SSRIs Target Psychological But Not Somatic Symptoms in MDD


Recent studies illustrate the importance of homing in on the somatic symptoms of depression


Researchers have been questioning the degree to which SSRIs affect MDD. The evidence from meta-analyses of placebo-controlled trials implies that the pharmacological effects of SSRIs may be small and that up to 75% of symptom relief may be attributable to nonspecific placebo effects and spontaneous remission.1,2

However, researchers from Northwestern University Feinberg School of Medicine, the University of Pennsylvania, Vanderbilt University, and the University of Alabama at Birmingham are challenging these data. They point out that efficacy data are based on total symptom scores and contend that antidepressant medications may simply influence some symptoms and not others.3

Their research-an 8-week double-blind, placebo-controlled trial of paroxetine-shows that SSRIs may affect the psychological but not the somatic symptoms of depression and anxiety.

Clinicians may need to consider novel combination therapies to more effectively manage a patient’s symptom complex.

The trial included 180 outpatients with moderate to severe MDD. One hundred twenty were randomly assigned to paroxetine and the remainder to placebo. Symptom measures administered before the trial and at week 8 included the 17-item Hamilton Rating Scale for Depression (HRSD), which was modified to include atypical symptoms; the 14-item Hamilton Rating Scale for Anxiety (HRSA); and the 21-item Beck Anxiety Inventory (BAI).

Symptoms for all measures were grouped according to whether they were somatic or psychological.4 Neuroticism was also assessed using a 12-item scale from the NEO-Five-Factor Inventory.

The researchers found that paroxetine significantly outperformed placebo on all psychological subscales (Ps < .001 for the HRSD and BAI and P = .01 for the HRSA,), but not on any of the somatic subscales (Ps ≥ .20). The score reduction for psychological symptoms in patients who received paroxetine was double that of the score reduction for somatic symptoms: 10.4% versus 4.6%.

The researchers also found that neuroticism correlated more closely with psychological than with somatic subscales; paroxetine significantly outperformed placebo in reducing neuroticism (P = .01).

Separate neurobiological pathways may be at work in psychological versus somatic symptoms, the researchers surmised. For example, “while depressed mood may be marked by abnormal activation of the medial prefrontal cortex and difficulty concentrating is strongly associated with hypoactivity in the dorsolateral prefrontal cortex, motor retardation may be embodied by dysregulation in the striatum and physical tiredness may be associated with dopamine depletion in nucleus accumbens.”3

Beyond provisionally establishing that paroxetine has a true pharmacological effect on the psychological but not somatic symptoms of depression and anxiety, this study suggests that clinicians may need to consider novel combination therapies to more effectively manage a patient’s symptom complex.

Separate neurobiological pathways may be at work in psychological versus somatic symptoms.

This is important especially in light of a recent Dutch study that showed that a greater burden of somatic symptoms predicts a worse prognosis.5

In this study, researchers affiliated with the University of Groningen in the Netherlands examined whether the type and number of somatic symptom clusters predicted the persistence of MDD out to 2 years. They found that when 2 or more cardiopulmonary, gastrointestinal, or general symptom clusters were present, MDD could be expected to persist (P ≤ .001).

The Dutch researchers said that their findings illustrate the importance of homing in on somatic symptoms in the diagnosis and management of MDD. They also called for research into treatments that will more efficiently target somatic as well as depressive symptoms.


1. Kirsch I, Sapirstein G. Listening to Prozac but hearing placebo: a meta-analysis of antidepressant medication. Prev Treat. 1998;1(2). doi: 10.1037/1522-3736.1.1.12a.
2. Kirsch I, Moore TJ, Scoboria A, Nicholls SS. The emperor’s new drugs: an analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prev Treat. 2002;5:23.
3. Schalet BD, Tang TZ, DeRubeis RJ, et al. Specific pharmacological effects of paroxetine comprise psychological but not somatic symptoms of depression. PLoS One. 2016;11:e0159647.
4. Simon GE, VonKorff M, Piccinelli M, et al. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341:1329-1335.
5. Bekhuis E, Boschloo L, Rosmalen JG, et al. The impact of somatic symptoms on the course of major depressive disorder. J Affect Disord. 2016;205:112-118.

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