The role of Serotonin Reuptake Inhibitors in the treatment of psychiatric illness: an update.
Subject: Depression, Mental (Drug therapy)
Depression, Mental (Patient outcomes)
Psychotherapy (Methods)
Psychotherapy (Health aspects)
Serotonin uptake inhibitors (Dosage and administration)
Serotonin uptake inhibitors (Complications and side effects)
Authors: Diaz, David R.
Poor, Maria C.
Pub Date: 09/22/2009
Publication: Name: Annals of the American Psychotherapy Association Publisher: American Psychotherapy Association Audience: Academic; Professional Format: Magazine/Journal Subject: Psychology and mental health Copyright: COPYRIGHT 2009 American Psychotherapy Association ISSN: 1535-4075
Issue: Date: Fall, 2009 Source Volume: 12 Source Issue: 3
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 208639913
Full Text: Even though there have been advances in pharmacotherapy for depression beyond Selective Serotonin Reuptake Inhibitors (SSRIs), they remain the mainstay for treatment of depression, especially since many are now available in generic form. They are used also for a variety of anxiety disorders, and one is indicated for bulimia nervosa and premenstrual dysphoric disorder



Selective Serotonin Reuptake Inhibitors (SSRIs) have been on the market since 1987 (when fluoxetine was introduced) and have subsequently dominated market share. They have largely replaced tricyclic antidepressants and monoamine oxidase inhibitors due to their favorable side effect profile and their ease of titration to therapeutic doses, not to mention escaping the lethality of tricyclics in overdose. SSRIs are thought to work by blocking reuptake ofserotonin. They appear to function at low doses, which frequently turn out to be their therapeutic doses--a huge advantage over their predecessors. Most clinicians believe that the members of the SSRI class are equally effective in large populations, yet responses may vary considerably with each medication in individual patients. One misconception is that these medications are more effective than their predecessors, which is not true. Rather, they tend to be utilized more because of the advantages just mentioned. Interestingly, some researchers and clinicians have noted that tricyclics and MAOI drugs may be more effective in severe depression than the SSRI class. In general, new antidepressant research has moved on to compounds with other mechanisms of action.

As a group, SSRIs are most often used to treat depression but some members of the family have other indications including post traumatic stress disorder, generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, and panic disorder, as well as bulimia nervosa and premenstrual dysphoric disorder.

SSRIs are contraindicated when patients are on MAOI medications and a two-week washout period is required from the MAOI to an SSRI. When one goes from the SSRI to a MAOI, the same two-week washout period applies except with fluoxetine, where five weeks are required. SSRIs should not be combined with some older antipsychotics, including pimozide and thioridazine. Combining SSRIs with tricyclic antidepressants may be done but only cautiously and under close supervision by an expert prescriber. The SSRI can cause an increase in the serum level of the tricyclic antidepressant and can cause delirium and toxicity. Generally speaking, SSRIs and other antidepressants should not be used in bipolar disorder or psychotic disorders, at least without accompanying mood stabilizers or antipsychotics. The worry here is that they may cause a manic "switch." The prescribing physician, as well as all other physicians working with the patient, should know about each and every other medication the patient is taking, whether prescription or over-the-counter. There are some drug-drug reactions that occur with SSRIs and other non-psychiatric medications, and some of these effects are limited to specific SSRIs. The prescriber should be aware of these issues. One SSRI should not be combined with another or with any other serotonergic medications unless cross-tapering for fear of the development of serotonin syndrome, which can be life-threatening. This syndrome could also occur as a result of combining SSRIs with the over-the-counter entity known as St. John's Wort.

When SSRI medications are weaned (abruptly in particular), there are well-documented reports of discontinuation syndrome, which can involve flu-like symptoms and/or a rapid, intense exacerbation of mood and anxiety symptoms even to the point of suicidal ideation. This may occur less with fluoxetine due to the lengthy half-life of the active compound and its metabolite. Incidentally, there are no dietary restrictions with SSRI medications. Any deaths with SSRI overdoses usually involve combining the drug with other drugs or alcohol. There were reports in the 1980s associating SSRIs with homicidal rage and suicide; further studies have not borne this out. Recently, however, concerns have been raised about an increase in suicidal behavior or impulses in adolescents on these medications. The risk appears greatest in the early stages of treatment. All patients should be monitored closely, but especially at the beginning few weeks of treatment. This being said, when depressed patients are treated effectively, the suicide rate drops accordingly.

A rule of thumb about dosing these medications is that with anxiety disorders, one generally starts with lower dosages and gradually works upward, even more slowly than with depression. Additionally, certain disorders, including obsessive compulsive disorder and bulimia nervosa, may require the highest doses indicated for longer periods of time than for depression to see results.

Side effects of SSRIs are generally milder than with other antidepressants, which increase their tolerability and patient compliance. Approximately three-fourths of patients do not experience significant side effects at the starting doses of SSRIs. If patients do experience side effects, they are usually time-limited to around two weeks. However, there are some patients that cannot tolerate these medications at all and do not show increased ability to tolerate them as time goes on. The most common side effects include gastrointestinal distress, sexual dysfunction, and anxiety. Other more rare effects can include insomnia, sedation, electrolyte disturbances, allergies, endocrine problems, and serotonin syndrome, which can be quite serious and even fatal. Gastrointestinal bleeding can be associated with SSRIs, especially if they are combined with non-steroidal anti-inflammatory drugs. Again, with rare exceptions, the side effects with these medications are generally more limited than with other alternatives.

There are differences of opinion about numbers of trials of SSPds, but most practitioners would probably choose a medication with a different mechanism of action after trials of two different SSRIs with adequate time at an adequate dosage. Certainly other alternatives exist, and new forms of treatment for depression are continually being developed, including some treatments that do not involve taking medications. These options of course have their advantages and disadvantages and will be explored in future articles.

An additional consideration is that a minority of patients report a loss of efficacy of their SSRI months or years after its introduction. This is not fully understood, but various remedies have been attempted, including increasing the dose, switching to another medication either in the SSRI class or outside of it, or augmenting with another agent. It is safe to say that SSRIs have revolutionized the treatment of depression and some other psychiatric disorders and have resulted in more people being adequately treated. Also, more patients have remained compliant with their treatment due to the better side-effect profile. As more and more medications of this class become available as generics, cost is less of an issue. While not a panacea, with appropriate caution taken about patients' medical conditions and other medications, SSRIs continue to be a mainstay of treatment for depression and anxiety and to relieve a lot of suffering.

This article is approved by the following for continuing education credit:

The American Psychotherapy Association provides this continuing education credit for Diplomates and certified members, whom we recommend obtain 15 CEs per year to maintain their status.

After studying this article, participants should be better able to do the following:

1. Review the many uses for the Selective Serotonin Reupatke Inhibitors

2. Illustrate the drawbacks or possible side effects of Selective Serotonin Reuptake Inhibitors

3. Understand possible drug interactions with Selective Serotonin Reuptake Inhibitors

KEY WORDS: SSRI, pharmacotherapy, depression



DISCLOSURE: The authors have nothing to disclose.


POST CE TEST QUESTIONS (Answer the following questions after reading the article, pages 45-46)

1. SSRIs are the newest family of antidepressants to be developed.

a) True

b) False

2. The FDA has approved at least one SSRI for all of the following indications except:

a) Generalized anxiety disorder

b) Bulimia nervosa

c) Depression

d) Schizophrenia

e) Premenstrual dysphoric disorder

3. lricyclic antidepressant use has become less popular since the advent of 5SRIs. This is probably because:

a) SSRIs ate less likely to be lethal in overdose

b) SSRIs are more effective than tricyclics

c) SSRIs are generally easy to titrate

d) A and C

e} A,B, and C

4. SSRIs should be used with caution with tricyclics because doing so can lead to toxicity.

a) True

b) False

5. SSRIs are contraindicated or only used with caution with:

a) Bipolar disorder

b) An MAO inhibitor

e) Tricyclic antidepressants

d) Thioridazine

e) All of the above

6. SSRIs should not be combined with other SSRIs or other serotonergic medications to avoid developing:

a) Manic symptoms

b) Low blood pressure

c) Serotonin syndrome

d) Skin rash

e) Hypothyroidism

7. Which disorder is known to require higher doses for longer periods with SSRIs?

a) Depression

b) Generalized Anxiety Disorder

c) Premenstrual Dysphoric Disorder

d) Obsessive Compulsive Disorder

e) Bipolar Disorder


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Sadock, B.J., & Sadock, V.A. (2007). Kaplan and Sadock's synopsis of psychiatry: Behavioral sciences/clinical psychiatry (10th ed.). New York: Lippinkott, Williams & Wilkins.

Williams, S.C. (2006). Depression--Augmentation or switch after initial SSRI treatment, New England Journal of Medicine, 354(24), 2611-2.

Yuan, Y., Tsoi, K., & Hunt, R.H. (2006). Selective Serotonin Reuptake lnhibitors and risk of upper GI bleeding: Confusion or confounding? American Journal of Medicine, 119(9), 719.

Earn CE Credit

To earn CE credit, complete the exam for this article on page 47 or complete the exam online at (select "Online CE").

Dr. David Diaz is a graduate of the Indiana University School of Medicine and its residency program in psychiatry and has been in practice 20 years. He is currently the medical director of an adult psychiatry unit at Larue D. Carter Memorial Hospital in Indianapolis and is active in the teaching of medical students and residents. He can be reached at

Dr. Maria Poor is a graduate of the Indiana University School of Medicine and its psychiatry residency program. She has been in practice in Indianapolis for 20 years. She is currently the medical director of an adult psychiatry unit at Larue D. Carter Memorial Hospital * in Indianapolis. She is active in the teaching of medical students and residents and has won recognition for her efforts. She can be contacted at
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