Q. What are the implications for medication management of weight loss surgery for morbidly obese patients with depression?

A. Obesity increases the risk of depression by over 40% after controlling for other factors (Johnston et al., 2004). With this risk factor in mind, individuals undergoing weight loss surgery for morbid obesity would be expected to have a higher risk for depression.

The mechanism contributing to this etiology is controversial, although serotonin modulation may play a role. Serotonin is believed to be involved in the complex process of integrating physiological and behavioral systems geared toward energy balance and appetite regulation (Rosmond, 2004). However, the unacceptable weight gain that occurs in most people suggests that the regulatory system may not be sufficient under all circumstances. As many psychiatrists are aware, insufficient serotonergic neuronal function in the central nervous system has been shown in many studies to occur in patents with depression. In such serotonin-deficient patients, treatment with medications increasing the concentration of synaptic serotonin provides an efficacious antidepressant response. Central nervous system serotonin deficiency may link etiological pathophysiology between obesity and depression.

To date, antidepressants have not been approved by the U.S. Food and Drug Administration specifically for the treatment of obesity, although clinicians have used them as pharmacological tools in managing weight in daily clinical practice. Keeping the aforementioned possible linked etiology between depression and obesity in mind, certain antidepressants may be helpful in providing a synergistic response following surgery for weight loss. For instance, in randomized, controlled trials involving patients with depression treated with antidepressants, selective serotonin reuptake inhibitors (e.g., Fluoxetine [Prozac], Sertraline [Zoloft] and fluvoxamine [Luvox]) were associated with limited weight gain and have subsequently specifically been studied for the treatment of obesity with inconclusive results (Appolinario et al., 2004). Additional data have also been published for other antidepressants (e.g., venlafaxine [Effexor], Citalopram [Celexa] and bupropion [Wellbutrin]). Appolinario and colleagues concluded, “Based on the available data for the efficacy of psychotropic agents in obesity and other related conditions, SSRIs may be considered for the management of certain subgroups of obese individuals with comorbid conditions such as depression, binge-eating disorder and type 2 diabetes mellitus.”

Individuals who successfully lose weight and maintain that weight loss have been shown to experience improved mood, self-confidence and quality of life (Miller-Kovach et al., 1999). Improvement in the psychological and behavioral manifestations of mood disorders has been associated with a longer duration of weight loss maintenance.

References

Appolinario JC, Bueno JR, Coutinho W (2004), Psychotropic drugs in the treatment of obesity: what promise? CNS Drugs 18(10):629-651.

Johnston E, Johnson S, McLeod P, Johnston M (2004), The relation of body mass index to depressive symptoms. Can J Public Health 95(3):179-183.

Miller-Kovach K, Hermann M, Winick M (1999), The psychological ramifications of weight management. J Womens Health Gend Based Med 8(4):477-482.

Rosmond R (2004), Obesity and depression: same disease, different names? Med Hypotheses 62(6):976-979.

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Q. Is it OK to use psychostimulants to augment antidepressants for depressive exhaustion and hypersomnia?

A. The relief of fatigue associated with depression slowly responds to antidepressant treatment and psychotherapy (Demyttenaere et al., 2004). Productivity and work performance are strongly correlated to improvement in energy while recovering from depression. Neurotransmittors such as serotonin, norepinephrine, dopamine and histamine mediate symptoms of fatigue in depressive disorder. Although there are limited data addressing the benefits of augmentation strategies on fatigue-related symptoms, there is a pharmacological rationale for augmentation of antidepressant treatment with stimulants or modafinil (Provigil).

By definition, augmentation strategies involve the use of a pharmacologic agent that is not considered to be a standard antidepressant but may boost or enhance the effect of an antidepressant (Fava, 2001). Stimulants and modafinil meet these criteria as augmenters and may specifically address the frequently residual symptoms of sleepiness and fatigue often persisting in patients suffering from depression (Stahl et al., 2003).

Modafinil, a wake-promoting agent with minimum effects on dopamine transmission, inhibits the sleep-promoting neurons from the ventrolateral preoptic nucleus (Gallopin et al., 2004) and activates hypothalamic histamine release (Ishizuka et al., 2003). Modafinil has received significant attention as an augmenting agent for depressed patients with fatigue:

 
• A three-week, open-label study assessed the use of adjunctive modafanil with selective serotonin reuptake inhibitors for 20 subjects who experienced sedation thought to be secondary to the SSRIs (Schwartz et al., 2004). Modafinil plus SSRIs significantly improved overall depressive symptoms, as shown by reductions in mean Hamilton Rating Scale for Depression (HAM-D) total scores. Subjective estimates of wakefulness were improved on the Epworth Sleepiness Scale (ESS) at assessments at all weeks and reduced fatigue was improved on the Fatigue Severity Scale (FSS). Most notably, at the final visit, modafinil had improved overall health status and health-related quality of life.  
• A six-week, open-label study assessed the augmentation of modafinil titrated up to 200 mg/day concomitantly with the initiation of Fluoxetine (Prozac) or Paroxetine (Paxil) in 29 patients with major depressive disorder and fatigue (Ninan et al., 2004). Adjunct modafinil rapidly and significantly reduced fatigue according to FSS scores within one week and improved wakefulness as measured by the ESS. Nausea and headache were the most common side effects.  
• The most convincing study was a six-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study where 136 depressed and fatigued patients received once-daily doses (100 mg to 400 mg) of modafinil or matching placebo as adjunctive treatment to ongoing antidepressant therapy (DeBattista et al., 2003). Within the first two weeks, modafinil augmentation rapidly improved fatigue and daytime wakefulness compared to placebo (as measured by the FSS and ESS). However, these results did not differ from placebo by week 6, suggesting that modafinil may be considered a short-term treatment for patients with fatigue and hypersomnolance.

Methylphenidate (Ritalin, Concerta, Metadate) and dextroamphetamine (Dexedrine), which release dopamine within major components of the mesocorticolimbic dopamine system (Naranjo et al., 2001), have been used as augmenting agents with antidepressants for individuals suffering from fatigue and hypersomnolence, especially as palliative care for individuals with medical comorbidities (Dein and George, 2002; Homsi et al., 2000; Roy and Bernier, 1999).

A 10-week, open-label study examined 11 outpatients older than 70 who were diagnosed with major depressive disorder to assess them for an accelerated response (Lavretsky et al., 2003). Methylphenidate 5 mg/day to 20 mg/day (mean dose=12.2.mg/day) was added for eight weeks to Citalopram (Celexa) (20 mg/day to 40 mg/day) prior to it being tapered and discontinued during weeks 9 and 10. Nine of the 11 patients completed the study. Six patients met criteria for accelerated response by day 14 (HAM-D score <10 and Clinical Global Impressions-Improvement [CGI-I] scale score of 1 or 2), and two more patients responded by week 3.

Additionally, stimulants have been shown to be a potentially effective, fast-acting antidepressant treatment for HIV patients with depression and debilitating fatigue (Breitbart et al., 2001; Wagner Rabkin, 2000). Concerns needing to be addressed while using stimulants include the activation of bipolar mania in predisposed individuals, the emergence of tic disorders, seizures, decreased appetite, increasing tolerance and insomnia.

References

Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J (2001), A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med 161(3):411-420.

DeBattista C, Doghramji K, Menza MA et al. (2003), Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 64(9):1057-1064.

Dein S, George R (2002), A place for psychostimulants in palliative care? J Palliat Care 18(3):196-199.

Demyttenaere K, De Fruyt J, Stahl SM (2004), The many faces of fatigue in major depressive disorder. Int J Neuropsychopharmacol 14:1-13.

Fava M (2001), Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 62(suppl 18):4-11.

Gallopin T, Luppi PH, Rambert FA et al. (2004), Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study. Sleep 27(1):19-25 [see comment].

Homsi J, Walsh D, Nelson KA et al. (2000), Methylphenidate for depression in hospice practice: a case series. Am J Hosp Palliat Care 17(6):393-398.

Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A (2003), Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci Lett 339(2):143-146.

Lavretsky H, Kim MD, Kumar A, Reynolds CF (2003), Combined treatment with methylphenidate and Citalopram for accelerated response in the elderly: an open trial. J Clin Psychiatry 64(12):1410-1414.

Naranjo CA, Tremblay LK, Busto UE (2001), The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry 25(4):781-823.

Ninan PT, Hassman HA, Glass SJ, McManus FC (2004), Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J Clin Psychiatry 65(3):414-420.

Roy M, Bernier J (1999), A rapid response with psychostimulants in the treatment of depressed persons with medical illnesses. Can J Psychiatry 44(3):283-284 [letter].

Schwartz TL, Azhar N, Cole K et al. (2004), An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy. J Clin Psychiatry 65(9):1223-1227.

Stahl SM, Zhang L, Damatarca C, Grady M (2003), Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry 64(suppl 14):6-17.