animal models and human studies suggest obese individuals may have leptin resistance. This may be caused by defects in the leptin signaling pathway at several levels, including impaired transport of leptin across the blood-brain barrier, reduced function of the leptin receptor, and defects in leptin signal transduction.

 Therefore, depression in obese individuals may also be due to a central deficit in leptin.

I have described how obesity may result in depression in the context of stress. What about the converse-depression resulting in obesity?

In his talk, Dr Licinio attributed this to antidepressant use. He described the rise in subjective stress levels over time experienced by individuals, due to factors such as money, work, economy, and family relationships, as described in the 2012 APA stress survey. This contributes to rising depression. To counteract the rising chronic depression, partly due to stress, Dr Licinio cited the trend of increasing antidepressant use in the US, the UK, and Australia since the late 1990s. Antidepressants have a well-known propensity to cause weight gain, possibly due to peripheral increase in insulin-like growth factor 1 (IGF-1).

 Furthermore, Dr Licinio mentioned that in depressed individuals, exposure to antidepressants for only a short period may have lasting effects on their propensity to gain weight when they are exposed to a high-fat diet. This may be due to epigenetic effects. Thus, the rise in antidepressant use over the past few decades may have contributed to obesity in depressed individuals with chronic stress.

In a world with increasingly scarce resources, it is likely that stress will continue to rise-contributing to depression and obesity. If the past is any indicator, obesity will continue to be an epidemic and may contribute to depression. Conversely, antidepressant use may make weight gain more likely. Neuroendocrine, immunological, and genetic targets such as leptin, IGF-1, and methylated genes may hold promise for future interventions for both of these diseases.

This article was originially posted on June 17, 2015 and has since been updated.

Dr Naidoo is a fourth-year psychiatry resident in the department of psychiatry and behavioral neurosciences at Wayne State University in Detroit.

 MagariÃ±os AM, GarcÃ­a Verdugo JM, McEwen BS. Chronic stress alters synaptic terminal structure in hippocampus.

 Elmquist JK, BjÃ¸rbaek C, Ahima RS, et al. Distributions of leptin receptor mRNA isoforms in the rat brain. 

 Katz RJ. Animal model of depression: pharmacological sensitivity of a hedonic deficit. 

 Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. 

 Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. 

 Ahima RS, BjÃ¸rbaek C, Osei S, Flier JS. Regulation of neuronal and glial proteins by leptin: implications for brain development. 

 Matochik JA, London ED, Yildiz BO, et al. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. 

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 MÃ¼nzberg H, Myers MG Jr. Molecular and anatomical determinants of central leptin resistance. 

 Licinio J, Wong ML. The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. 

Stress may be a common mediator in both obesity and depression. Here are the top 5 reasons to monitor obesity in depressed patients and practice psychoeducation on a routine basis.

Cutting the Fat: Obesity and Depression

In the Indian parable of the blind men and the elephant, a group of blind men touch various parts of an elephant to identify it. One man feels the beast’s trunk and thinks it may be a hose. Another feels its body and thinks it is a wall. Yet another feels its tail and concludes it is snake.

This story may be interpreted as one person’s truth not being a total truth-and that multiple perspectives are required to fully understand a concept. This seems to be the growing consensus with the schizophrenia spectrum disorders. At the APA 2015 conference, the theme of multiple perspectives was evident across the pathophysiology, diagnosis, and treatment of the psychotic disorders.

[[{"type":"media","view_mode":"media_crop","fid":"38624","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_7143363786598","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3855","media_crop_rotate":"0","media_crop_scale_h":"174","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Schizophrenia is a highly heritable disorder, which suggests a major role for various alleles in its etiology. At the conference, Anil Malhotra, MD, discussed a recent multistage schizophrenia genome-wide association study published in the journal 

 In that study, all available schizophrenia samples with published or unpublished genome-wide association study genotypes (36,989 cases and 113,075 controls) were combined into a systematic analysis. The results were 108 conservatively defined loci that met genome-wide significance, which coded for approximately 341 different genes. The identified loci likely represented the low-hanging fruit, with larger effect sizes, and it is likely that many more loci-and therefore more functional units-exist with reduced relative impact.

What is fascinating is that when the group cross-referenced the genes in a drug target database, 20 drug targets were identified for which there are approved drugs. Calcium channel modifiers, NMDA antagonists, nicotine partial agonists, and the well-known 

 receptor antagonists were identified. This indicates that even viewed through a strictly genetic lens, schizophrenia is not a single disorder, but rather a spectrum-some possibly channelopathies, some glutamatergic-related, some dopamine- and glutamate-related, and possibly other variants as well.

In an associated talk, Matcheri Keshavan, MD, noted that the 341 genes could be organized into functional gene networks, consisting of immunity-related genes and ones involved in the glutamate system.

Rajiv Tandon, MD, discussed the attempt of DSM-5 to embrace the heterogeneity of schizophrenia, through the new 0-4 subscale rating across 8 dimensions: hallucinations, delusions, disorganized speech, negative symptoms, disorganized behavior, mood, motor, and cognition. It is important to consider all 8 when constructing and monitoring a treatment plan.

Henry A. Nasrallah, MD, discussed treatment by considering that at present only positive symptoms, motor and, at times, mood, are targets for intervention. He suggested a 3-pronged approach, conceptualizing biological treatment from neurodevelopmental, neurochemical, and neurodegenerative viewpoints. Neurodevelopmentally, one should encourage patients to minimize the risk of perinatal infection, such as toxoplasmosis, which has been linked to 

 He also recommended perinatal vitamin D, to reduce gestational diabetes risk. From a neurochemical and neurodegenerative standpoint, he recommended using atypical antipsychotics, which are associated with increased neurogenesis through neurotrophic growth factors into the hippocampus. He recommended avoiding typical antipsychotics, such as haloperidol, fluphenazine, and perphenazine, all of which are 

 This is particularly concerning, given that preventing exacerbations of schizophrenia is thought to be important in reducing brain volume loss. Lithium and SSRIs were also mentioned as having effects associated with increased brain-derived neurotrophic factor in the brain.

The elephant parable can be interpreted as a metaphor for multiple perspectives to find total truth. Schizophrenia is now viewed as a spectrum with multiple parts to be examined by researchers. Given the above, it seems more likely that what we will find is that there is no elephant at all, but a collection of different parts, each with its own etiology and treatment.

This article was originally posted on 5/22/2015 and has since been updated.

Dr Naidoo is a fourth year psychiatry resident in the Department of Psychiatry and Behavioral Neurosciences at Wayne State University in Detroit. 

 Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. 

 Torrey EF, Yolken RH. Toxoplasma gondii and schizophrenia. 

 Nasrallah HA. Haloperidol is clearly neurotoxic. Should it be banned? 

Multiple perspectives are required to fully understand a concept. This seems to be the growing consensus with the schizophrenia spectrum disorders.

Author | Yedishtra Naidoo, MD

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