Dear Editor:

I found the article by Drs. Targum and Fava, “Fatigue as a Residual Symptom of Depression” [Innov Clin Neurosci 2011;8(10):40–43], to be quite interesting. Dr. Targum’s questions to Dr. Fava, a specialist of psychopharmacology, were so didactic that it made this article sufficient to bridge the gap between research and practice. Nevertheless, I believe the article lacked sufficient discussion regarding several important elements, even though I understand that the article was limited to discussing fatigue related to major depressive disorder (MDD).

My dissatisfaction with the article is mainly due to the lack of explanation for another important aspect related to MDD: comorbid insomnia. Dr. Fava himself has already stressed such correlates elsewhere.1,2 For example, he previously states that whether insomnia is a precursor, symptom, residual symptom, or side effect of depression or its treatment, clinicians must give serious attention and attempt to resolve sleep disturbances.1 Based on this viewpoint, I feel some additional comments and questions should be addressed in order to elaborate on the current discussion by Drs. Targum and Fava.

Patients with MDD commonly experience insomnia complaints, including difficulty falling asleep, difficulty maintaining sleep, awakening early, and experiencing nonrestorative sleep. Previous epidemiological studies have estimated insomnia complaints to occur in up to 90 percent of patients with MDD.2 Moreover, insomnia is among the most common residual symptom of MDD, and pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants can cause insomnia, as the authors suggested.[1,2]

As Dr. Fava mentioned in a recent article,2 it is true that a paradigm shift in treating insomnia and coexisting psychiatric disorders has occurred. Proposed criteria for insomnia in the forthcoming Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) reflects the research recommendations by United States National Institutes of Health (NIH), which has been widely adopted in the field of clinical sleep science.[3] The new terminology insomnia disorder signifies a 24-hour disease, implying both nighttime insomnia symptoms and the daytime impairment related to it. Therefore, based on this new “insomnia” definition, fatigue itself can be regarded as a core symptom of insomnia. Rather than treating insomnia as a symptom of MDD, the current empirically supported literature now recommends that each condition be treated independently. Importantly, Dr. Fava also suggests that insomnia and insomnia-related daytime symptoms respond differently from and independently of depression symptoms. I agree with his remarks that MDD and insomnia represent at least two different dimensions of a single disorder, if not two separate disorders.

Although clinicians often use depressive symptoms, such as fatigue, to characterize the daytime consequences of insomnia, strictly speaking, the criteria overlap between insomnia and MDD has only been restricted to the symptoms of insomnia itself.4 In recent literature, while daytime sleepiness, hypersomnia, and fatigue are common symptoms of depression, such symptoms can occur independently or they may occur secondarily to insomnia comorbidity or the side effects of antidepressant medication themselves. Thus, while Drs. Targum and Fava stress the importance of recognizing, differentiating, and treating fatigue in patients with MDD, we need to take into account both aspects of insomnia and depression equally.[5]

I am also concerned that, in their current article, Drs. Targum and Fava only comment on new medications that may soon be available for the treatment as residual fatigue. I wonder if their conclusion might mislead the readers into having too much optimism for the development of new evaluation tools and novel pharmacological agents in the next few years. Further research studying on whether insomnia is a modifiable risk factor in depression treatment would be valuable, since effective antidepressant treatment surely affects sleep in some way.[1,4] We psychiatrists and mental health professionals should have empathy for such individuals manifesting fatigue in the current 24/7 society.

1. Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry. 2004;65:27–32.
2. Fava M, Asnis GM, Shrivastava RK, et al. Improved insomnia symptoms and sleep-related next-day functioning in patients with comorbid major depressive disorder and insomnia following concomitant zolpidem extended-release 12.5mg and escitalopram treatment: a randomized controlled trial. J Clin Psychiatry. 2011;72:914–928.
3. National Institutes of Health (NIH). National Institutes of Health State of the Science conference statement on manifestations and management of chronic insomnia in adults. 2005. June 13–15. Sleep. 2005;28:1049–1057.
4. Staner L. Comorbidity of insomnia and depression. Sleep Med Rev. 2010;14:35–46.
5. Abe Y, Mishima K, Kaneita Y, et al. Stress coping behaviors and sleep hygiene practices in a sample of Japanese adults with insomnia. Sleep Biologic Rhythm. 2011;9:35–45.

With regards,

Yuichiro Abe, MD, PhD
Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan

Author Response

Dr. Targum and I appreciate the comments from Dr. Abe. We do agree with Dr. Abe that fatigue can be secondary to insomnia and, in fact, in the paper that Dr. Abe references by Fava et al [J Clin Psychiatry. 2011;72:914–928], zolpidem augmentation of SSRI treatment of MDD with insomnia did not lead to a significantly greater improvement in depressive symptoms than SSRI plus placebo treatment, although both insomnia and daytime fatigue did improve significantly. The findings of this study by Fava et al do suggest the potential independence of insomnia from MDD itself, despite the fact that insomnia is one of the common key symptoms of MDD.

With regards,
Maurizio Fava, MD
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts