Dr. Rapgay is assistant clinical professor of psychiatry in the Department of Psychiatry at the Neuropsychiatric Institute, UCLA School of Medicine in Los Angeles, and director of the university’s Behavioral Medicine Program.

Acknowledgments: The author would like to thank Lidia Zylowska, MD, for her editorial assistance.


 

Abstract

Among the Eastern medical traditions, Tibetan medicine is considered to have the most comprehensive definition, classification, diagnostics, and treatment of mental disorders. The system includes herbal, physical, nutritional, behavioral, psychological, and spiritual interventions to treat mental illnesses (such as anxiety disorders) known as “heart energy disorders” (sNing rLung in Tibetan). Although there is no evidence yet of the clinical efficacy of these treatment modalities, the Tibetan system provides an alternative model of defining anxiety disorders and of treating them from a mind-body perspective.

 

Introduction

Tibetan medicine is gradually becoming known in the Western world, particularly for the way it defines, categorizes, and treats mental illnesses. The origin of Tibetan medicine began when Indian Ayurvedic medicine came to Tibet in the fourth century. The Tibetan kings, particularly during the seventh and eighth centuries, began to encourage the development of an integrated system of medicine by inviting Indian, Chinese, Persian, Greek, Nepalese, and Kashmiri physicians to Tibet.1 During the 11th century, the best known Tibetan physician, Yuthok Yonten Gonpo, combined the various systems of medicine into one integrated system. He presented the new system known as Sowa Ripga (science of healing) in his compilation of The Four Tantras, which serves as the core text taught to students of Tibetan medicine.2

Tibet had many medical schools before the country was invaded by the Chinese. The two most prominent schools in Lhasa, the country’s capital city, included one that specialized in monastics and another for lay trainees. Each district and monastery in Tibet would select two or more of their best students to train at these schools for 7 years. When the students graduated, they were assigned to practice in their local districts or monasteries.

In exile, the main site of Tibetan medical learning and training is in Dharamsala, India, the headquarters of the Dalai Lama. Today, Tibetan medicine is widely practiced in Tibet, India, China, Southeast Asia, Bhutan, Nepal, Mongolia, and Russia. Although Tibetan medicine is fairly new to the West, there are a number of Tibetan practitioners in Europe and the United States.3

Overall, there is very little research in the area of Tibetan medicine. The existing pilot studies on Tibetan medicine are primarily in the treatment of medical disorders,4 and no such studies address the treatment of mental illnesses. However, there is widespread recognition that among all the traditional systems of medicine, Tibetan medicine stands out in terms of its conceptualization and treatment of mental illnesses.

 

The Theory of Tibetan Medicine

The Tibetan medical theory is based on the three psychophysiological systems (Nepa Sum in Tibetan). The psychophysiological systems are sometimes referred to as the three basic energies or constitutions. Each system is related to different elements—air, fire, water, earth, and space—which denote unique physiological characteristics. In Tibetan language, the three systems are known as rLung, Tkripa, and Badkan. rLung, also known as the wind system, involves the activities of the air and space elements and relates to the central and secondary nervous systems. rLung  is thought to include all psychological states and functions. Tkripa, also known as the bile system, involves the function of the fire and air elements and refers to function of the endocrine and vascular systems of the body. Badkan, also known as the phlegm system, involves the activities of earth and water elements and relates to the functions and activities of the lymphatic and digestive systems in the body.5

Based on Buddhist theories, Tibetan medicine identifies three driving principles that influence the three psychophysiological systems. These three principles are the instinctual forces: drives of attachment, aggression, and ignorance.5 According to Buddhist concept, the innate state of ignorance, which refers to a state of not knowing, creates tension and anxiety in the organism. Such tension leads to attempts to relieve the tension by seeking to search for stimuli and conditions that relieve the tension. The organism becomes attached to such tension-relieving stimuli.

However, such attachment to tension-relieving stimuli, can create new anxious feelings of loss, threat, etc. When the source of tension relief is threatened, the organism often responds with aggression. However, aggression then creates new forms of psychological and physiological tensions. These psychological states predispose the organism to disturbances of the three psychophysiological systems. However, additional causative factors and triggers need to be present for pathology to manifest.6

Causative and triggering factors such as imbalance in diet, nutrition, toxicity, infection, injury, and emotional and spiritual distress result in excesses, deficiencies, or disturbances in individual or multiple psychophysiological systems. When the causative factors are not treated, the psychophysiological systems exacerbate beyond their usual homeostatic functions. Consequently, other homeostatic functions are disrupted, resulting in signs and symptoms indicative of a particular disease.7

The Tibetan physician uses observation, palpation, and questioning to determine diagnosis. Observation involves urine analysis and tongue examination while palpation involves pulse examination. Questioning refers to clinical interview and history-taking. Based on the above assessment, treatment is planned. Treatment consists of  behavior therapy, nutrition therapy, herbal therapy, five detoxifying treatments (nasal cleansing, enemas, purgatives, emetics, blood vessel cleansing with oral herbals), and invasive therapies.

Etiology, Diagnosis and Treatment of Anxiety Disorders in Tibetan Psychiatry

Among the ancient traditions of medicine, Tibetan medicine is widely regarded as possessing the oldest written system of psychiatry medicine that is currently practiced. The Tibetan medical texts identify two broad categories of mental illnesses—the neurotic and psychotic types.8 The neurotic types are broadly classified as “heart energy disorder” (sNing rLung in Tibetan) equivalent to general anxiety disorders, and “life-sustaining wind disorders” (Sog rLung in Tibetan) or general depression.  There are four broad categories of psychotic disorders, two of which are schizophrenia and manic depression.9 In neurotic disorders, the imbalances of the rLung system do not interfere with other psychophysiological systems.  However, in the case of psychotic disorders, there is wide-spread interference of other systems which, in turn, further disrupts the rLung homeostatic functions.
 

Etiology of Heart Energy Disorders

In Tibetan medicine, anxiety disorders (Ning–rLung in Tibetan, which means “heart energy”) are either mild or severe. Heart energy refers to the dysregulation of the autonomic nervous functions responsible for many of the anxiety symptoms. Mild heart energy disorders refer to general anxiety disorders; severe heart energy disorders refer to anxiety-related psychoses.10
 

Heart energy disorders are caused by distal and immediate factors. Distal causes are the primodal causes of the disorder, while immediate conditions refer to the triggers that activate the symptoms and signs of the disorder. Distal causes are the primal driving principles of attachment, aggression, and ignorance. At a primal level, heart energy disorders are predominantly caused by attachment issues. The contributory conditions that turn these disruptions into pathological entities are: (1) rLung-producing nutrition; (2) rLung-producing behavior; (3) rLung-producing emotional and psychological factors; and (4) rLung-producing toxicity, injury, etc.11
 

According to the Tibetan medical text The Four Tantras, heart energy disorders are marked by autonomic nervous system dysregulation, particularly in association with activity of the heart.12 The rLung system is characterized by its various functions, such as lightness, roughness, mobility. These functions manifest themselves respectively as dizziness, dry or itchy skin, and a shifting nature of symptoms such as pain.  
 

Tibetan medicine appears to identify most of the common causes and conditions, as well as signs and symptoms, of anxiety disorders. The following conditions are thought to cause general and severe anxiety disorders: psychological and physical trauma, worrying, agitation, excessive anger, rumination,  insomnia, work-related stress, excessive bleeding, excessive physical and verbal exertion, loss, poor nutrition, medical illness, and toxicity.
 

Pathogenesis of Heart Energy Disorder

Tibetan tradition presents a different model of looking at the pathogenesis of psychiatric disorders, and, in particular, understanding  the comorbidity of anxiety and depression.
 

Causative factors such as psychological factors—ie, fear of  specific objects, worrying—create disturbances in the rLung homeostatic functions. Failure to control the dysregulation results in further exacerbation of the central and secondary nervous systems, as well as psychological functions.13 At this phase of the pathogenesis, signs and symptoms of heart energy disorders occur. When the homeostatic dysregulation of the rLung system does not interfere with other systems, mild and moderate heart energy disorders occur. However, when other systems are disrupted, severe heart energy disorders result. For instance, when the pathological process of the rLung system interferes with the Badkan system, interference with the phlegm homeostatic functions results in a comorbidity of depression. Symptoms and signs of phlegm imbalances, such as loss of interest, or mental and physical stagnation, manifests in the patient.14
 

Diagnostic Procedure for General and Severe Anxiety Disorder

While the Tibetan diagnostic procedures are very different from those used in modern medicine, the procedures involve intimate human contact that might contribute towards fostering the doctor-patient relationship as well as the healing process.
 

The initial part of the physician examination involves analysis of the urine and the tongue. A sample of urine is collected in the early morning and the patient is required to avoid foods and behavior the night before that may impact the quality and quantity of urine. The Tibetan physician examines the urine by looking for nine characteristics of the urine, such as the size of the bubbles on stirring, rate at which they disappear, color of urine, sedimentation, presence of albumin, and rate of discoloration. For example, in heart energy disorder, the urine appears to be clear, like water, with huge bubbles that form rapidly on stirring and disappear instantly once stirring is stopped. There is minimal odor, vapor, and albumin in the urine. In the case of severe heart energy disorders with bile complications, the urine may crackle when it begins to disappear, be darker in color, and have a strong odor and albumin. In the case of phlegm complications, the urine has stagnant, small, congestive bubbles which increase on stirring, minimal odor, and a whitish hue.
 

Palpation, which is the next diagnostic procedure, involves palpating the right and left radial arteries of the patient with the physician’s right and left middle fingers of each hand respectively. Each of the fingertips of the physician represents and reads a specific organ of the patient. The medical texts identify specific pulse features and characteristics for each disorder. Heart energy disorder involves a rapid, fluctuating, surface pulse beat which stops completely when pressure is applied. In particular, the pulse under the physician’s index fingers, which represents the physiological functions of the area around the heart, tends to be fast and fluctuating. In the case of severe anxiety disorders, with bile or agitation complications, the pulse tends to be fast, thin, and to cease on pressure. In the case of the phlegm complications, the pulse is slow and weak, but stop under pressure.
 

Specific acupressure points on the body are sensitive to pressure with more sensitivity in the case of severe heart energy disorders. The main points are on the sternum between the two nipples, and the 1st, 6th, and 7th thoracic vertebrae.15
 

Treatment of General and Severe Anxiety Disorders

Tibetan medicine presents a very different, alternative approach to the treatment of anxiety disorders, sequentially matching levels of treatment with the severity of the disorder. After physical and clinical evaluation, treatment is planned on the basis of severity and comorbidity of the heart energy disorder. The treatment for heart energy disorders involves four stages of treatment.
 

Stage I: Behavioral Therapy

The treatment of choice for mild heart energy disorders involve naturopathic and nonpharmacological methods. The two main naturopathic treatments are behavior and nutrition. Tibetan medicine, unlike Indian Ayurveda, recommends behavior over nutrition as the initial therapy, since behavior involves spiritual, psychological, health, and social-related interventions.
 

There are three types of behavioral therapy: daily behavior, seasonal, and occasional. Daily behavior refers to daily psychological, physical, and spiritual behavior. Psychological and social behavior recommendations involve guidelines about interpersonal relationships and unhealthy behavior patterns. Spiritual behavior involves following guidelines for leading a moral and religious life. Seasonal behavior deals with adapting behavior such as conduct, exercise, activity, and dress according to seasonal changes. Occasional behavior involves regulating bodily and natural urges such as not suppressing hunger, thirst, sneezing, yawning, breathing, and sleep.
 

For heart energy disorders, engaging in spiritual practices that are soothing and relaxing, such as counting the breath meditation, equanimity, and visualization-based meditation, are recommended. Patients are encouraged to participate in social services and perform acts of generosity. Interventions such as cognitive restructuring, diaphragmatic breathing, and spiritual practices are recommended for adaptation to stressful and traumatic situations and conflicts, and reduction of worrying and rumination. Seasonal behavior refers to avoiding behaviors  such as excessive exercising during summer, exposure to cold during winter, and eating the wrong seasonal foods.
 

Stage II: Nutrition Therapy

The nutrition stage involves recommendations of appropriate quantity of food to eat, nutrition for heart energy disorders, and nutrition for each of the seasons. Appropriate quantity of food for heart energy disorders involves eating three meals a day. The diet includes protein in the form of meat as well as other sources of protein, while sugar, caffeine, raw light-green vegetables and raw night-shade vegetables, should be avoided. During winter, the meals should be well cooked and herbal medicated wine is highly recommended. In the summer, high protein intake should be reduced—for instance, from red meat to white.16
 

Stage III: Herbal Therapy

When naturopathic approaches fail or are not adequate to treat disorders, the physician resorts to herbal therapy. Herbal therapy can be administered in nine different formulations, including syrups, powdered remedies, decoctions, and nutritional supplements. Single herbs are regarded as generally toxic and, therefore, are rarely used in traditional medicine. The use of single herbs in the US is more a Western phenomena. Tibetan pharmacopoeia consists of more than 400 formulas, with each herbal formula consisting of anywhere from 3 to 90 herbal and other ingredients.
 

Stage IV: External Treatment

When patients do not respond to herbal therapy, stage IV, which is external treatment, is recommended. This stage is composed of three subphases of external treatments: (1) five-detoxification treatment; (2) medicated massage, fomentation, and moxabustion with or without acupuncture; and (3) surgery. The five-detoxification treatment involves a preliminary treatment with oleation (application of medicated oil on the body) and herbal steaming, followed by the actual detoxification therapy using enemas, purgatives, emetics, nasal therapy, and blood detoxification. For instance, in the case of severe heart energy disorder, after strengthening the patient with nutritional supplements, a series of herbal enemas are administered over a period of several days or more to eliminate excessive rLung.
 

When the five detoxifying treatments are not effective, the second subphase of the treatment is recommended. This involves three types of treatment: massage and acupressure with herbal medicated oils, fomentation, and moxabustion with or without acupuncture. When these fail, the third subphase of treatment involving various forms of minor surgery is recommended. The medical texts depict various major surgical procedures for cataracts, rhinoplasty, and removal of any anal fistulas. However, such interventions were discontinued many centuries ago when a queen died from brain surgery.17
 

Depending on the needs of the patient, psychological and spiritual interventions are administered during any or all of the four stages of treatment. The psychospiritual interventions involve using the five stages of meditation. The first is sensory meditation such as basic breathing-based meditation—eg, counting the breath, focusing on inhalation and exhalation, and diaphragmatic breathing. Yantra yoga, involving specific movements regulated with breathing and concentration on the breath, may be prescribed. The second stage, cognitive meditation, involves labeling all thoughts, sensations, and emotions that arise as the patients attempt to focus on the breath.   Once the patients are mindful of their own cognitive and emotional states, the third stage, analytical meditation, is recommended. This involves analyzing automatic thoughts and basic assumptions. The goal, as in cognitive therapy, is to come up with a more appropriate cognition of the situation. Once the patients have acquired the appropriate cognition of the event, they are taught the fourth stage, affective meditation, to recognize and generate the appropriate emotions. When the patients generate the appropriate cognition and emotions, they are taught the final meditation stage, visualizations, to dynamically integrate the sensory, cognitive, and affective processes.18
 

Conclusion

The Tibetan system provides an alternative model of diagnosing and treating anxiety disorders that integrates medical, behavioral, psychological, and spiritual approaches of managing anxiety disorders. The system seeks to include patients in their diagnosis and treatment by acknowledging the patient’s complaints, incorporating them with the physician’s medical diagnosis, and clarifying treatment options for both. This method provides a new way of conceptualizing the role of mind-body medicine in anxiety disorders and creates a framework for assessment and treatment of anxiety disorders to faciliate the doctor-patient relationship beyond the medical model.  PP
 

References

1.    Tsarong TJ. Fundamentals of Tibetan Medicine. Dharamsala, India: Tibetan Medical Centre; 1988.
2    Dhonden Y, Tsering G. What is Tibetan Medicine? New Delhi, India: Tibetan Reviews Publications; 1978.
3.    Badmajew P, Badmajew V. Healing Herbs, the Heart of Tibetan Medicine. Berkeley, Calif: Red Lotus Press; 1988.
4.    Dhonden Y. Ambrosia Tantra. Dharamsala, India: Library of Tibetan Works and Archives; 1977.
5.    Rapgay L. The Tibetan Book of Healing. Salt Lake City, UT: Passage Press; 1996.
6.    Clifford T. Tibetan Buddhist Medicine and Psychiatry. Yorke Beach, ME: Samual Weiser, Inc; 1984.
7.    Rinpoche R. Tibetan Medicine. Berkeley, Calif: University of California Press; 1976.
8.    Burang T. Tibetan Medicine. London, England: Robinson and Watkins Books; 1987.
9.    Clark B. The Quintessence Tantras of Tibetan Medicine. Ithaca, NY: Snow Lion Publications; 1995.
10.   Rapgay L. Mind and Mental Health in Tibetan Medicine. New York, NY: Potola Publications; 1988.
11.  Finckh E. Studies in Tibetan Medicine. Ithaca, NY: Snow Lion Publications; 1988.
12.  Rapgay L. Tibetan Art of Urinalysis.  Dharamsala, India: Tibetan Medical Series; 1988.
13. Kangkar LD. Lectures on Tibetan Medicine. Dharamsala, India: Library of Tibetan Works and Archives; 1986.
14.  Dash B. Formulary of Tibetan medicine. Delhi, India: Classics India Publications; 1988.
15. Clifford T. Tibetan Buddhist Medicine and Psychiatry. Yorke Beach, ME: Samuel Weiser, Inc; 1984.
16. Dhonden Y. Ambrosia Tantra. Dharamsala, India: Library of Tibetan Works and Archives; 1977.
17. Rinpoche R. Tibetan Medicine. Berkeley, Calif: University of California Press; 1976.
18. Clifford T. Tibetan Buddhist Medicine and Psychiatry. Yorke Beach, ME: Samuel Weiser, Inc.; 1984.

 

 

 

Dr. Rosse is chief of psychiatry at the Department of Veterans Affairs Medical Center and professor in the Department of Psychiatry at Howard University in Washington, DC. Dr. Fanous is staff psychiatrist in the Mental Health Service Line at the Department of Veterans Affairs Medical Center and assistant professor in the Department of Psychiatry at Georgetown University School of Medicine in Washington, DC; and assistant clinical professor in the Department of Psychiatry at the Medical College of Virginia Commonwealth University in Richmond. Ms. Gaskins is psychology technician in the Mental Health Service Line at the Department of Veterans Affairs Medical Center. Dr. Deutsch is associate chief of staff for mental health in the Mental Health Service Line at the Department of Veterans Affairs Medical Center and professor in the Department of Psychiatry at Georgetown University School of Medicine.

Disclosure: Dr. Deutsch is a consultant to Janssen. Drs. Rosse and Fanous, and Ms. Gaskins, report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Richard B. Rosse, MD, Chief of Psychiatry, Department of Veterans Affairs Medical Center, 50 Irving St, NW, Washington, DC 20422; Tel: 202-745-8156; Fax: 202-745-8169; E-mail: Richard.Rosse@med.va.gov.

 

 
 

Abstract

Although the most commonly used antidepressants (ie, selective serotonin reuptake inhibitors) have a lower incidence of side effects compared to the earlier antidepressants (ie, tricylic antidepressants), some less serious and a few potentially serious side effects are associated with the range of newer antidepressants and adjuvant agents used to augment the efficacy of antidepressants. Primary care physicians engaged in the modern practice of psychopharmacologic treatment of depression need to be aware of the range of side effects, from minor to more serious. This article focuses on the more common side effects of antidepressants used in the modern treatment of depression.

 

Introduction

This article focuses on the medications used in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This was the largest and longest study on the effectiveness of treatments for depression and led to the best evidence-based treatment for depression to date. Table 1 outlines the side effects of some of the more commonly used antidepressants that were studied in STAR*D including potential augmenting (adjuvant) medications for improving antidepressant efficacy (eg, adding bupropion up to 400 mg to a selective serotonin reuptake inhibitor [SSRI] in a patient with less than a remission response to their SSRI).The STAR*D study showed that on first exposure to an antidepressant, only 28% to 33% of patients will go into full remission. Total remission of depressive symptoms (not just response, ie, an amelioration of depressive symptoms) is now the aim of modern antidepressant psychopharmacology.1

 

Typically, SSRIs are the first agents used to treat depression in clinical practice due to their safety and low incidence of serious side effects. Table 1 provides a list of side effects common with most SSRIs (listed for the two prototypic SSRIs used in the STAR*D study, namely citalopram and sertraline).2 One of the important findings of the STAR*D study is that antidepressant efficacy is often improved with the addition of various antidepressant adjuvant (augmenting) medications (eg, triiodothyronine [T3] or lithium, with T3 causing fewer side effects).3 Primary care physicians (PCPs) will need to familiarize themselves with the switch and augmentation strategies tested in the STAR*D study. Readers should note that there are other antidepressants and adjuvant medications available that do not appear in Tables 1 or 2. Nortriptyline is the prototypic tricyclic antidepressant (TCA) that was used in the STAR* D study, just as citalopram and sertraline were the stand-in SSRIs. However, TCAs are rarely used now as a first-line antidepressant in treating depression.

 

When medications are combined, the potential for side effects can increase, and it can become difficult to differentiate which agent is responsible for the side effect(s). Hence, the primary antidepressant should be introduced first and the adjuvant agent added at a later time to analyze the etiology of potential future side effects. Augmentation of citalopram with either bupropion sustained release (SR) or buspirone was found in the STAR*D study to be useful. However, augmentation with bupropion SR did have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects.2 If the dosing strategies in Table 1 are adhered to, the incidence of adverse side effects should be diminished.

Medication side effects or adverse events can range from less serious annoyances to very serious, life-threatening situations (Table 2). The more side effects that a patient experiences, the less adherent patients are likely to be. Whether serious or not, it is important to manage the side effects experienced by the patient.

 

Minor Side Effects

Headache

Headaches can range from mild to severe, and may not be related to the antidepressant being used by the patient. Many studies of SSRIs show prevalences of headache to be greater in the placebo group than in the active drug groups. However, there is still a minority of patients who appear to get headaches on SSRIs. They typically respond to analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), or to an ice pack on the headache area.

 

Fatigue

Complaints of fatigue, lethargy, and tiredness are common, especially during the early weeks of antidepressant treatment. Possible antidotes include taking a brief nap during the day or getting some mild exercise such as walking. Sometimes, the medication can be taken 1–2 hours before bedtime so that the side effect can be put to use by helping the patient fall sleep. (Insomnia is a common problem in patients with depressive disorders.)

 

Sedation

It should be standard practice to educate or warn patients that antidepressants have potential sedative effects and could impair judgment, thinking, and motor skills, as well as their ability to drive, use machines, or perform tasks that require alertness, coordination, or physical dexterity. Interventions for fatigue can also be beneficial for counteracting antidepressant-induced sedation. Some clinicians try moderate doses of modafinil or other stimulants (eg, methylphenidate, dextroamphetamine/amphetamine composite medication) to counteract the sedation induced by antidepressants.

 

Sexual Side Effects

SSRIs are associated with delayed orgasm or an inability to achieve orgasm (anorgasmia). This can occur in both men and women perhaps more than half the time at regular or higher therapeutic doses. Most cases of sexual dysfunction stop after 1–3 days of the medication being stopped.

Possible remedies include dose lowering or trying to schedule sexual activity before taking medication for the day. Clinicians can also switch to an antidepressant less associated with these side effects. These antidepressants include bupropion or mirtazapine. If erectile dysfunction is an issue, agents such as sildenafil, vardenafil, tadalafil, or alprostadil (the latter given by injection into the side of the penis) may be considered.

Clinicians may try stopping medication for only the day that sexual activity will occur (or lower the dose on that day, returning to regular higher dose the other days of the week (this may not work so well for antidepressants with half-lives >24 hours, such as fluoxetine). However, this intervention of stopping SSRIs before planned sexual acttivity can cause an SSRI discontinuation syndrome (especially for SSRIs with a shorter half-life).

 

Insomnia

Insomnia occurs because some antidepressants cause stimulation that can interfere with sleep. To counteract this effect, medication can be taken in the morning. (In fact, SSRIs are typically first tried as an AM dose.) Lower-dose mirtazapine is quite sedating and might be best for patients with severe insomnia. Stimulation associated with antidepressants can be a negative side effect when taken at night, but a positive experience when taken in the morning, with the medication providing a needed energy boost. Antidepressant-induced insomnia can be dealt with by giving the antidepressant with a sedating medication (eg, a benzodiazepine or trazodone) at bedtime. To avoid insomnia, medications such as bupropion are never dosed at bedtime.
Patients should be encouraged to practice good sleep hygiene, including avoiding caffeinated drinks before bedtime, getting regular exercise at least 4–5 hours before bedtime, and developing a relaxing bedtime routine.

 

Gastrointestinal Side Effects

Nausea is one of the most common reasons people stop taking antidepressants. Nausea typically begins within 1 week of starting treatment and often goes away on its own within a few weeks. Anecdotally, this common side effect has been reduced by taking antidepressants with food or with an antacid (there are no studies to the authors’ knowledge supporting this intervention for nausea). If available, a slow-release form of an antidepressant might lessen gastric upset and nausea, or the dosage might be decreased and the upward dose titration slowed.

 

Constipation

To treat or prevent constipation (much more common with the TCAs), patients should increase fiber and fluid intake as well as mobility (ie, physical activity).

 

Weight Gain

Overall, SSRIs (except paroxetine) are thought to have no or only slight weight-inducing effects (although there are no doubt exceptions to this). Hence, with the SSRIs, it is prudent to carefully monitor patients’ weight, since the amelioration of depressive symptoms can be associated with improved appetite and weight gain. Mirtazapine can also be associated with weight gain, while bupropion is associated with potentially problematic weight loss in already underweight patients.

 

SSRI Discontinuation Syndrome

Not all patients taking antidepressants experience SSRI discontinuation syndrome, but for those who do the syndrome often presents with flu-like symptoms such as headache, diarrhea, nausea, vomiting, chills, dizziness, fatigue, and insomnia. Symptoms can even include agitation, impaired concentration, vivid dreams, depersonalization, irritability, and suicidal thoughts. Symptoms last anywhere from one to several weeks and vary in intensity.3

In order to avoid this syndrome, clinicians should educate patients to not suddenly stop taking SSRIs. Patients can use a pill splitter to more slowly taper off their SSRIs. Another option is to switch to the liquid form of the medication so that patients can reduce their dosages more slowly to avoid discomfort when they discontinue an SSRI. Another option is for patients to switch from their shorter-acting SSRI to fluoxetine for the final discontinuation. Fluoxetine has a 9.3 day half-life (which is longer than the 24-hour or so half-lives of many other SSRIs) and usually has the mildest discontinuation effects of all the SSRIs.4 Antidepressants with shorter half-lives (eg, paroxetine or fluvoxamine) have a higher risk of SSRI discontinuation syndrome.

 

Serious Side Effects

SSRI-Induced Mania/Hypomania

Estimates are that 3% to 10% of depressed individuals may be at risk for developing hypomania or mania when treated with antidepressants. Patients with underlying bipolar disorder seem susceptible to antidepressant-induced mania/hypomania. There is a high rate of instances when bipolar depression is misdiagnosed as unipolar depression.5,6 The rate of antidepressant-induced hypomania in patients with major depressive disorder (MDD) is thought to correspond with the rate of misdiagnosis of bipolar depression as unipolar depression. Besides the induction of mania/hypomania by antidepressants, there can be “dysphoric” hypomanic/manic (“mixed”) states that can be difficult to differentiate from depression, or the more subtle induction of “rapid cycling” of manic and depressive episodes (ie, increasing the number of depressive and hypomanic/manic episodes peer year) that fade after discontinuation of antidepressants. It should be noted that some clinicians and researchers view these states as having a high-risk suicide potential.7,8 If the PCP is concerned about having precipitated mania in a patient, he or she should seek consultation with a mental health colleague.

 

Agitation, Jitteriness, Restlessness, and Anxiety/Panic

Agitation, restlessness, and anxiety can result from the stimulating effect of some antidepressants. Patients might not be able to relax or sit still. Clinicians should be alert for racing or impulsive thoughts along with high energy, as they may be signs of antidepressant-induced hypomania or mania.

Patients with a history of panic disorder (Table 3) or anxiety who are being treated with antidepressants should have a gradual escalation in dosage to minimize these side effects, typically seen during the initial days of treatment with antidepressants. It may be difficult to place patients back on an antidepressant after they have experienced an antidepressant-induced panic anxiety state. It has also been shown that the presence of agitation and anxiety in a patient with depression is a risk factor for suicide. It is this latter fact which makes this constellation of side effects potentially serious.9,10

 

To prevent the inadvertent precipitation of a panic attack when using an antidepressant, it may be useful to inquire about the symptoms (Table 3) and then recommend using a low dose of an antidepressant at initiation of therapy, with very slow upward titration. Education about this potential paradoxical increase in anxiety/panic while being introduced to an antidepressant is likely to improve adherence with medication. A benzodiazepine can often be employed to prophylax/treat antidepressant-induced panic or anxiety.

 

Increased Risk of Suicide

Whether or not the SSRIs increase suicide rates—especially in adolescents—has been a matter of contention, but the Food and Drug Administration has come down on the side of accepting the notion that SSRIs can increase suicide rates during the initial few months of a course of drug therapy or at times of dose changes (either increases or decreases; Table 4).11

 

During treatment with antidepressants, patients should be asked at every visit ( there should be more frequent visits in the early months of treatment) about their suicidal thoughts (Table 5). Any patient being treated for depression should have a “suicide prevention plan” in case suicidal ideation emerges or re-emerges. This plan could include going to the nearest emergency room, calling suicide hot lines, encouraging family education about depression and suicide, providing Internet sites for patients with suicidal ideation,12,13 and ways to contact their mental healthcare workers if suicidal ideation emerges. The “suicide prevention plan” provides alternative behaviors to suicidal behaviors.10,14-17

 

 

 

 

 

 

 

 

 

 

Hyponatremia/SIADH

SSRIs may lead to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), characterized by hyponatremia, a potentially fatal condition that is typically asymptomatic until it becomes severe. It is a relatively infrequent but serious complication of SSRI use. (One author estimated its occurrence with fluoxetine in approximately 6.3 cases out of 1,000.18) Risk factors for the development of SIADH/hyponatremia with SSRIs include older age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium concentrations. Baseline serum sodium levels should be obtained in those at higher risk who are going to start on an SSRI. Mental status changes are frequently the earliest manifestation of SIADH/hyponatremia.19,20

Following discontinuation of the offending SSRI, the serum sodium concentration should normalize within approximately 2 weeks. Switching to another SSRI might still result in SIADH, hence plasma sodium concentrations must be monitored not only in the first weeks of treatment but throughout the full course of patients switched to another SSRI after a bout of SSRI-induced SIADH. The clinician might also consider use of a non-SSRI such as the aminoketone bupropion.

 

Serotonin Syndrome

Serotonin syndrome can be mild (in which case it may not be detected) or dramatic and life threatening.21 An often-cited differential point for differentiating neuroleptic malignant syndrome (NMS) from serotonin syndrome involves abnormal reflexes, where there will be hyperreflexia and clonus in serotonin syndrome versus bradyreflexia in NMS. Information from a recently released Food and Drug Administration warning related to serotonin syndrome and various antidepressants can be found in Tables 6 and 7.22

 

 

Prevention of serotonin syndrome with the avoidance of drug interactions that might cause it should be the mainstay of treating serotonin syndrome. Clinicians should also remember that single SSRIs (especially in high dose and overdose) can result in serotonin syndrome.23 Patients who are going to be placed on SSRIs, especially those who are going to be on other serotonergic medications (such as triptans for migraines) along with their SSRIs, should be educated about this syndrome in order to make them partners in the early detection of this rare side effect.24

The most important treatment is to discontinue the offending agents. The syndrome usually resolves within 24 hours after the withdrawal of the offending medications.25-27

 

Seizures

Four out of every 1,000 people who receive bupropion in doses <450 mg/day experience seizures. When doses exceed 450 mg/day, the risk increases 10-fold. Bupropion should not be used in patients with epilepsy and other conditions that lower the seizure threshold (eg, alcohol withdrawal, active brain tumors). Seizures are a very rare event in patients taking SSRIs.4

 

Upper Gastrointestinal Bleeding and SSRIs

Serotonin enhances platelet activation that is induced by adenosinediphosphoric acid and thrombin in whole blood.28 The depletion of serotonin from platelets, subsequent to reuptake blockade, would therefore be expected to diminish hemostasis. Upper gastrointestinal bleeding (UGIB) has been a concern in SSRI treatment following the publication of numerous case reports.29-31 Studies employing large patient databases have been useful in examining the relationship between SSRI use and subsequent UGIB. A recent study in the Danish population found that users of SSRIs were hospitalized with UGIB at a rate 3.6 times greater than age- and sex-matched controls.29 Yuan and colleagues30 concluded that the evidence supporting increased UGIB in the context of SSRI use in the general population is limited. However, there is greater evidence that SSRI use is associated with increased UGIB in the elderly,31 concomitant NSAID use, and patients with a past history of UGIB. Clinicians should therefore be aware of this potential serious adverse event of SSRIs.

 

Birth Defects and Breastfeeding in Patients Taking SSRIs

The treatment of maternal depression during pregnancy is an important clinical issue. The fetal safety of SSRIs was an early concern after the introduction of fluoxetine in the 1980s as a result of the high-reported prevalence of depression among women (up to 20%) and the fact that >50% of all pregnancies are unplanned.32 An early study raised concerns that fluoxetine use during pregnancy was associated with perinatal complications and minor malformations,33 although this association may have been more directly related to the severity of depression. A prospective controlled study32 comparing 267 women who contacted one of nine “teratology information service centers” because of concerns regarding SSRI use during pregnancy and 267 women exposed to nonteratogenic agents failed to find differences on several important outcome measures, including major malformations, spontaneous and elective abortions, stillbirths, birth weight, and gestational age. The women were contacted 6–9 months after delivery.

A study of 1,403 pregnant women identified in a population-based registry in Quebec34 suggested that a paroxetine dose >25 mg/day during the first trimester of pregnancy may be associated with increased risk of major congenital and cardiac abnormalities relative to other antidepressants. Thus, a dose-related effect of paroxetine during first-trimester exposure on cardiac malformations may exist. The impression that paroxetine is distinguished from other SSRIs in terms of a heightened association between its use during early pregnancy and infant cardiovascular defects, notably ventricular and atrium septum defects, emerged in a study of the Swedish Medical Birth Registry of 6,481 women who used SSRIs in early pregnancy between July 1, 1995 through the end of 2004.35 This study did not find any support for a postulated association of maternal use of SSRIs during pregnancy and craniostenosis or omphalocele. Another large meta-analytic study of published obstetrical outcomes of women exposed to SSRIs during pregnancy did not find any association with heightened risk for major cardiovascular or minor malformations; however, there was a significantly increased risk of spontaneous abortion.36 Based on a retrospective study of 3,581 pregnant women drawn from two United States managed care insurance databases that excluded concurrent first-trimester use of known teratogens (eg, lithium, valproic acid, carbamazepine), paroxetine use during the first-trimester was associated with a 1% increase in the absolute risk for congenital malformations over the baseline rate of occurrence.37 Various organ systems were affected and the most common cardiovascular malformations were ventricular septal defects. This study was conducted by GlaxoSmithKline, the manufacturer of paroxetine, and led to the issuance of an FDA warning regarding risk of major congenital malformations (Table 8).37,38

 

Congenital malformations do not appear to occur more frequently with maternal use of most SSRIs during pregnancy (paroxetine may be an exception); however, these medications do cross the placenta, appear in umbilical cord blood at birth, and are associated with metabolic effects and emergence of serotonin syndrome in the neonate.39 Serotonin syndrome due to SSRI administration is well-described in adults and includes changes in mental state, myoclonus, hyperreflexia, tremor, and fever, among other symptoms.21 It is not clear that long-term sequelae are associated with the emergence of serotonin syndrome in neonates. However, SSRI exposure during pregnancy does have metabolic and clinical consequences, albeit often subtle, for the neonate. Thus, the risk to the developing infant and mother of untreated maternal MDD, panic disorder, or obsessive-compulsive disorder during pregnancy must be weighed against potential risk to the fetus. With the availability of other antidepressants, paroxetine use should be avoided in pregnant women in need of treatment with an SSRI.

 

Breastfeeding and SSRIs

Postpartum depression occurs in approximately 10% to 15% of women, many of whom may require antidepressants while breastfeeding.40 Of all the SSRIs, citalopram and fluoxetine are associated with the highest exposures to nursing infants, which are usually significantly <10% of the maternal dose per body weight. Studies of maternal/infant pairs of plasma and serum samples suggest that infant levels of nortriptyline, paroxetine, fluvoxamine, and sertraline are often undetectable, whereas levels of fluoxetine and citalopram were found to exceed 10% of the maternal levels in a high percentage of nursing infants.41,42 Data suggest that serious adverse side effects with clinical consequences are not usually encountered in the infant during breastfeeding by mothers treated with SSRIs; thus, breastfeeding need not be discouraged.40 However, fluoxetine and citalopram are not the preferred SSRIs for the treatment of nursing mothers.

 

Conclusion

Though antidepressants help alleviate the potentially impairing syndrome of depression, it is important to recognize their side effects to more effectively help maintain compliance. PCPs should also be aware that some symptoms in a patient treated with an SSRI might be an adverse event associated with high morbidity and even fatality, such as SIADH and serotonin syndrome, the latter of which can present with symptoms (eg, agitation, anxiety, twitching, confusion) interpreted as worsening depression. However, the PCP should not get scared off from using these life-saving medications. An increased awareness of the side effects of the most current and commonly used antidepressants should improve the PCP’s confidence to treat the most common disabling illness in this country. These mediations can typically be used with great tolerance and benefit in the majority of depressed patients. PP

 

References

1. Rush AJ, Trivedi M, Fava M. Depression, IV: STAR*D treatment trial for depression. Am J Psychiatry. 2003;160(2):237.
2. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
3. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
4. Haddad P, Lejoyeux M, Young A. Antidepressant discontinuation reactions. BMJ. 1998;316(7138):1105-1106.
5. Ghaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin K. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord. 1999;52(1-3):135-144.
6. Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disorder. 2005;85(3):245-258.
7. Akiskal HS, Benazzi F. The DSM-IV and ICD-10 categories of recurrent [major] depressive and bipolar II disorders: evidence that they lie on a dimensional spectrum. J Affect Disord. 2006;92(1):45-54.
8. Benazzi F. Challenging the unipolar-bipolar division: does mixed depression bridge the gap? Prog Neuropsychopharmacol Biol Psychiatry. 2007;30;31(1):97-103.
9. Amsterdam JD, Hornig-Rohan M, Maislin G. Efficacy of alprazolam in reducing fluoxetine-induced jitteriness in patients with major depression. J Clin Psychiatry. 1994;55(9):394-400.
10. Hansen L. A critical review of akathisia, and its possible association with suicidal behaviour. Hum Psychopharmacol. 2001;16(7):495-505.
11. Class suicidality labeling language for antidepressants. Available at: www.fda.gov/cder/drug/antidepressants/PI_template.pdf. Accessed May 29, 2007.
12. National suicide prevention life-line. 1-800-273-TALK. Available at: www.suicidepreventionlifeline.org. Accessed May 29, 2007.
13. Stop a Suicide Today. Available at: www.stopasuicide.org. Accessed May 29, 2007.
14. Acharya N, Rosen AS, Polzer JP, et al. Duloxetine: meta-analyses of suicidal behaviors and ideation in clinical trials for major depressive disorder. J Clin Psychopharmacol. 2006;26(6):587-594. Erratum in: J Clin Psychopharmacol. 2007;27(1):57.
15. Szanto K, Mulsant BH, Houck PR, et al. Emergence, persistence, and resolution of suicidal ideation during treatment of depression in old age. J Affect Disord. 2007;98(1-2):153-161.
16. Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry. 2006;63(12):1358-1367.
17. Stahl SM, Mendels J, Schwartz GE. Effects of reboxetine on anxiety, agitation, and insomnia: results of a pooled evaluation of randomized clinical trials. J Clin Psychopharmacol. 2002;22(4):388-392.
18. Barclay TS, Lee AJ. Citalopram-associated SIADH. Ann Pharmacother. 2002;36(10):1558-1563.
19. Romero S, Pintor L, Serra M, et al. Syndrome of inappropriate secretion of antidiuretic hormone due to citalopram and venlafaxine. Gen Hosp Psychiatry. 2007;29(1):81-84.
20. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006;40(9):1618-1622.
21. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705-713.
22. FDA Public Health Advisory. Combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Available at: www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm. Accessed May 29, 2007.
23. Isbister G, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004:42(3):277-285.
24. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
25. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615-619.
26. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13(1):100-109.
27. Boddy R, Ali R, Dowsett R. Use of sublingual olanzapine in serotonin syndrome [abstract]. J Toxicol Clin Toxicol. 2004:42:725.
28. Li N, Wallen NH, Ladjevardi M, Hjemdahl P. Effects of serotonin on platelet activation in whole blood. Blood Coagul Fibrinolysis. 1997;8(8):517-523.
29. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59-64.
30. Yuan Y, Tsoi K, Hunt RH. Selective serotonin reuptake inhibitors and risk of upper GI bleeding: confusion or confounding? Am J Med. 2006;119(9):719-727.
31. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ. 2001;323(7314):655-658.
32. Kulin NA, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA. 1998;279(8):609-610.
33. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med. 1996;335(14):1010-1015.
34. Berard A, Ramos E, Rey E, Blais L, St-Andre M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1):18-27.
35. Kallen BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol. 2007;79(4):301-308.
36. Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials. Reprod Toxicol. 2006;22(4):571-575.
37. Williams M, Wooltorton E. Paroxetine (Paxil) and congenital malformations. CMAJ. 2005;173(11):1320-1321.
38. FDA Public Health Advisory. Paroxetine. Available at: www.fda.gov/cder/drug/advisory/paroxetine200512.htm. Accessed May 29, 2007.
39. Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry. 2003;60(7):720-726.
40. Lee A, Woo J, Ito S. Frequency of infant adverse events that are associated with citalopram use during breast-feeding. Am J Obstet Gynecol. 2004;190(1):218-221.
41. Hendrick V, Fukuchi A, Altshuler L, Widawski M, Wertheimer A, Brunhuber MV. Use of sertraline, paroxetine and fluvoxamine by nursing women. Br J Psychiatry. 2001;179:163-166.
42. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078. 

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Dr. Rosse is chief of psychiatry at the Department of Veterans Affairs Medical Center and professor in the Department of Psychiatry at Howard University in Washington, DC. Dr. Fanous is staff psychiatrist in the Mental Health Service Line at the Department of Veterans Affairs Medical Center and assistant professor in the Department of Psychiatry at Georgetown University School of Medicine in Washington, DC; and assistant clinical professor in the Department of Psychiatry at the Medical College of Virginia Commonwealth University in Richmond. Ms. Gaskins is psychology technician in the Mental Health Service Line at the Department of Veterans Affairs Medical Center. Dr. Deutsch is associate chief of staff for mental health in the Mental Health Service Line at the Department of Veterans Affairs Medical Center and professor in the Department of Psychiatry at Georgetown University School of Medicine.

Disclosure: Dr. Deutsch is a consultant to Janssen. Drs. Rosse and Fanous, and Ms. Gaskins, report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Richard B. Rosse, MD, Chief of Psychiatry, Department of Veterans Affairs Medical Center, 50 Irving St, NW, Washington, DC 20422; Tel: 202-745-8156; Fax: 202-745-8169; E-mail: Richard.Rosse@med.va.gov.

 

 
 

Abstract

Although the most commonly used antidepressants (ie, selective serotonin reuptake inhibitors) have a lower incidence of side effects compared to the earlier antidepressants (ie, tricylic antidepressants), some less serious and a few potentially serious side effects are associated with the range of newer antidepressants and adjuvant agents used to augment the efficacy of antidepressants. Primary care physicians engaged in the modern practice of psychopharmacologic treatment of depression need to be aware of the range of side effects, from minor to more serious. This article focuses on the more common side effects of antidepressants used in the modern treatment of depression.

 

Introduction

This article focuses on the medications used in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This was the largest and longest study on the effectiveness of treatments for depression and led to the best evidence-based treatment for depression to date. Table 1 outlines the side effects of some of the more commonly used antidepressants that were studied in STAR*D including potential augmenting (adjuvant) medications for improving antidepressant efficacy (eg, adding bupropion up to 400 mg to a selective serotonin reuptake inhibitor [SSRI] in a patient with less than a remission response to their SSRI).The STAR*D study showed that on first exposure to an antidepressant, only 28% to 33% of patients will go into full remission. Total remission of depressive symptoms (not just response, ie, an amelioration of depressive symptoms) is now the aim of modern antidepressant psychopharmacology.1

 

Typically, SSRIs are the first agents used to treat depression in clinical practice due to their safety and low incidence of serious side effects. Table 1 provides a list of side effects common with most SSRIs (listed for the two prototypic SSRIs used in the STAR*D study, namely citalopram and sertraline).2 One of the important findings of the STAR*D study is that antidepressant efficacy is often improved with the addition of various antidepressant adjuvant (augmenting) medications (eg, triiodothyronine [T3] or lithium, with T3 causing fewer side effects).3 Primary care physicians (PCPs) will need to familiarize themselves with the switch and augmentation strategies tested in the STAR*D study. Readers should note that there are other antidepressants and adjuvant medications available that do not appear in Tables 1 or 2. Nortriptyline is the prototypic tricyclic antidepressant (TCA) that was used in the STAR* D study, just as citalopram and sertraline were the stand-in SSRIs. However, TCAs are rarely used now as a first-line antidepressant in treating depression.

 

When medications are combined, the potential for side effects can increase, and it can become difficult to differentiate which agent is responsible for the side effect(s). Hence, the primary antidepressant should be introduced first and the adjuvant agent added at a later time to analyze the etiology of potential future side effects. Augmentation of citalopram with either bupropion sustained release (SR) or buspirone was found in the STAR*D study to be useful. However, augmentation with bupropion SR did have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects.2 If the dosing strategies in Table 1 are adhered to, the incidence of adverse side effects should be diminished.

Medication side effects or adverse events can range from less serious annoyances to very serious, life-threatening situations (Table 2). The more side effects that a patient experiences, the less adherent patients are likely to be. Whether serious or not, it is important to manage the side effects experienced by the patient.

 

Minor Side Effects

Headache

Headaches can range from mild to severe, and may not be related to the antidepressant being used by the patient. Many studies of SSRIs show prevalences of headache to be greater in the placebo group than in the active drug groups. However, there is still a minority of patients who appear to get headaches on SSRIs. They typically respond to analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), or to an ice pack on the headache area.

 

Fatigue

Complaints of fatigue, lethargy, and tiredness are common, especially during the early weeks of antidepressant treatment. Possible antidotes include taking a brief nap during the day or getting some mild exercise such as walking. Sometimes, the medication can be taken 1–2 hours before bedtime so that the side effect can be put to use by helping the patient fall sleep. (Insomnia is a common problem in patients with depressive disorders.)

 

Sedation

It should be standard practice to educate or warn patients that antidepressants have potential sedative effects and could impair judgment, thinking, and motor skills, as well as their ability to drive, use machines, or perform tasks that require alertness, coordination, or physical dexterity. Interventions for fatigue can also be beneficial for counteracting antidepressant-induced sedation. Some clinicians try moderate doses of modafinil or other stimulants (eg, methylphenidate, dextroamphetamine/amphetamine composite medication) to counteract the sedation induced by antidepressants.

 

Sexual Side Effects

SSRIs are associated with delayed orgasm or an inability to achieve orgasm (anorgasmia). This can occur in both men and women perhaps more than half the time at regular or higher therapeutic doses. Most cases of sexual dysfunction stop after 1–3 days of the medication being stopped.

Possible remedies include dose lowering or trying to schedule sexual activity before taking medication for the day. Clinicians can also switch to an antidepressant less associated with these side effects. These antidepressants include bupropion or mirtazapine. If erectile dysfunction is an issue, agents such as sildenafil, vardenafil, tadalafil, or alprostadil (the latter given by injection into the side of the penis) may be considered.

Clinicians may try stopping medication for only the day that sexual activity will occur (or lower the dose on that day, returning to regular higher dose the other days of the week (this may not work so well for antidepressants with half-lives >24 hours, such as fluoxetine). However, this intervention of stopping SSRIs before planned sexual acttivity can cause an SSRI discontinuation syndrome (especially for SSRIs with a shorter half-life).

 

Insomnia

Insomnia occurs because some antidepressants cause stimulation that can interfere with sleep. To counteract this effect, medication can be taken in the morning. (In fact, SSRIs are typically first tried as an AM dose.) Lower-dose mirtazapine is quite sedating and might be best for patients with severe insomnia. Stimulation associated with antidepressants can be a negative side effect when taken at night, but a positive experience when taken in the morning, with the medication providing a needed energy boost. Antidepressant-induced insomnia can be dealt with by giving the antidepressant with a sedating medication (eg, a benzodiazepine or trazodone) at bedtime. To avoid insomnia, medications such as bupropion are never dosed at bedtime.
Patients should be encouraged to practice good sleep hygiene, including avoiding caffeinated drinks before bedtime, getting regular exercise at least 4–5 hours before bedtime, and developing a relaxing bedtime routine.

 

Gastrointestinal Side Effects

Nausea is one of the most common reasons people stop taking antidepressants. Nausea typically begins within 1 week of starting treatment and often goes away on its own within a few weeks. Anecdotally, this common side effect has been reduced by taking antidepressants with food or with an antacid (there are no studies to the authors’ knowledge supporting this intervention for nausea). If available, a slow-release form of an antidepressant might lessen gastric upset and nausea, or the dosage might be decreased and the upward dose titration slowed.

 

Constipation

To treat or prevent constipation (much more common with the TCAs), patients should increase fiber and fluid intake as well as mobility (ie, physical activity).

 

Weight Gain

Overall, SSRIs (except paroxetine) are thought to have no or only slight weight-inducing effects (although there are no doubt exceptions to this). Hence, with the SSRIs, it is prudent to carefully monitor patients’ weight, since the amelioration of depressive symptoms can be associated with improved appetite and weight gain. Mirtazapine can also be associated with weight gain, while bupropion is associated with potentially problematic weight loss in already underweight patients.

 

SSRI Discontinuation Syndrome

Not all patients taking antidepressants experience SSRI discontinuation syndrome, but for those who do the syndrome often presents with flu-like symptoms such as headache, diarrhea, nausea, vomiting, chills, dizziness, fatigue, and insomnia. Symptoms can even include agitation, impaired concentration, vivid dreams, depersonalization, irritability, and suicidal thoughts. Symptoms last anywhere from one to several weeks and vary in intensity.3

In order to avoid this syndrome, clinicians should educate patients to not suddenly stop taking SSRIs. Patients can use a pill splitter to more slowly taper off their SSRIs. Another option is to switch to the liquid form of the medication so that patients can reduce their dosages more slowly to avoid discomfort when they discontinue an SSRI. Another option is for patients to switch from their shorter-acting SSRI to fluoxetine for the final discontinuation. Fluoxetine has a 9.3 day half-life (which is longer than the 24-hour or so half-lives of many other SSRIs) and usually has the mildest discontinuation effects of all the SSRIs.4 Antidepressants with shorter half-lives (eg, paroxetine or fluvoxamine) have a higher risk of SSRI discontinuation syndrome.

 

Serious Side Effects

SSRI-Induced Mania/Hypomania

Estimates are that 3% to 10% of depressed individuals may be at risk for developing hypomania or mania when treated with antidepressants. Patients with underlying bipolar disorder seem susceptible to antidepressant-induced mania/hypomania. There is a high rate of instances when bipolar depression is misdiagnosed as unipolar depression.5,6 The rate of antidepressant-induced hypomania in patients with major depressive disorder (MDD) is thought to correspond with the rate of misdiagnosis of bipolar depression as unipolar depression. Besides the induction of mania/hypomania by antidepressants, there can be “dysphoric” hypomanic/manic (“mixed”) states that can be difficult to differentiate from depression, or the more subtle induction of “rapid cycling” of manic and depressive episodes (ie, increasing the number of depressive and hypomanic/manic episodes peer year) that fade after discontinuation of antidepressants. It should be noted that some clinicians and researchers view these states as having a high-risk suicide potential.7,8 If the PCP is concerned about having precipitated mania in a patient, he or she should seek consultation with a mental health colleague.

 

Agitation, Jitteriness, Restlessness, and Anxiety/Panic

Agitation, restlessness, and anxiety can result from the stimulating effect of some antidepressants. Patients might not be able to relax or sit still. Clinicians should be alert for racing or impulsive thoughts along with high energy, as they may be signs of antidepressant-induced hypomania or mania.

Patients with a history of panic disorder (Table 3) or anxiety who are being treated with antidepressants should have a gradual escalation in dosage to minimize these side effects, typically seen during the initial days of treatment with antidepressants. It may be difficult to place patients back on an antidepressant after they have experienced an antidepressant-induced panic anxiety state. It has also been shown that the presence of agitation and anxiety in a patient with depression is a risk factor for suicide. It is this latter fact which makes this constellation of side effects potentially serious.9,10

 

To prevent the inadvertent precipitation of a panic attack when using an antidepressant, it may be useful to inquire about the symptoms (Table 3) and then recommend using a low dose of an antidepressant at initiation of therapy, with very slow upward titration. Education about this potential paradoxical increase in anxiety/panic while being introduced to an antidepressant is likely to improve adherence with medication. A benzodiazepine can often be employed to prophylax/treat antidepressant-induced panic or anxiety.

 

Increased Risk of Suicide

Whether or not the SSRIs increase suicide rates—especially in adolescents—has been a matter of contention, but the Food and Drug Administration has come down on the side of accepting the notion that SSRIs can increase suicide rates during the initial few months of a course of drug therapy or at times of dose changes (either increases or decreases; Table 4).11

 

During treatment with antidepressants, patients should be asked at every visit ( there should be more frequent visits in the early months of treatment) about their suicidal thoughts (Table 5). Any patient being treated for depression should have a “suicide prevention plan” in case suicidal ideation emerges or re-emerges. This plan could include going to the nearest emergency room, calling suicide hot lines, encouraging family education about depression and suicide, providing Internet sites for patients with suicidal ideation,12,13 and ways to contact their mental healthcare workers if suicidal ideation emerges. The “suicide prevention plan” provides alternative behaviors to suicidal behaviors.10,14-17

 

 

 

 

 

 

 

 

 

 

Hyponatremia/SIADH

SSRIs may lead to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), characterized by hyponatremia, a potentially fatal condition that is typically asymptomatic until it becomes severe. It is a relatively infrequent but serious complication of SSRI use. (One author estimated its occurrence with fluoxetine in approximately 6.3 cases out of 1,000.18) Risk factors for the development of SIADH/hyponatremia with SSRIs include older age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium concentrations. Baseline serum sodium levels should be obtained in those at higher risk who are going to start on an SSRI. Mental status changes are frequently the earliest manifestation of SIADH/hyponatremia.19,20

Following discontinuation of the offending SSRI, the serum sodium concentration should normalize within approximately 2 weeks. Switching to another SSRI might still result in SIADH, hence plasma sodium concentrations must be monitored not only in the first weeks of treatment but throughout the full course of patients switched to another SSRI after a bout of SSRI-induced SIADH. The clinician might also consider use of a non-SSRI such as the aminoketone bupropion.

 

Serotonin Syndrome

Serotonin syndrome can be mild (in which case it may not be detected) or dramatic and life threatening.21 An often-cited differential point for differentiating neuroleptic malignant syndrome (NMS) from serotonin syndrome involves abnormal reflexes, where there will be hyperreflexia and clonus in serotonin syndrome versus bradyreflexia in NMS. Information from a recently released Food and Drug Administration warning related to serotonin syndrome and various antidepressants can be found in Tables 6 and 7.22

 

 

Prevention of serotonin syndrome with the avoidance of drug interactions that might cause it should be the mainstay of treating serotonin syndrome. Clinicians should also remember that single SSRIs (especially in high dose and overdose) can result in serotonin syndrome.23 Patients who are going to be placed on SSRIs, especially those who are going to be on other serotonergic medications (such as triptans for migraines) along with their SSRIs, should be educated about this syndrome in order to make them partners in the early detection of this rare side effect.24

The most important treatment is to discontinue the offending agents. The syndrome usually resolves within 24 hours after the withdrawal of the offending medications.25-27

 

Seizures

Four out of every 1,000 people who receive bupropion in doses <450 mg/day experience seizures. When doses exceed 450 mg/day, the risk increases 10-fold. Bupropion should not be used in patients with epilepsy and other conditions that lower the seizure threshold (eg, alcohol withdrawal, active brain tumors). Seizures are a very rare event in patients taking SSRIs.4

 

Upper Gastrointestinal Bleeding and SSRIs

Serotonin enhances platelet activation that is induced by adenosinediphosphoric acid and thrombin in whole blood.28 The depletion of serotonin from platelets, subsequent to reuptake blockade, would therefore be expected to diminish hemostasis. Upper gastrointestinal bleeding (UGIB) has been a concern in SSRI treatment following the publication of numerous case reports.29-31 Studies employing large patient databases have been useful in examining the relationship between SSRI use and subsequent UGIB. A recent study in the Danish population found that users of SSRIs were hospitalized with UGIB at a rate 3.6 times greater than age- and sex-matched controls.29 Yuan and colleagues30 concluded that the evidence supporting increased UGIB in the context of SSRI use in the general population is limited. However, there is greater evidence that SSRI use is associated with increased UGIB in the elderly,31 concomitant NSAID use, and patients with a past history of UGIB. Clinicians should therefore be aware of this potential serious adverse event of SSRIs.

 

Birth Defects and Breastfeeding in Patients Taking SSRIs

The treatment of maternal depression during pregnancy is an important clinical issue. The fetal safety of SSRIs was an early concern after the introduction of fluoxetine in the 1980s as a result of the high-reported prevalence of depression among women (up to 20%) and the fact that >50% of all pregnancies are unplanned.32 An early study raised concerns that fluoxetine use during pregnancy was associated with perinatal complications and minor malformations,33 although this association may have been more directly related to the severity of depression. A prospective controlled study32 comparing 267 women who contacted one of nine “teratology information service centers” because of concerns regarding SSRI use during pregnancy and 267 women exposed to nonteratogenic agents failed to find differences on several important outcome measures, including major malformations, spontaneous and elective abortions, stillbirths, birth weight, and gestational age. The women were contacted 6–9 months after delivery.

A study of 1,403 pregnant women identified in a population-based registry in Quebec34 suggested that a paroxetine dose >25 mg/day during the first trimester of pregnancy may be associated with increased risk of major congenital and cardiac abnormalities relative to other antidepressants. Thus, a dose-related effect of paroxetine during first-trimester exposure on cardiac malformations may exist. The impression that paroxetine is distinguished from other SSRIs in terms of a heightened association between its use during early pregnancy and infant cardiovascular defects, notably ventricular and atrium septum defects, emerged in a study of the Swedish Medical Birth Registry of 6,481 women who used SSRIs in early pregnancy between July 1, 1995 through the end of 2004.35 This study did not find any support for a postulated association of maternal use of SSRIs during pregnancy and craniostenosis or omphalocele. Another large meta-analytic study of published obstetrical outcomes of women exposed to SSRIs during pregnancy did not find any association with heightened risk for major cardiovascular or minor malformations; however, there was a significantly increased risk of spontaneous abortion.36 Based on a retrospective study of 3,581 pregnant women drawn from two United States managed care insurance databases that excluded concurrent first-trimester use of known teratogens (eg, lithium, valproic acid, carbamazepine), paroxetine use during the first-trimester was associated with a 1% increase in the absolute risk for congenital malformations over the baseline rate of occurrence.37 Various organ systems were affected and the most common cardiovascular malformations were ventricular septal defects. This study was conducted by GlaxoSmithKline, the manufacturer of paroxetine, and led to the issuance of an FDA warning regarding risk of major congenital malformations (Table 8).37,38

 

Congenital malformations do not appear to occur more frequently with maternal use of most SSRIs during pregnancy (paroxetine may be an exception); however, these medications do cross the placenta, appear in umbilical cord blood at birth, and are associated with metabolic effects and emergence of serotonin syndrome in the neonate.39 Serotonin syndrome due to SSRI administration is well-described in adults and includes changes in mental state, myoclonus, hyperreflexia, tremor, and fever, among other symptoms.21 It is not clear that long-term sequelae are associated with the emergence of serotonin syndrome in neonates. However, SSRI exposure during pregnancy does have metabolic and clinical consequences, albeit often subtle, for the neonate. Thus, the risk to the developing infant and mother of untreated maternal MDD, panic disorder, or obsessive-compulsive disorder during pregnancy must be weighed against potential risk to the fetus. With the availability of other antidepressants, paroxetine use should be avoided in pregnant women in need of treatment with an SSRI.

 

Breastfeeding and SSRIs

Postpartum depression occurs in approximately 10% to 15% of women, many of whom may require antidepressants while breastfeeding.40 Of all the SSRIs, citalopram and fluoxetine are associated with the highest exposures to nursing infants, which are usually significantly <10% of the maternal dose per body weight. Studies of maternal/infant pairs of plasma and serum samples suggest that infant levels of nortriptyline, paroxetine, fluvoxamine, and sertraline are often undetectable, whereas levels of fluoxetine and citalopram were found to exceed 10% of the maternal levels in a high percentage of nursing infants.41,42 Data suggest that serious adverse side effects with clinical consequences are not usually encountered in the infant during breastfeeding by mothers treated with SSRIs; thus, breastfeeding need not be discouraged.40 However, fluoxetine and citalopram are not the preferred SSRIs for the treatment of nursing mothers.

 

Conclusion

Though antidepressants help alleviate the potentially impairing syndrome of depression, it is important to recognize their side effects to more effectively help maintain compliance. PCPs should also be aware that some symptoms in a patient treated with an SSRI might be an adverse event associated with high morbidity and even fatality, such as SIADH and serotonin syndrome, the latter of which can present with symptoms (eg, agitation, anxiety, twitching, confusion) interpreted as worsening depression. However, the PCP should not get scared off from using these life-saving medications. An increased awareness of the side effects of the most current and commonly used antidepressants should improve the PCP’s confidence to treat the most common disabling illness in this country. These mediations can typically be used with great tolerance and benefit in the majority of depressed patients. PP

 

References

1. Rush AJ, Trivedi M, Fava M. Depression, IV: STAR*D treatment trial for depression. Am J Psychiatry. 2003;160(2):237.
2. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
3. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
4. Haddad P, Lejoyeux M, Young A. Antidepressant discontinuation reactions. BMJ. 1998;316(7138):1105-1106.
5. Ghaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin K. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord. 1999;52(1-3):135-144.
6. Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disorder. 2005;85(3):245-258.
7. Akiskal HS, Benazzi F. The DSM-IV and ICD-10 categories of recurrent [major] depressive and bipolar II disorders: evidence that they lie on a dimensional spectrum. J Affect Disord. 2006;92(1):45-54.
8. Benazzi F. Challenging the unipolar-bipolar division: does mixed depression bridge the gap? Prog Neuropsychopharmacol Biol Psychiatry. 2007;30;31(1):97-103.
9. Amsterdam JD, Hornig-Rohan M, Maislin G. Efficacy of alprazolam in reducing fluoxetine-induced jitteriness in patients with major depression. J Clin Psychiatry. 1994;55(9):394-400.
10. Hansen L. A critical review of akathisia, and its possible association with suicidal behaviour. Hum Psychopharmacol. 2001;16(7):495-505.
11. Class suicidality labeling language for antidepressants. Available at: www.fda.gov/cder/drug/antidepressants/PI_template.pdf. Accessed May 29, 2007.
12. National suicide prevention life-line. 1-800-273-TALK. Available at: www.suicidepreventionlifeline.org. Accessed May 29, 2007.
13. Stop a Suicide Today. Available at: www.stopasuicide.org. Accessed May 29, 2007.
14. Acharya N, Rosen AS, Polzer JP, et al. Duloxetine: meta-analyses of suicidal behaviors and ideation in clinical trials for major depressive disorder. J Clin Psychopharmacol. 2006;26(6):587-594. Erratum in: J Clin Psychopharmacol. 2007;27(1):57.
15. Szanto K, Mulsant BH, Houck PR, et al. Emergence, persistence, and resolution of suicidal ideation during treatment of depression in old age. J Affect Disord. 2007;98(1-2):153-161.
16. Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry. 2006;63(12):1358-1367.
17. Stahl SM, Mendels J, Schwartz GE. Effects of reboxetine on anxiety, agitation, and insomnia: results of a pooled evaluation of randomized clinical trials. J Clin Psychopharmacol. 2002;22(4):388-392.
18. Barclay TS, Lee AJ. Citalopram-associated SIADH. Ann Pharmacother. 2002;36(10):1558-1563.
19. Romero S, Pintor L, Serra M, et al. Syndrome of inappropriate secretion of antidiuretic hormone due to citalopram and venlafaxine. Gen Hosp Psychiatry. 2007;29(1):81-84.
20. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006;40(9):1618-1622.
21. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705-713.
22. FDA Public Health Advisory. Combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Available at: www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm. Accessed May 29, 2007.
23. Isbister G, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004:42(3):277-285.
24. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
25. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615-619.
26. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13(1):100-109.
27. Boddy R, Ali R, Dowsett R. Use of sublingual olanzapine in serotonin syndrome [abstract]. J Toxicol Clin Toxicol. 2004:42:725.
28. Li N, Wallen NH, Ladjevardi M, Hjemdahl P. Effects of serotonin on platelet activation in whole blood. Blood Coagul Fibrinolysis. 1997;8(8):517-523.
29. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59-64.
30. Yuan Y, Tsoi K, Hunt RH. Selective serotonin reuptake inhibitors and risk of upper GI bleeding: confusion or confounding? Am J Med. 2006;119(9):719-727.
31. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ. 2001;323(7314):655-658.
32. Kulin NA, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA. 1998;279(8):609-610.
33. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med. 1996;335(14):1010-1015.
34. Berard A, Ramos E, Rey E, Blais L, St-Andre M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1):18-27.
35. Kallen BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol. 2007;79(4):301-308.
36. Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials. Reprod Toxicol. 2006;22(4):571-575.
37. Williams M, Wooltorton E. Paroxetine (Paxil) and congenital malformations. CMAJ. 2005;173(11):1320-1321.
38. FDA Public Health Advisory. Paroxetine. Available at: www.fda.gov/cder/drug/advisory/paroxetine200512.htm. Accessed May 29, 2007.
39. Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry. 2003;60(7):720-726.
40. Lee A, Woo J, Ito S. Frequency of infant adverse events that are associated with citalopram use during breast-feeding. Am J Obstet Gynecol. 2004;190(1):218-221.
41. Hendrick V, Fukuchi A, Altshuler L, Widawski M, Wertheimer A, Brunhuber MV. Use of sertraline, paroxetine and fluvoxamine by nursing women. Br J Psychiatry. 2001;179:163-166.
42. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078.