What Do Antidepressants Do in Healthy Brains?

The easiest answer to the title question is “cause side effects”.  A more important theoretical and practical aspect of this question is: Do antidepressants have a general property experienced by everyone or are their effects only seen in the presence of depression?  Antidepressant drugs have research support for a variety of non-depression indications including: chronic pain, fibromyalgia, migraine prophylaxis, irritable bowel syndrome and pathological crying and laughing.  So there are quite a few non-depressed individuals taking antidepressants making the title question is important.

Serretti and colleagues from Italy recently summarized published research on this issue.  Additionally, they performed some meta-analyses when appropriate to look for effects across studies.   They note the review suggests that antidepressant effects in the normal or healthy brain may be different under acute than under chronic treatment.   They authors conclude there is some evidence that antidepressants increase social behaviors and reduce negative effects in the healthy brain.  They structure their review based on antidepressant class and I will note the highlights of their paper by class.

Studies of Selective Serotonin Reuptake Inhibitors (SSRIs)

The selective serotonin reuptake inhibitors (i.e fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro)) are the most commonly prescribed class of antidepressants.   SSRIs do not reduce sub-threshold symptoms of anxiety or depression as measured by the State-Trait Anxiety Inventory (STAI) and the Beck Depression Inventory (BDI).  They do tend to reduce negative affect as measured by the Positive and Negative Affect scale.  In addition, SSRIs do reduce the amount time spent in REM sleep in healthy individuals.  The clinical implication of this is unknown. Escitalopram appears to decrease activation in several fMRI tasks with some evidence for decreased activation of the amygdala compared to baseline activation.

Studies of Norepinephrine Reuptake Inhibitors (NRIs)

This class of drug is represented by reboxetine, an antidepressant not found in the United States.  The drug atomoxetine (Strattera) used for attention deficit hyperactivity disorder (ADHD) is sometimes assigned to this class of compound.  A single dose of reboxetine appears to influence social behavior by increasing cooperativeness in communication, reducing focus on self and reduced anxiety ratings.  It also appears to enhance recognition of positive environmental stimuli such as processing happy facial expressions and positive words.  Some of these effects persist over at least one or two weeks.  Brain imaging studies show reduced amygdala responses to fearful faces.

Studies of Serotonin and Norepinephrine Reuptake Inhibitors (SSNRIs)

This class of agents includes the compounds venlafaxine (Effexor), desvenlafaxine (Pristiq) and duloxetine (Cymbalta).   There are many fewer studies involving these agents as researchers tend to often one to focus a single neurotransmitter.   A single dose study of duloxetine demonstrated showed enhanced recognition of both happy and sad faces.  Early responses to these compounds tend to reflect transient side effects rather than a specific brain response in healthy individuals. 

Other agents: Noradrenergic and specific serotenergic antidepressants (NaSSAs), tricyclic antidepressants, monoamine oxidase inhibitors

This miscellaneous class would include mirtazapine (Remeron), amitriptyline (Elavil), and phenelzine (Parnate).  Mirtazapine appears to have some sedative side effects in healthy individuals and along with amitriptyline (and other tricyclics) have the potential to impair psychomotor performance including driving performance.  Tricyclic antidepressants also (like SSRIs) share the ability to reduce REM sleep duration in healthy individuals.

The authors conclude that this review tends to confirm that the human response to antidepressants is similar to the response in rats.  Early exposure to antidepressants tends to increase anxiety but over time anxiety behaviors tend to decrease to below baseline.  Early anti-depressant exposure reduces socializing behaviors in rats but increases them in the long term.   There are very few human studies that have been carried out for more than a week or two.  This means the long-term effect of exposure to antidepressants agents is unknown.


The brain imaging data suggest that antidepressants influence emotional experience and processing in healthy individuals.  There is a variety of individual variation in emotional experience and processing, but the antidepressants appear to move healthy individuals along this domain.

One interesting aspect of this issue is that we know very little about the comparison of side effect patterns in non-depressed individuals.  Do healthy controls experience the same type of side effects to the same degree as depressed individuals?  We have a wealth of data comparing side effects of antidepressants compared to control within depressed populations.  But the volume of data comparing side effects between depressed individuals and non-depressed is small.

Molecular model of the antidepressant escitalopram (Lexapro) courtesy of Creative Commons author Ben Mills.

Serretti A, Calati R, Goracci A, Di Simplicio M, Castrogiovanni P, & De Ronchi D (2010). Antidepressants in healthy subjects: what are the psychotropic/psychological effects? European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 20 (7), 433-53 PMID: 20079613