Evidence-Based Reviews

How to manage depression in overweight or obese patients

Current Psychiatry. 2012 July;11(7):33-40

References

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Table 2

Pharmacotherapy and weight gain: Adjunctive agents

Agent	Use in depression	Effect on weight
SGAs
Olanzapine	Psychotic depression	Large gain
Clozapine	Adjunct; psychotic depression	Large gain
Quetiapine	Primary; adjunct	Large gain
Aripiprazole	Adjunct	Small gain
Risperidone	Psychotic depression	Small gain
Ziprasidone	Psychotic depression	Small loss
Mood stabilizers
Divalproex	Treatment resistance, bipolar disorder	Moderate to large gain
Lamotrigine	Treatment resistance	Neutral
SGAs: second-generation antipsychotics Source: References 22,23

Box

Depression and obesity: The ‘inflammation connection’

Research suggests that both depression and obesity are associated with immune dysregulation and inflammation.^a-d Although the complexities of these interactions are beyond the scope of this article, having a model for understanding the role of inflammation in overweight or obese patients with depression (OW/OB-D) may be useful. Data supporting a role for immune dysregulation in OW/OB-D patients rests on the following findings:

Fat and muscle are endocrine organs: Fat is not just a storage organ for energy-rich lipids but also a rich source of cytokines, including monocyte chemotactic protein-1 (MCP-1), interleukin-2, and tumor necrosis factor-α (TNF-α). The increase in MCP-1 in fat tissue triggers a cascade of events that leads to chronic inflammation in adipose tissue. These substances can be released into circulation, stimulating inflammatory responses in other tissues. Data suggest that obesity’s effects on cardiovascular disease are mediated by these adipose-derived inflammatory hormones. There is a strong relationship between the volume of adipose tissue and the amount of pro-inflammatory hormones released; therefore, reducing weight reduces inflammatory burden on the body.

Pedersen^e pointed out that muscle also is an endocrine organ. Among the cytokines (or “myokines”) muscle produces are interleukin-6 (IL-6), interleukin-8, and brain-derived neurotrophic factor. During exercise, the amount of IL-6 released from muscles may increase by 100-fold. Although IL-6 usually is considered a pro-inflammatory regulator, it—or other muscle-derived myokines—may be responsible for some of exercise’s beneficial effects.^e

If this hypothesis is correct, patients whose exercise includes resistance training—which increases muscle mass—are not just getting stronger or burning calories but may be facilitating release of hormones that could counteract obesity’s inflammatory effects.

Cytokine levels are elevated in depression and obesity: A substantial body of evidence shows that depressed patients have elevated circulating levels of inflammation markers. In particular, the proinflammatory cytokines IL-6 and interleukin-1β and the acute phase reactant C-reactive protein (CRP) are elevated in depressed patients.^f Studies also show that blood levels of IL-6, TNF-α, and CRP are elevated in obese patients.^g

Fat-derived cytokines alter metabolic pathways related to mood and inflammation: Among the many possible pathways linking cytokine actions and depression, the effects of TNF-α on serotonin metabolism have been studied extensively.^h,i TNF-α activates brain indoleamine 2,3-dioxygenase, leading to rapid depletion of serotonin and exacerbation of depressive symptoms.^j

Regarding physical problems, evidence suggests adipose-tissue-derived pro-inflammatory agents are involved in development of metabolic syndrome, a condition characterized by insulin resistance, glucose intolerance, atherogenic dyslipidemia, visceral adiposity, hypercoagulation, chronic inflammation, oxidative stress, and hypertension.^k These conditions are strong risk factors for type II diabetes, coronary artery disease, hypertension, and stroke.

Anti-inflammatory agents for depression

Data suggest a model in which weight gain leads to an increase in pro-inflammatory cytokines. When released into the circulation, these cytokines produce a variety of deleterious effects, including blockade of serotonin synthesis in the brain that leads to depressive symptoms. Evidence suggests that anti-inflammatory agents might disrupt this process.

Celecoxib. The anti-inflammatory agent celecoxib acts by inhibiting cyclooxygenase-2, the rate-limiting enzyme in the synthesis of prostaglandin, a powerful inflammation mediator. Three double-blind, placebo-controlled trials have compared groups of:

depressed patients receiving reboxetine with and without celecoxib^l or fluoxetine, 40 mg/d, with and without celecoxib^m
bipolar disorder patients taking mood stabilizers or atypical antipsychotics with and without celecoxib, 400 mg/d.ⁿ

These studies suggest that celecoxib may accelerate improvement in depressive symptoms. Celecoxib’s potential for increased cardiovascular risk may limit its use.

Aspirin. Mendlewicz et al^o conducted an open-label study in which 24 depressed patients who failed to respond to 4 weeks of antidepressant treatment received adjunctive acetylsalicylic acid, 160 mg/d, for another 4 weeks. They found that 52% of patients responded when aspirin was added to their regimen, and the improvement was seen during the first week of treatment.

References

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O’Connor JC, André C, Wang Y, et al. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci. 2009;29(13):4200-4209.
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Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11(7):680-684.
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Mendlewicz J, Kriwin P, Oswald P, et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21(4):227-231.