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Karen Pierce, MD

Primary Psychiatry. 2003;10(4):69, 70,75,76


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Floyd R. Sallee, MD, PhD, and Alex Smirnov, MD

Primary Psychiatry. 2003;10(4):41-48


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Harlan R. Gephart, MD

Primary Psychiatry. 2003;10(4):27-28


Dr. Gephart is medical director of the Center for Attention-Deficit/Hyperactivity Disorder in Redmond, WA, and clinical professor of pediatrics at the University of Washington in Seattle.       

Disclosure: Dr. Gephart is on the advisory board and receives research grants from McNeil. He is on the speaker’s bureau for Eli Lilly, McNeil, and Novartis. 

In 1902 the eminent British physician Dr. George Still, in his classic article “Some abnormal psychical conditions in children,” published in Lancet,1 gave the first medical description of the condition now known as attention-deficit/hyperactivity disorder (ADHD). Where have we come in the past 100 years since that historic publication?

Well, for one thing, we have seen many name changes for ADHD over the decades, from “postencephalitic syndrome” to “hyperkinesis of childhood” to the most enduring term, “the hyperactive child.” Along the way we have even used terms like “minimal brain damage” and “minimal brain dysfunction.” Since very few children with ADHD have documented evidence of neurologic insult, the term “brain damage” is inaccurate. Fortunately, we gave up the term “minimal” since, for most families, that word hardly begins to describe the magnitude of the problem. Like the fable of the blind men who each described the body of the elephant depending on what part they touched, the terms that have been used to describe ADHD (eg, impulsiveness, innattention, hyperactivity) depended on what aspect of the disorder was being focused on.

By 1980 we had settled upon “attention deficit” as the main distinguishing symptom, although it is apparent that ADHD?children and adults can have excellent sustained attention as long as things are interesting and motivating. It is when things get tedious, effortful, boring, and mundane that attention wavers, or is lost, causing some researchers to wonder if ADHD is not more a disorder of inhibition. Further compounding the problem, we incorporated the word “hyperactive” in the name, but then immediately put in a disclaimer that some of these kids are not really hyperactive, only “inattentive.”

Despite all the confusion in terminology, we have learned a great deal about ADHD over the years. For example, we have learned that ADHD is highly genetic for the majority of children and adults with the disorder. It is even more genetically based than schizophrenia, and almost as genetically determined as one’s height.

We know that ADHD is diagnosed 3–4 times more often in boys than girls.2 This ratio of boys to girls has lowered over the years as more girls, who usually have the inattentive type of ADHD and are often overlooked, are now being diagnosed with this disorder.

ADHD was thought to be the “yuppy” diagnosis of the 1990s, unique to America. More recently, studies from New Zealand, Canada, Germany, and England, among others, have demonstrated that ADHD is a worldwide condition with a prevalence rate of 3% to 7%, depending on the rigidity of the criteria used. In the United States, the American Academy of Pediatrics (AAP) 3 estimates a 4% to 12% prevalence in school-aged children.

Research on ADHD has exploded in the past decade, greatly enhancing our knowledge of this disorder. Although the specific etiology of ADHD?remains obscure, it is most likely a heterogeneous behavioral disorder with multiple possible etiologies including environmental agents, central nervous system insults, genetic origins, and neuroanatomical and neurochemical factors. How these all come together, and what the trigger mechanisms are, remains to be determined. Needless to say, the recent research findings in single photon emission computed tomography scanning and functional magnetic resonance imaging, though not yet of use in clinical diagnosis and management, are exciting indeed, and will likely lead to a specific method of testing for ADHD.

Nonetheless, there have been other significant events in recent years that have greatly aided and facilitated both the diagnostic process for ADHD as well as the application of treatment modalities. First and foremost were the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)4criteria for ADHD published in 1994, which not only clearly designated the major ADHD symptoms, but categorized them into three subtypes of ADHD: hyperactive/impulsive, inattentive, and combined. The DSM-IV4 also provided us with other diagnostic rules to follow in assessment of this disorder, to maximize accuracy in diagnosis and minimize overdiagnosis. Such rules include obtaining information from two sources, (eg, home and school), making sure the symptoms are of prolonged duration (>6 months), and clarifying that symptoms are significant only if they result in a substantial impairment in the child or adult.

The DSM-IV4 criteria are not without their own set of problems or weaknesses. For example, how can the same criteria apply to all age groups? Also, diagnosis requires that the informant eg, teacher, knows the patient well enough to provide accurate information. Nonetheless, the criteria have become the backbone for the American Academy of Child and Adolescent Psychiatry5 and the AAP3 published guidelines on diagnosing ADHD. They have also brought some sense of order and consistency nationwide (if not worldwide) to the diagnostic process of ADHD.

The AAP guidelines for treatment of ADHD, published in October 2001,3 were a major step toward bringing some consensus to physicians who treat ADHD, from both the psychiatric and primary care perspectives. The guidelines remind us that ADHD is a chronic condition for which there is no cure, that optimal results follow a “team approach” involving child, parent, educator, and health care provider, and that when desired outcomes are not achieved, one needs to go “back to the drawing board” to look for reasons why, such as nonadherence to treatment plans, or untreated or missed comorbid conditions.


AAP Guidelines for the Treatment of ADHD

The following is a list of AAP guidelines for the treatment of ADHD.3

(1) Primary care clinicians should establish a treatment program that recognizes ADHD as a chronic condition.

(2) The treating clinician, parents, and the child, in collaboration with school personnel, should specify appropriate target outcomes to guide management.

(3) The clinician should recommend stimulant medication and/or behavior therapy, as appropriate, to improve target outcomes in children with ADHD.

(4) When the selected management for a child with ADHD has not met target outcomes, clinicians should evaluate the original diagnosis, use of all appropriate treatments, adherence to the treatment plan, and presence of coexistent conditions.

(5) The clinician should periodically provide a systematic follow-up for the child with ADHD. Monitoring should be directed toward targeting outcomes and adverse effects, with information gathered from parents, teachers, and the child.

In this issue of Primary Psychiatry, several national authorities on ADHD share their insights on various aspects of diagnosis and treatment of this disorder.

In an excellent article, Floyd R. Sallee, MD, PhD, and Alex Smirnov, MD, present an overview of ADHD with particular emphasis on “state-of-the-art” knowledge in diagnosis, treatment, and research, culminating in a discussion about atomoxetine, the latest medication approved by the Food and Drug Administration for ADHD in children and adults.

Next, Andrew Adesman, MD, speaking as a developmental pediatrician, describes the two evidenced-based treatments for ADHD: stimulant medication and behavior therapy (FDA approval of atomoxetine is the first exception to the rule). It is important to remember that behavior therapy really means parent training in behavior modification principles, not play therapy or cognitive therapy—techniques which are not helpful in ADHD treatment.

Almost all children with ADHD struggle mightily in school. And though ADHD is not a learning disorder per se, it has a major impact on school achievement, behavior, and self-esteem. Sandra Rief, nationally recognized authority on teaching children with ADHD, shares her wisdom and practical insights in an article on educating children with this disorder.

As the AAP guidelines note,3 failure to achieve target outcomes may be a result of unrecognized or untreated coexistent conditions. Karen Pierce, MD, child psychiatrist who served as liaison to the American Academy of Pediatrics committee on ADHD, walks us through the maze of comorbid conditions that complicate ADHD.

In recent years it has become obvious to all of us working with ADHD patients, that the condition is not “outgrown,” despite our early misgiving advice to parents. The majority of children with ADHD continue to manifest some degree of symptomatology if not impairment, into adult life.6 However, the presenting problem in adulthood might be reflected as comorbid anxiety, depression, or job or marital dysfunction. Once again, Dr. Pierce draws our attention to these important considerations in the next article, on adult ADHD.

Finally, Gloria Pitts, DO, and Patricia A. Wallace, PhD, raise issues that are long overdue, eg, do the diagnostic criteria apply equally to culturally diverse populations and racial minorities, such as Hispanics, African Americans, and Asians? After all, the overwhelming research in ADHD has been conducted in a white population. Is it appropriate or fair to generalize the findings from one ethnic group to another?

All in all, this issue makes for stimulating and provocative reading. We hope you the readers come away from this issue with not only some information to apply to your practice setting, but also some thoughts to provoke discussion.  PP



1. Still GF. Lectures to the Royal College of Physicians: some abnormal psychical conditions in children. Lancet. 1902(suppl):1008-1012.

2. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56:1073-1086.

3. American Academy of Pediatrics. Clinical practice guidelines: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108:1033-1044.

4. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association; 1994.

5. Dulcan M. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry. 1997;36(suppl 10):85S-121S.

6. Goldman L, Genel M. Diagnosis and treatment of attention deficit hyperactivity disorder in children and adolescents. JAMA. 1998;279:1100-1107.


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Gloria Pitts, DO, and Patricia A. Wallace, PhD

Primary Psychiatry. 2003;10(4):84-88


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Donald S. Robinson, MD

Primary Psychiatry. 2003;10(4):51-52


Dr. Robinson is a consultant with Worldwide Drug Development, in Melbourne, Florida. He was formerly vice president of Central Nervous System Drug Development for Bristol-Myers Squibb.

Disclosure: Dr. Robinson is a consultant for Somerset Pharmaceuticals, Inc.


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Anita H. Clayton, MD

Primary Psychiatry. 2003;10(4):38-40


Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.

Disclosure: Dr. Clayton receives grants from Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer.


Depression in Women

Depressive disorders occur twice as frequently in women as in men,1 yet, until the last 5 years, most of the published literature pertained to men. There are, however, significant differences between women and men, including biological differences, psychosocial and behavioral factors of gender, age-related differences, and racial/ethnic differences, which may contribute to the difference in mental disorder prevalence observed. The biological differences include reproductive system function, brain structure and function, and drug interactions/metabolism. Depressive illness is frequently associated with reproductive life-phase transitions, such as the onset of puberty, the reproductive period, the menopausal transition, and the postmenopausal years. Changes in reproductive system function may explain the increased incidence of depression in women during reproductive life events.


Sex Hormones

The infradian or near-monthly cycling of sex hormones including estrogen, progesterone, and testosterone, may influence symptoms in premenstrual dysphoric disorder (PMDD), first onset of a major depressive disorder (MDD) episode, and a premenstrual exacerbation of depressive symptoms. Exogenous hormones, such as hormonal contraceptives and hormone replacement therapy (HRT), may be associated with depressive illness in some women. Significant changes in sex steroids may affect mood in pregnant women, during the postpartum period, and during the menopausal transition. These changes may occur in a pulsatile fashion (over minutes to hours), with a circadian or diurnal pattern, on an infradian cycle, or circannually (seasonally). Estrogen enhances the efficiency of serotonergic neurotransmission,2 thereby affecting mood, sleep, appetite, and concentration/memory.

Sex hormones in women increase blood levels of most medications, except during pregnancy when metabolism and volume of distribution are also increased.3 Oral contraceptives may alter the blood levels of some drugs, and oral contraceptives may be rendered ineffective by other medications (eg, carbamazepine). Some women may have increased metabolism of medications in the late luteal phase, requiring a dosage increase premenstrually to maintain the therapeutic effect.


Reproductive Life Events

Mood disorders occur about twice as frequently in women as in men,1 with the exception of bipolar affective illness. This gender difference is linked to the reproductive years in women, with increased risk of depression in women beginning at puberty, and persisting through midlife.4 As such, the clinical presentation of depressive illness in women is often associated with reproductive life events, an increased risk of a seasonal pattern, atypical features, frequent comorbidity of psychiatric and medical illnesses, and a chronic or recurrent course of illness.

Reproductive life events associated with mood disorders include the late luteal phase in reproductive-age women, pregnancy and the postpartum period, the menopausal transition, and treatment with hormonal therapies (oral contraceptives and HRT). PMDD is defined as the cyclic occurrence of premenstrual symptoms that have resolved by the end of the menstrual period.1 As such, women with major depression or dysthymia who experience a premenstrual exacerbation of depressive symptoms are not diagnosed with PMDD, as symptoms do not resolve during the follicular phase of the menstrual cycle. Symptoms include depressed or labile mood, anxiety, irritability, and somatic symptoms such as headache, breast tenderness, joint aches, sleep disturbance, and food cravings. Severe mood symptoms are associated with impairment in occupational or social function in approximately 5% of women.5 The mean age of onset of PMDD is the mid-twenties, with worsening symptoms until menopause.

Prior history of MDD puts a woman at greater risk for development of PMDD, and the risk is bidirectional. PMDD has been linked to serotonin dysregulation, with mood symptoms triggered by normal fluctuations in sex steroids. Thus, current treatment of choice is with selective serotonin reuptake inhibitors (SSRIs), taken either continuously, just during the late luteal phase, or when symptomatic.6


Maternity and the Postpartum Period

Depressive feelings associated with maternity, or “baby blues,” occurs in up to 75% of women with mild mood symptoms occurring between postpartum days 3 and 14.7 Spontaneous resolution occurs by 2 weeks postpartum in most women, but about 8% to 15% of women experience worsening symptoms, such that they meet diagnostic criteria for MDD by week 4 postpartum.7 Even fewer women experience an associated puerperal psychosis (1:1,000), which usually represents MDD with psychotic features or bipolar illness with psychosis.7 For 60% of women, their index episode of depression occurs in the postpartum period,8 while 30% have a prior history of MDD. At least 50% of women who experience postpartum depression suffer a recurrence of MDD with a subsequent pregnancy.9

While symptoms may be subtle and interpreted as related to the changes associated with care of an infant, treatment of postpartum depression often requires full doses of an antidepressant plus an augmenting strategy (eg, psychotherapy, thyroid supplementation, or a second antidepressant). Breastfeeding infants are exposed to the antidepressant in the breast milk, but no significant negative effects are known. If the child is at least 3 months of age, the primary physiologic benefits of breastfeeding have been realized, so weaning will reduce infant exposure to the antidepressant. Antidepressant treatment should not be withheld if the woman chooses to continue breastfeeding with informed consent. Treatment for a full 12 months is recommended.


Menopausal Transition

Some women are at risk for depression during the menopausal transition. The menopausal transition begins approximately 5 years before menopause, with the onset of menstrual changes/irregular menses, and increasing levels of follicle-stimulating hormone (FSH), and ends 1 year after cessation of menses. The period of risk for depression corresponds with the menopausal transition, but continues for up to 5 years following menopause. Women at risk include those with a prior history of depression,3 abrupt menopause via surgical or chemical means,10 a family history of depression, an early or prolonged menopausal transition10 (eg, before 45 years of age or for >5 years), and the presence of higher FSH levels.11 Cultural, social, and family factors also affect a woman’s response to the changes she experiences with perimenopause.11 In addition, a great deal of overlap exists between symptoms of the climacteric and criteria for depression, making the diagnosis difficult (Figure). Also, atypical features of mood reactivity, hypersomnia, hyperphagia or weight gain, rejection sensitivity, and leaden paralysis (sensation of heavy limbs and head) may complicate the picture. Treatment with an antidepressant is indicated if the criteria for MDD are met. Estrogen has been found to be useful treatment for depression in the menopausal transition,12 and in combination with an antidepressant after menopause,13 but recent concerns about risks associated with HRT have limited its use.


Comorbid Disorders in Women

Other factors to consider include comorbid psychiatric and medical conditions, and seasonal presentation of depression, where 80% are women and atypical features are common. Psychiatric conditions that are frequently comorbid with depression include anxiety disorders, somatoform disorders, eating disorders, borderline personality disorder, and sexual disorders. Medical conditions associated with depression include thyroid disorders, migraine, pain disorders such as fibromyalgia, irritable bowel syndrome, and obesity. The presence of a comorbid disorder makes the diagnosis more complex and finding the appropriate treatment more difficult.



General treatment considerations in MDD in women comprise a healthy lifestyle (eg, exercise, vitamin supplements B, E, and calcium, reduction of caffeine and alcohol), pharmacotherapy, light therapy, psychotherapy, electroconvulsive therapy, and combination treatment. Newer antidepressants, such as SSRIs, are better tolerated and appear to provide greater therapeutic efficacy than tricyclic antidepressants in reproductive-age women.14 Medications with significant noradrenergic effects may have greater efficacy in women with atypical features than antidepressant medications with effects specific for the serotonin system. Lower doses should be used in women than are indicated for men, except during pregnancy, where higher doses may be needed when psychotropics are used in order to compensate for the increased metabolism and volume of distribution. Metabolism may also be increased in the late luteal phase in some women, requiring increased medication doses.

Counseling of reproductive-age women about potential medication effects on the fetus with an unintended pregnancy is important. Coexisting disorders, either psychiatric or medical, may decrease acute tolerability to any medication, particularly if anxiety is comorbid. Long-term side effects of sexual dysfunction and weight gain can be significant problems in women who are more likely to experience recurrent or chronic depression requiring long-term treatment. Augmentation strategies may include the addition of hormonal treatments, such as estrogen or thyroid supplements, a second antidepressant, psychotherapy, a mood stabilizer, psychostimulants, atypical antipsychotics, and pindolol (Table),14,15 and should be utilized to realize full remission of depressive symptoms. Thus, recognition of the physiological substrate of sex differences, factors complicating diagnosis and treatment, and issues in the management of depression in women, can aid in the achievement of full remission while maintaining quality of life. PP


1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington DC: American Psychiatric Association; 1994.

2. Young EA, Korszun A, Altemus M. Sex differences in neuroendocrine and neurotransmitter systems. In: Kornstein SG, Clayton AH, eds. Women’s Mental Health: a Comprehensive Textbook. New York, NY: The Guilford Press; 2002:3-30.

3. Hamilton JA, Yonkers KA. Sex differences in pharmacokinetics of psychotropic medications, part I: physiological basis for effects. In: Jensvold MF, Halbreich U, Hamilton HA, eds. Psychopharmacology and Women: Sex, Gender, and Hormones. Washington, DC: American Psychiatric Press; 1996:11-42.

4. Kessler RC, McGonagle KA, Swartz M, et al. Sex and depression in the National Comorbidity Survey, I: lifetime prevalence, chronicity, and recurrence. J Affect Disord. 1993;29:77-84.

5. Reid RL. Premenstrual syndrome. N Engl J Med. 1991;324:1208-1210.

6. Steiner M, Pearlstein T. Premenstrual dysphoria and the serotonin system: pathophysiology and treatment. J Clin Psychiatry. 2000;61(suppl 12):17-21.

7. O’Hara MW. Postpartum Depression: Causes and Consequences. New York, NY: Springer-Verlag; 1995.

8. Cox JL, Conner Y, Kendell RE. Prospective study of the psychiatric disorders of childbirth. Br J Psychiatry. 1982;140:111-117.

9. Nonacs R, Cohen LS. Postpartum mood disorders: diagnosis and treatment guidelines. J Clin Psychiatry. 1998;59(suppl 2):34-40.

10. Avis NE, Bramvilla D, McKinlay SM, et al. A longitudinal analysis of the association between menopause and depression: results from the Massachusetts Women’s Health Study. Ann Epidemiol. 1994;4:214-220.

11. Huerta R, Mena A, Malacara JM, Diaz de Leon J. Symptoms at perimenopausal period: its association with attitudes toward sexuality, life-style, family function, and FSH levels. Psychoneuroendocrinology. 1995;20:135-148.

12. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58:529-534.

13. Schneider LS, Small GW, Hamilton S, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Am J Geriatr Psychiatry. 1997;5:97-106.

14. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline and imipramine in chronic depression. Am J Psychiatry. 2000;157:1445-1452.

15. Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000;61(suppl 2):13-19.


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Linda S. Kahn, PhD, and Uriel Halbreich, MD
Primary Psychiatry. 2003;10(2):41-45


Dr. Kahn is research assistant professor, and Dr. Halbreich is professor of psychiatry, research professor of OB/GYN, and director of biobehavioral research in the BioBehavioral Program at the State University of New York in Buffalo.

Disclosure: Dr. Halbreich has received grant support from Pfizer and Eli Lilly. Dr. Kahn reports no financial, academic, or other support of this work.

Please direct all correspondence to: Uriel Halbreich, MD, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Hayes C Annex, Suite 1, 3435 Main Street, Building 5, Buffalo, NY 14214-3016; Tel: 716-829-3811; Fax: 716-829-3812; E-mail:



How are premenstrual syndromes (PMS) identified and diagnosed, and what are the best approaches to treatment?PMS is a self-reported condition encompassing a broad array of symptoms which physicians must distinguish from other affective and general medical conditions in women. The hallmark of PMS is the cyclical occurrence of symptoms premenstrually, and their alleviation and remission shortly following the onset of menses. The pathophysiology of PMS involves multiple factors—particularly genetic vulnerability, environmental inputs, and the interaction between gonadal hormone fluctuations and neurotransmitters. For women with very mild symptoms, conservative nonpharmacologic treatment is recommended, including exercise, healthy nutrition, relaxation, and social support. For women with moderate to severe symptoms, especially if these symptoms are mood- and behavior-related, a variety of efficacious treatment options are available, with selective serotonin reuptake inhibitors being the treatment of choice.


Premenstrual syndromes (PMS) are a broad, diversified cluster of emotional, behavioral, and physical symptoms that occur cyclically for a time span ranging from several days to over 2 weeks before menses. Symptoms subside shortly after the beginning of the menstrual period. Most women experience some symptoms premenstrually, particularly physical symptoms, at some time in their reproductive years (when a woman is menstruating), but they do not perceive these symptoms as either distressing or debilitating.1 It has been reported that 35% of women may have moderate PMS symptoms which do not meet standard diagnostic criteria, but may necessitate treatment,2,3 while 3% to 9% of women have dysphoric PMS severe enough to warrant pharmacologic treatment.4,5 These women may experience marked disruptions in work, relationships, productivity, and quality of life. These disruptions underscore the need to recognize and appropriately treat premenstrual syndromes. This review will briefly summarize current assessment guidelines, diagnostic criteria, and treatment aspects of premenstrual syndromes.


There is no current consensus on the definition of PMS. During the 1950s, the term “premenstrual syndrome” became associated with the physical and psychological symptoms occurring up to 2 weeks prior to menses and remitting after the onset of menstruation.6 Since then, distinct diagnostic criteria were developed by the American Psychiatric Association,7 the World Health Organization,8 and the American College of Obstetricians and Gynecologists.9

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV)7 criteria for premenstrual dysphoric disorder (PMDD) is the most rigorous, and requires the prospective confirmation of at least 5 of 11 total symptoms, and work/school, home, or social impairment (Table 1). PMDD is considered to be the most severe form of PMS because its symptoms mirror those of major depressive disorder, even though they are of a shorter and cyclic duration.10 However, the overlap between severe PMS and PMDD has been estimated to be approximately 79%.6,11

The International Classification of Diseases, Tenth Edition8 includes PMS (or premenstrual tension syndrome) under “pain and other conditions associated with female genital organs and menstrual cycle,” and its criteria are less formulated than that of the DSM-IV. The American College of Obstetrics and Gynecology criteria require the presence of one affective or somatic symptom during the 5 days prior to menses in the three previous menstrual cycles.

Etiology and Pathophysiology

The etiology of PMS probably involves multiple factors, including diversified genetic vulnerability, sensitivity to hormonal fluctuations, possible imbalance between rate of fluctuation of gonadal hormones (but not in their absolute levels) and changes in function of the brain and other organs.12-14 There is evidence suggesting that sensitivity to cyclic hormonal changes may have a genetic basis.15

Gonadal steroids, estrogen and progesterone, have been postulated as the main contributing factors to PMS since Frank’s landmark research during the early 1930s.16 Other hypotheses include decreased estrogen levels, decreased progesterone levels, and differences in estrogen progesterone level ratios. Particular focus was given to low progesterone, which became a rationale for progesterone suppository treatment—one of the most publicized treatment modalities for PMS.17 However, that treatment modality has not been confirmed by well-controlled studies. It has been suggested that most women with PMS might have increased, not decreased, levels of progesterone.18,19

Others believe that the levels of gonadal hormones in women with PMS are normal.20,21 However, these women might have differences in cyclicity or rate of fluctuations as well as increased sensitivity to “normal” fluctuations.19 Changes occurring during the early luteal phase might be as significant as those occurring during the symptomatic period itself.19 The reports that women do not have PMS in anovulatory cycles,22,23 that suppression of ovulation is a very effective treatment modality,24-26 and that hysterectomy and bilateral oophorectomy dramatically improve severe PMS symptoms27 support the notion that fluctuations in gonadal hormones and other ovulation-related processes are important factors in the pathobiology of PMS. Gonadal hormones probably interact with neurotransmitters and other processes that are putatively involved in regulation of mood and behavior.

Research undertaken since the 1980s has implicated serotonin and other neurotransmitters in the pathophysiology of PMS and PMDD.10,12,28 Animal studies have demonstrated that serotonergic neurons in the brain “modulate aspects of behavior also regulated by sex steroids.”28,29 This includes not only sexual behavior, but also aggression/irritability—a common PMS symptom.28 At the same time, the sex steroids estrogen, progesterone, and testosterone influence brain serotonergic activity and neurotransmission.28 Serotonergic dysfunction in PMS also has been postulated, based on decreased platelet uptake of serotonin,30 blunted response to serotonin agonists,31 and consistent therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of PMS.32

It has also been suggested that γ-aminobutyric acid (GABA) and the GABAA receptor may also be involved in the etiology of PMS. Women with PMDD and a past history of major depressive disorder (MDD) were found to have low plasma GABA levels. In women with PMDD but no past MDD, plasma GABA levels decreased from the nonsymptomatic, mid-follicular phase to the symptomatic, late luteal phase.33 The GABAA receptor is influenced by progesterone, and some of its metabolites. Progesterone and estrogen also interact with serotonergic and noradrenergic systems. These interactions are probably of importance in the pathophysiology of PMS/PMDD.


Up to 300 different premenstrual complaints have been reported in patients with PMS,34 but only a few are consistent complaints assessed and identified in epidemiological studies. The most common include irritability, tension, depression, bloatedness, mastalgia, and headache.35-37 Clinically, the most commonly identified symptoms are depressed mood, mood swings, anxiety/tension, anger/irritability, low interest, decreased concentration, poor energy and changes, mostly increases, in sleep, appetite, and physical symptoms.38 The hallmark of PMS is the cyclical occurrence of symptoms premenstrually and their subsequent alleviation and remission with the onset of menses. Any symptom that appears during the premenstrual period may be considered to be related to PMS.

Many chronic disorders, both physical and psychiatric, are exacerbated premenstrually, or fluctuate in severity during the menstrual cycle and involve diversified body systems.39 Their main common denominator is the cyclicity, timing, the association with the menstrual cycle and the possible association with changes in gonadal hormones’ functions. These include neurological disorders, lung diseases, diseases of metabolism and enzymes, immune and autoimmune disorders, and gynecological disorders.39

Differential Diagnosis

There are no current diagnostic laboratory tests or other objective measurements to identify PMS. Rather, the diagnostic process relies mostly on prospective self-reporting of symptoms—optimally for two menstrual cycles. Several instruments, including the Daily Rating Form,40,41 have been developed and administered to patients to be used for self-reporting.

The Daily Rating Form, along with a self-questionnaire on medical, obstetric, gynecological, and psychiatric history, can be mailed ahead of time to the patient before her first office visit. The first visit should be scheduled for the late-luteal symptomatic phase. During this visit, the physician should review the patient’s self-report in detail, take a history, and differentiate PMS or PMDD from other possible disorders (Table 2). Routine biological tests should be undertaken to rule out other possible underlying medical conditions (Table 3). Tests include thyroid function, chemistry panel, liver function tests, complete blood count, and urinalysis. Although none of these tests are specific for PMS, they are administered to rule out other medical conditions.

The physician should also take a personal and family history of mood disorders or other mental problems. Many women who seek treatment for PMS actually have chronic disorders or an exacerbation of chronic MDD, dysthymic disorder, panic disorders, and other dysphoric disorders.42 These situations must be distinguished from PMS to develop an adequate treatment plan.

Treatment of Premenstrual Syndrome

A variety of treatment modalities are available for PMS. Conservative, nonpharmacologic treatment is recommended for women with mild PMS. This includes changes in life style, exercise, general healthy nutrition, relaxation, and social support.6,9,10,43

For women with moderate to severe PMS or PMDD, SSRIs are the first line of treatment because they are both effective and tolerated (Table 3).9,44 Several double-blind, placebo-controlled studies32,45-47 have demonstrated the efficacy of continuous administration of fluoxetine 20 mg/day for PMS and PMDD. The efficacy of continuous administration of sertraline 50–100 mg/day for PMDD has also been amply demonstrated.48-50 Fluoxetine and sertraline are approved by the Food and Drug Administration for PMDD indications. Paroxetine and citalopram have also proven effective form of treatment.51

Recent evidence suggests that intermittent administration of low-dose SSRIs during the luteal phase significantly improves both psychological and physical premenstrual symptoms even within the first cycle of treatment.52,53 Administration of long-acting, once weekly fluoxetine 90 mg, at the beginning and mid-luteal phase is probably equally effective.54

Anxiolytics may be administered during the luteal phase of the menstrual cycle for women with PMS and persistent anxiety that does not abate after a trial of SSRIs.6 Alprazolam, a short-acting benzodiazepine with antidepressant properties, has been shown to be effective in the management of PMS and PMDD at a dose of 2.25–0.5 mg TID which is administered during the luteal phase.11,55,56 However, these medications should be used with caution for long-term management of PMS and PMDD, due to their unfavorable side-effect profile and addictive potential.10

The link between PMS/PMDD symptomatology and the fluctuations of sex steroids associated with ovulation has led to the development of hormonal interventions, which should be considered second-line pharmacologic treatment.44 The goal of these therapies is to suppress ovulation, thereby reducing or eliminating PMS symptoms. The most well-known hormonal therapies include gonadotropin-releasing hormone (GnRH) agonists, danazol, progesterone, estrogen, and oral contraceptives. GnRH agonists induce a temporary, “medical oophorectomy.” Several studies reported complete resolution of premenstrual symptoms during GnRH therapy.23,24,57,58 The hypoestrogenic state induced by GnRH administration may result in postmenopausal symptoms as well as decreased bone mineral density and risk of osteoporosis during long-term treatment. Due to these concerns, several studies have evaluated “add-back” estrogen-progestin supplementation in patients treated with GnRH.59-61 However, these medications may precipitate mood symptoms, at least during the initiation of treatment, among women with severe PMS or PMDD.6,62

Danazol, an androgen derivative, has been shown to reduce symptoms of PMS, in dosages sufficient to suppress ovulation.26 However, significant side effects, including weight gain, mood changes, fluid retention, and acne, have prevented danazol from becoming a widely accepted treatment for PMS/PMDD.

Progesterone has long been advocated as a treatment for severe premenstrual symptoms.63 The rationale for progesterone therapy was the apparent temporal relationship between PMS symptoms and decreases in plasma progesterone levels, but empirical support for this theory is lacking.64,65 Moreover, double-blind, placebo-controlled trials of progesterone supplementation for the treatment of PMS have not demonstrated efficacy.21,66

Several controlled studies have reported the effectiveness of estrogen alone or with cyclical progesterone in the treatment of severe PMS.67-69 The suppression of ovulation seems to be a key factor in the efficacy of high-dose estrogen therapy, which must be cycled with progesterone to avoid endometrial hyperplasia.70 However, the addition of progesterone may precipitate a partial return of symptoms.

Some oral contraceptives have been used to treat PMS symptoms, even though their effectiveness has not been well-established.71-73 The goal of oral contraceptive therapy is to reduce hormonal fluctuations which might contribute to premenstrual dysphoria. However, findings of clinical trials on the use of oral contraceptives for PMS treatment have been inconsistent.74

Several randomized trials have suggested possible therapeutic benefits from dietary supplementation with calcium,75,76 magnesium,77 Vitamin B6,78 chasteberry,79 and other alternative therapies.44,80 A recent compreh ensive review80 evaluated randomized control trials of complementary/alternative therapies for PMS and found pervasive methodological problems. Further investigations on alternative therapies need to be undertaken before any of them can be considered viable treatment modalities.


PMS is quite prevalent in the general population. It is a self-reported, subjective disorder that requires the ruling out of other affective and general medical conditions to determine appropriate diagnosis and treatment. Women with mild symptoms should be encouraged to pursue nonpharmacologic therapy. For women with moderate to severe symptoms, several efficacious treatment options are available, with intermittent-luteal phase SSRIs as the treatment of choice for PMDD, and suppression of ovulation as a second-line treatment. PP


1. Singh BB, Berman BM, Simpson RL, Annechild A. Incidence of premenstrual syndrome and remedy usage: a national probability sample study. Altern Ther Health Med. 1998;4:75-79.

2. Steiner M, Brown E, McDougall M. The burden of illness of premenstrual symptoms. J Wom Health Gender-Based Med. 2002;11:324.

3. Wittchen HU, Becker E, Lieb R, Krause P. Prevalence, incidence and stability of premenstrual dysphoric disorder in the community. Psychol Med. 2002;32:119-132.

4. Angst J, Sellaro R, Merikangas KR, Endicott J. The epidemiology of perimenstrual psychological symptoms. Acta Psychiatr Scand. 2001;104:110-116.

5. Sveindottir H, Backstrom T. Prevalence of menstrual cycle symptom cyclicity and premenstrual dysphoric disorder in a random sample of women using and not using oral contraceptives. Acta Obstet Gynecol Scand. 2000;79:405-413.

6. Rapkin A. A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder. Psychoneuroendocrinology. In press.

7. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington DC: American Psychiatric Association, Inc.; 1994.

8. International Classification of Diseases. 10th ed. Geneva, Switzerland: World Health Organization; 1996.

9. American College of Obstetricians and Gynecologists (ACOG). Premenstrual Syndrome. Clinical Management Guidelines for Obstetrician-Gynecologists. Washington DC: ACOG; 2000.

10. Born L, Palova E, Steiner M. Premenstrual syndromes: guidelines for treatment. In: Gaszner P, Halbreich U, eds. Women’s Mental Health: An Eastern European Perspective. Budapest, Hungary:?The Section of the Interdisciplinary Collaboration of the World Psychiatric Association; 2002:56-72.

11. Freeman EW, Rickels K, Sondheimer SJ, Polansky MP. A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA. 1995;274:51-57.

12. Halbreich U. Premenstrual syndromes: closing the 20th century chapters. Curr Opin Obstet Gynecol. 1999;11:265-270.

13. Halbreich U. Premenstrual dysphoric disorders: a diversified cluster of vulnerability traits to depression. Acta Psychiatr Scand. 1997;95:169-176.

14. Halbreich U, Tworek H. Altered serotonergic activity in women with dysphoric premenstrual syndromes. Int J Psychiatry Med. 1993;23:1-27.

15. Kendler KS, Karkowski LM, Corey LA, Neale MC. Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression. Am J Psychiatry. 1998;155:1234-1240.

16. Frank R. The hormonal causes of premenstrual tension. Arch Neurol Psychiatry. 1931;26:1053-1057.

17. Dalton K. The Premenstrual Syndrome. London, England: Heinemann; 1964.

18. Backstrom T, Sanders D, Leask R, Davidson D, Warner P, Bancroft J. Mood, sexuality, hormones, and the menstrual cycle. II. Hormone levels and their relationship to the premenstrual syndrome. Psychosom Med. 1983;45:503-507.

19. Halbreich U, Endicott J, Goldstein S, Nee J. Premenstrual changes and changes in gonadal hormones. Acta Psychiatr Scand. 1986;74:576-586.

20. Rubinow DR, Schmidt PJ, Roca CA. Hormone measures in reproductive endocrine-related mood disorders: diagnostic issues. Psychopharmacol Bull. 1998;34:289-290.

21. Rubinow DR, Hoban MC, Grover GN, et al. Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects. Am J Obstet Gynecol. 1988;158:5-11.

22. Backstrom T, Hammarback S, Johansson UB. Etiological aspects of menstrual cycle linked mood changes. In: Van Hall EV, Everland W, eds. The Free Woman. Park Ridge and Carnforth: Parthenon Publishers; 1989:625-632.

23. Hammarback S, Backstrom T. Induced anovulation as treatment of premenstrual tension syndrome: a double-blind crossover study with GnRH-agonists vs. placebo. Acta Obtet Gynecol Scand. 1988;67:159-166.

24. Muse K, Cetel N, Futterman L, Yen SC. The premenstrual syndrome: effects of ‘medical ovariectomy’. N Eng J Med. 1984;311:1345-1349.

25. Bancroft J, Boyle H, Fraser HM. The use of an LHRH agonist in the treatment and investigation of the premenstrual syndrome. In: Kerns KW, Fink G, Harmar AJ, eds. Proceedings of the 13th Annual Meeting of the International Foundation for Biochemical Endocrinology. New York, NY: Plenum Publishing; 1985:46-73.

26. Halbreich U, Rojansky N, Palter S. Elimination of ovulation and menstrual cyclicity (with danazol) improves dysphoric premenstrual syndromes. Fertil Steril. 1991;56:1066-1069.

27. Casper RF, Hearn MT. The effect of hysterectomy and bilateral oophorectomy in women with severe premenstrual syndrome. Am J Obstet Gynecol. 1990;162:105-109.

28. Eriksson E, Andersch B, Ho HP, Landen M, Sundblad C. Diagnosis and treatment of premenstrual dysphoria. J Clin Psychiatry. 2002;63:16-23.

29. Ericsson E, Humble M. Serotonin in psychiatric pathophysiology, a review of data from experimental and clinical research. In: Pohl R, Gershon S, eds. The Biological Basis of Psychiatric Treatment. Basel, Switzerland: S. Karger Publishing; 1990:66-119.

30. Taylor DL, Mathew RJ, Ho BT, Weinman ML. Serotonin levels and platelet uptake during premenstrual tension. Neuropsychobiology. 1984;12:16-18.

31. Su TP, Schmidt PJ, Danaceau M, Murphy DL, Rubinow DR. Effect of menstrual cycle phase on neuroendocrine and behavioral responses to the serotonin agonist m-chlorophenylpiperazine in women with premenstrual syndrome and controls. J Clin Endocrinol Metabol. 1997;82:1220-1228.

32. Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group. N Eng J Med. 1995;332:1529-1534.

33. Halbreich U, Petty F, Yonkers K, Kramer GL, Rush AJ, Bibi KW. Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder. Am J Psychiatry. 1996;153:718-720.

34. Halbreich U, Endicott J, Schacht S, Nee J. The diversity of premenstrual changes as reflected in the Premenstrual Assessment Form. Acta Psychiatr Scand. 1982;65:46-65.

35. Woods NF, Most A, Dery GK. Prevalence of perimenstrual symptoms. Am J Public Health. 1982;72:1257-1264.

36. Ramcharan S, Love EJ, Fick GH, Goldfien A. The epidemiology of premenstrual symptoms in a population-based sample of 2,650 urban women: Attributable risk and risk factors. J Clin Epidemiol. 1992;45:377-392.

37. Merikangas KR, Foeldenyl M, Angst J. The Zurich Study. XIX. Patterns of menstrual disturbances in the community: results of the Zurich Cohort Study. Eur Arch Psychiatry Clin Neurosci. 1993;243:23-32.

38. Hurt SW, Schnurr PP, Severino SK, et al. Late luteal phase dysphoric disorder in 670 women evaluated for premenstrual complaints. Am J Psychiatry. 1992;149:525-530.

39. Halbreich U. Menstrually related disorders–towards interdisciplinary international diagnostic criteria. Cephalalgia. 1997;17 (suppl 20):1-4.

40. Endicott J, Nee J, Cohen J, Halbreich U. Premenstrual changes: Patterns and correlates of daily ratings. J Affect Disord. 1986;10:127-135.

41. Endicott J, Harrison W. Daily rating of severity of problems form. New York Department of Research Assessment and Training, New York State Psychiatric Institute; 1990.

42. Halbreich U. Premenstrual Syndromes. In: Halbreich U, ed. Balliere’s Clinical Psychiatry: International Practice and Research. London, England: Balliere, Tindall; 1996:667-686.

43. Johnson WG, Carr-Nangle RE, Bergeron KC. Macronutrient intake, eating habits, and exercise as moderators of menstrual distress in healthy women. Psychosomatic Medicine. 1995;57:324-30.

44. Pearlstein T, Steiner M. Non-antidepressant treatment of premenstrual syndrome. J Clin Psychiatry. 2000;61:22-27.

45. Menkes DB, Taghavi E, Mason PA, Spears GF, Howard RC. Fluoxetine treatment of severe premenstrual syndrome. Br Med J. 1992;305:346-347.

46. Stone AB, Pearlstein TB, Brown WA. Fluoxetine in the treatment of late luteal phase dysphoric disorder. J Clin Psychiatry. 1991;52:290-293.

47. Wood SH, Mortola JF, Chan YF, Moossazadeh F, Yen SS. Treatment of premenstrual syndrome with fluoxetine: a double-blind, placebo-controlled, crossover study. Obstet Gynecol. 1992;80:339-344.

48. Yonkers KA, Halbriech U, Freeman E, et al. Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. A randomized controlled trial. Sertraline Premenstrual Dysphoric Collaborative Study Group. JAMA. 1997;278:983-988.

49. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: a randomized controlled trial. Arch Gen Psychiatry. 1999;56:932-939.

50. Pearlstein TB, Halbreich U, Batzar ED, et al. Psychosocial functioning in women with premenstrual dysphoric disorder before and after treatment with sertraline or placebo. J Clin Psychiatry. 2000;61:101-109.

51. Dimmock PW, Wyatt KM, Jones PW, O’Brien PM. Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review. Lancet. 2000;356:1131-1136.

52. Halbreich U, Bergeron R, Yonkers KA, Freeman E, Stout AL, Cohen L. Efficacy of intermittent, luteal phase sertraline treatment of premenstrual dysphoric disorder. Obstet Gynecol. 2002;100:1219-1229.

53. Cohen L, Miner C, Brown E, et al. Premenstrual daily fluoxetine for premenstrual dysphoric disorder: a placebo-controlled, clinical trial using computerized diaries. Obstet Gynecol. 2002;100:435-444.

54. Miner C, Brown E, McCray S, Gonzales J, Wohlreich M. Weekly luteal-phase dosing with enteric-coated fluoxetine 90 mg in premenstrual dysphoric disorder: a randomized, double-blind, placebo- controlled clinical trial. Clin Ther. 2002;24:417-433.

55. Harrison WM, Endicott J, Rabkin JG, Nee JC, Sandberg D. Treatment of premenstrual dysphoria with alprazolam and placebo. Psychopharmacol Bull. 1987;23:150-153.

56. Harrison WM, Endicott J, Nee J. Treatment of premenstrual dysphoria with alprazolam. A controlled study. Arch Gen Psychiatry. 1990;47:270-275.

57. Freeman EW, Sondheimer SJ, Rickels K. Gonadotropin-releasing hormone agonist in the treatment of premenstrual symptoms with and without ongoing dysphoria: a controlled study. Psychopharmacol Bull. 1997;33:303-309.

58. Sundstrom I, Nyberg S, Bixo M, Hammarback S, Backstrom T. Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in a low dose regimen. Acta Obstet Gynecol Scand. 1999;78:891-899.

59. Mortola JF, Girton L, Fischer U. Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin [see comments]. J Clin Endocrinol Metabol. 1991;72:252A-252F.

60. Adashi EY. Long-term gonadotrophin-releasing hormone agonist therapy: the evolving issue of steroidal ‘add-back’ paradigms. Hum Reprod. 1994;9:1380-1397.

61. Leather AT, Studd JW, Watson NR, Holland EF. The treatment of severe premenstrual syndrome with goserelin with and without ‘add-back’ estrogen therapy: a placebo-controlled study. Gynecol Endocrinol. 1999;13:48-55.

62. Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338:209-216.

63. Dalton K. The Premenstrual Syndrome. Springfield, Ill: Charles C. Thomas; 1984.

64. Hammarback S, Backstrom T, Holst J, von Schoultz B, Lyrenas S. Cyclical mood changes as in the premenstrual tension syndrome during sequential estrogen-progestagen postmenopausal replacement therapy. Acta Obstetricia et Gynecologica Scandinavica. 1985;64:393-397.

65. Schmidt PJ, Nieman LK, Grover GN, Muller KL, Merriam GR, Rubinow DR. Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Eng J Med. 1991;324:1174-1179.

66. Rapkin AJ, Chang LC, Reading AE. Premenstrual syndrome: a double blind placebo controlled study of treatment with progesterone vaginal suppositories. J Obstet Gynecol. 1987;7:217-220.

67. Magos AL, Brincat M, Studd JW. Treatment of the premenstrual syndrome by subcutaneous estradiol implants and cyclical oral norethisterone: placebo controlled study. Br Med J Clin Res Ed. 1986;292:1629-1633.

68. Watson NR, Studd JW, Savvas M, Garnett T, Baber RJ. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet. 1989;2:730-732.

69. Smith RN, Studd JW, Zamblera D, Holland EF. A randomized comparison over 8 months of 100 micrograms and 200 micrograms twice weekly doses of transdermal oestradiol in the treatment of severe premenstrual syndrome. Br J Obstet Gynaecol. 1995;102:475-484.

70. Watson NR, Studd JW, Riddle AF, Savvas M. Suppression of ovulation by transdermal oestradiol patches. BMJ. 1988;297:900-901.

71. Kouri EM, Halbreich U. Hormonal treatments for premenstrual syndrome. Drugs of Today. 1998;34:603-610.

72. Muse K. Hormonal manipulation in the treatment of premenstrual syndrome. Clin Obstet Gynecol. 1992;35:658-666.

73. Harrison W, Sharpe L, Endicott J. Treatment of premenstrual symptoms. Gen Hosp Psychiatry. 1985;7:54-65.

74. Kahn LS, Halbreich U. Oral contraceptives and mood. Expert Opin Pharmacother. 2001;2:1367-1382.

75. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179:444-452.

76. Thys-Jacobs S, Ceccarelli S. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med. 1989;4:183-189.

77. Walker AF, De Souza MC, Vickers MF, Abeyasekera S, Collins ML, Trinca LA. Magnesium supplementation alleviates premenstrual symptoms of fluid retention.
J Womens Health. 1998;7:1157-1165.

78. Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318:1375-1381.

79. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study. BMJ. 2001;322:134-137.

80. Stevinson C, Ernst E. Complementary/alternative therapies for premenstrual syndrome: a systematic review of randomized controlled trials. Am J Obstet Gynecol. 2001;185:227-235.


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Facial Paralysis and Bell’s Palsy in Children: Current Diagnostic Concepts and Management Controversies

Michael S. Salman, MSc, MRCP


Primary Psychiatry. 2003;10(2):67-70


Dr. Salman is a clinical research fellow in the Division of Neurology at the Hospital for Sick Children in Toronto.

Disclosure: The author reports no financial, academic, or other support of this work.

Acknowledgment: Dr. Salman would like to thank Dr. Daune MacGregor for editing and appraising the manuscript, and for her general and continuous support.

Please direct all correspondence to: Michael S. Salman, MSc, MRCP, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8; Tel: 416-813-1500; Fax: 416-813-6334; E-mail:



How is facial paralysis in children different from adults? Facial paralysis is uncommon in children. Before making the diagnosis of Bell’s palsy (acute idiopathic facial weakness), a prompt search for other causes must be made, especially when the child is <2 years of age, with facial weakness that progresses 3 weeks after onset or fails to improve within a few weeks, and is recurrent or bilateral. There is evidence that implicates herpes simplex virus and, to a lesser extent, varicella zoster virus reactivation in the pathogenesis of Bell’s palsy in children. This may explain its excellent prognosis in that age group. Management includes supportive treatment, such as artificial tears and eye patching. The current medical literature does not provide evidence for significant benefit from the use of steroids in pediatric Bell’s palsy. A trial involving a larger number of children is needed to document if steroids provide moderate benefit in Bell’s palsy. There is not enough information to recommend the routine use of acyclovir in pediatric Bell’s palsy, however, there is some evidence of benefit for using acyclovir in facial paralysis caused by varicella zoster virus reactivation.


Bell’s palsy is defined as acute idiopathic facial muscle paralysis. It is a diagnosis of exclusion and its annual incidence is about 20/100,000.1 Bell’s palsy in the pediatric population has a different natural history, differential diagnosis, and different prognosis than in adults and, hence, deserves special consideration. This review attempts to address these issues with emphasis on establishing the correct diagnosis and reviewing evidence-based medical literature regarding management of Bell’s palsy.

Facial paralysis has been described since ancient times. In 1821, Sir Charles Bell2 drew attention to the anatomical course and function of the facial nerve. His name was linked to facial nerve paralysis at a time when nocause can be found.

Anatomy of the Facial Nerve

The facial corticobulbar tracts descend from the facial cortical motor area through the corona radiata and the internal capsule. The tracts then pass through the ventromedial lower pons, near the corticospinal tract, and descend mainly to the level of the upper medulla. The fibers decussate in the upper medulla and ascend in the dorsolateral medulla to synapse mainly in the contralateral facial nucleus.3

The facial motor nucleus supplying the upper facial muscles receive bilateral cortical innervation from the appropriate motor cortex. The lower facial muscles receive innervation from the contralateral motor cortex. A unilateral cortical (upper motor neuron) lesion spares the upper facial muscles and causes weakness of the contralateral lower facial muscles. This is seen in pediatric strokes caused by middle cerebral artery occlusion. Lesions affecting the facial motor nucleus and nerve cause weakness of all facial muscles ipsilaterally.

The facial nerve nucleus lies dorsolaterally in the caudal pons and upper medulla. The facial nerve leaves the brainstem at the pontomedullary junction. It enters the apex of the petrous part of the temporal bone with the eight cranial nerve and gives branches to the lacrimal gland, and stapedius muscle in the inner ear, sensation to the auricular skin, and the sublingual/submandibular salivary glands, and supplies the anterior two thirds of the tongue with taste fibers. Just before exiting the skull through the stylomastoid foramen, the facial nerve lies close to the inner ear and mastoid air cells. Finally, the facial nerve innervates the muscles of facial expression ipsilaterally.4

Adult Versus Pediatric Facial Paralysis

Children represent approximately 10% of the total number of cases with facial paralysis.5,6 Bell’s palsy accounts for approximately 50% of the adult cases and approximately 35% of the pediatric cases.6

The natural history of Bell’s palsy in adults is less favorable than in children. Adult studies report complete resolution in 70% to 80% of cases,7 compared with 90% to 96% of pediatric cases.8.9 This probably relates to the etiology of the disease, which is likely to be viral in origin in the pediatric population. Therefore, it is not surprising that the disease course and response to treatment in children is different than in their adults counterparts.

Clinical Presentation of Bell’s Palsy

A prodromal viral illness precedes the onset of Bell’s palsy by 1–4 weeks in 60% of cases. The onset of the paresis is abrupt and can progress over 1–7 days (but not weeks or months) to complete paralysis. The paresis involves all the ipsilateral facial muscles, including the forehead muscles. There is no predilection to either side of the face.5 Eyelid closure and blinking are asymmetrical, leaving the cornea vulnerable to dryness and exposure keratitis. The subject’s smile is asymmetrical, which is especially noticeable when looking at the alae nasi (nasal folds between the nares and the corner of the lips). Facial muscle twitching is not seen. The paresis can be accompanied by mild facial pain or otalgia (50%), subjective altered sensation over the affected side of the face (40%) or tongue (20%), and change of taste (50%).10,11

Facial Nerve Function Evaluation

In some case reports, photographs of the face have been used to show the degree of facial paralysis.6,11,12 Few clinical tools have been developed to assess the function of the facial nerve in a more standardized way. This is of particular importance in clinical trials evaluating the effect of different treatment modalities. The Adour/Swanson grading scale gives a facial paralysis recovery profile.13The House-Brackmann Facial Nerve Grading System14 has gained more popularity in clinical trials.15-17  The House-Brackmann Facial Nerve Grading System has six grades; grade I is normal, while there is total paralysis in grade VI.

Another practical tool is the Facial Nerve Cooperative Study Group Score of the Ministry of Health and Welfare of Japan, where it has been used in patients with Bell’s palsy.18 The score is based on 10 clinical observations including asymmetry of the face at rest, wrinkling of the forehead, blinking of the eyes, closing the eyes lightly and tightly, closing one eye, movement of the alae nasi, grinning, whistling, and closing the lip tightly. More recently, the Sunnybrook Facial Grading System was shown to be reliable when applied by novice users.19  


When a child presents with facial paralysis, it is important to avoid labeling it as Bell’s palsy until other causes have been considered and excluded (Table 1).20-29 This is especially important in children <2 years of age.A thorough history and clinical examination will help identify congenital, traumatic, and infective causes, which account for the majority of cases in the first 2 years of life.

Important symptoms that may help in localizing the site of the lesion along the course of the facial nerve include lacrimation, which can be quantified using the Schirmer tear test (dry eyes indicate involvement of the facial nerve at or proximal to the geniculate ganglion), hyperacusis (sensitivity to sound), salivation (dry mouth), and loss of taste (indicates distal involvement of the facial nerve).

Congenital absence of the orbicularis oris muscle, found at the corners of the mouth, is a common source of diagnostic confusion in early infancy and is frequently mislabeled as Bell’s palsy. It causes asymmetrical smile or cry. However, forehead muscles, eye closure (seen during crying or sleeping), and blinking are all symmetrical and normal.

Möbius syndrome causes facial diplegia due to aplasia of the facial nerve nuclei. It is associated with bilateral sixth cranial nerve palsy (the eyes are unable to move laterally even with oculocephalic head maneuver), deafness, palatal and lingual palsy, deficiency of the pectoral muscles, and extremities defects (syndactyly, missing or extra digits). Special attention must be paid to examining the central nervous system for evidence of brainstem and other cranial nerves involvement (eg, deafness, vertigo, dizziness, vomiting, difficulty swallowing).

The external auditory canal and tympanic membrane must be examined for evidence of varicalla zoster virus vesicles, seen in Ramsay-Hunt syndrome (herpes zoster oticus). The timing of the vesicle appearance tend be delayed in children.23 Hence, Ramsay Hunt syndrome may be initially indistinguishable from Bell’s palsy.24 The presence of tinnitus, hearing loss, nausea, vomiting, vertigo, and nystagmus, though less common in children than adults with Ramsay Hunt syndrome, may aid in making the correct diagnosis.23

The presence of mastoid bone redness and tenderness should be established or excluded. Bilateral parotid gland inspection and palpation should be done to evaluate asymmetrical enlargement caused by infiltrating mass or tumor recurrence.

Unless the history or clinical exam reveals additional abnormal and unexpected findings, no further tests are indicated for the diagnosis of Bell’s palsy. Some experts suggest doing a complete blood count to exclude the presence of leukemia because facial paralysis is an unusual presenting sign of leukemia. Table 2 lists the investigations that may aid the physician in the diagnosis of facial paralysis.

Recurrent or Bilateral Facial Paralysis

Recurrent or bilateral facial paralysis is uncommon and accounts for approximately 6% to 12% of all cases in both the adult and the pediatric population.10,30 The rate of full clinical recovery is approximately 70%, which is lower than in unilateral Bell’s palsy.30 Prompt search for other causes is recommended, eg, Möbius syndrome, Lyme disease and other infections, Guillain-Barré syndrome, myasthenia gravis, leukemia, and trauma. Melkersson-Rosenthal syndrome is a rare familial disease that causes bilateral, or alternating and recurrent facial paralysis accompanied by facial edema and transversely fissured tongue (cheilitis).

Pathophysiology of Bell’s Palsy

Many patients with Bell’s palsy have been found to have rising antibody titers to herpes simplex virus.31 Different pathophysiological processes have been suggested,31 including active viral invasion or immune processes causing demyelination and facial nerve swelling. Other mechanisms include vascular ischemia and heredity (based on few case reports with familial recurrence of facial paralysis). In early life, the anatomy of the skull makes the facial nerve more susceptible to damage by infections and trauma.32

Treatment of Bell’s Palsy

Supportive Treatment

Supportive measures include the use of artificial tear drops and patching the affected eye especially at night to prevent dryness, exposure keratitis, and subsequent corneal ulceration.

Medical Treatment

Recent systematic reviews7,33-35 in adult onset Bell’s palsy suggested that steroids are probably effective in improving facial functional outcome, especially if the paralysis is complete.34 A Cochrane systematic review, with stricter inclusion criteria,36 concluded that steroids were not beneficial. These systematic reviews did not analyze the pediatric cases separately.

A recent pediatric systematic review by Salman and MacGregor37 failed to find evidence for benefit from trials involving the use of steroids in pediatric Bell’s palsy. In the only randomized, controlled pediatric trial in Bell’s palsy,17 the outcome was not improved with steroids use. This study was not double-blinded or placebo-controlled.

Acyclovir is an antiviral drug that is used to treat herpes simplex and varicella zoster viral infections. There are reports showing benefits in Ramsay-Hunt syndrome21 and in patients with zoster sine herpete (acute facial paralysis associated with varicella zoster virus reactivation without vesicles).38 The routine use of acyclovir in Bell’s palsy is not proven and cannot be recommended. In one systematic review7 it was concluded that acyclovir in combination with steroids may be possibly effective in improving facial functional outcome in adult patients. A recent Cochrane review on the subject has been retracted.39,40

Steroids and/or acyclovir may confer moderate rather than significant benefits in Bell’s palsy. Such an effect would only be detected in trials with a large large number of participants. The effect of steroids and/or acyclovir should be tested in severely affected patients with complete paralysis. Specific benefits in this group may be seen, but this remains to be established in a purpose-designed clinical trial.

Other treatments have been used in Bell’s palsy and include Vitamin B12,18 acetyl carnitine,41 hyperbaric oxygen,42 and pentoxiphylline.33 These treatments have been previously reviewed.33 There is a lack of evidence for their benefit in pediatric Bell’s palsy.

Surgical Treatment

Many surgical techniques have been advocated to improve facial nerve function in patients with facial paralysis12 and there is no evidence to support surgical decompression in patients with Bell’s palsy.7


In the pediatric age group, the prognosis for full recovery is excellent in approximately 95% of cases. The remainder recover partially, especially if their paralysis was complete at the onset. The blink reflex and electroneuronography (nerve conduction and electromyography) of the facial nerve have been used to aid prognosis.4,8

Long-term complications with facial paralysis may occur (Table 3).43 Surgical techniques aimed at improving function, plastic surgery aimed at improving facial appearance and facial muscle functioning, ie, smiling and cosmesis, are available and have been reviewed recently.4

What is New in Bell’s Palsy?

A significant number of children with Bell’s palsy have rising antibody titers against herpes simplex virus and as such, they are not truly idiopathic. Some cases of herpes simplex virus-seronegative with acute periphral facial paralysis are caused by varicella zoster reactivation in the geniculate ganglion without vesicular rash (zoster sine herpete).44,45 The use of tests for the rapid diagnoses of varicella zoster virus suggests that the early use of acyclovir in the appropriate settings may aid in the full recovery from facial paralysis.38 Magnetic resonance imaging is used to delineate the site of the facial-nerve lesion accurately46 and to aid prognosis.47


Facial paralysis in the pediatric age group has many etiologies, especially during the first 2 years of life. Herpes simplex and, to a lesser extent, varicella zoster viruses may account for many cases of Bell’s palsy (the idiopathic group). The use of acyclovir in such cases is controversial as there is usually a significant time delay before these viruses are detected. The prognosis of pediatric Bell’s palsy without treatment is excellent. The use of steroids in Bell’s palsy does not result in significant benefit. Larger clinical trials are needed to show if steroids confer moderate benefits and better functional recovery. Further trials are needed to investigate the use of acyclovir in pediatric Bell’s palsy. PP


1. Rowlands S, Hooper R, Hughes R, Burney P. The epidemiology and treatment of Bell’s palsy in the UK. Eur J Neurol. 2002;9:63-67.

2. Bell C. On the nerves, giving an account of some experiments on their structure and functions which lead to a new arrangement of the system. Phil Trans Roy Soc Lond. 1821;111:398.

3. Terao S, Miura N, Takeda A, Takahashi A, Mitsuma T, Sobue G. Course and distribution of facial corticobulbar tract fibres in the lower brain stem. J Neurol Neurosurg Psychiatry. 2000;69:262-265.

4. Riordan M. Investigation and treatment of facial paralysis. Arch Dis Child. 2001;84:286-287.

5. Devriese PP, Schumacher T, Scheide A, de Jongh RH, Houtkooper JM. Incidence, prognosis and recovery of Bell’s palsy. A survey about 1,000 patients (1974-1983). Clin Otolaryngol. 1990;15:15-27.

6. Devriese PP. Bell’s palsy in children. Acta Otorhinolaryngol Belg. 1984;38:261-267.

7. Grogan PM, Gronseth GS. Practice parameter: Steroids, acyclovir, and surgery for Bell’s palsy (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56:830-836.

8. Inamura H, Aoyagi M, Tojima H, Kohsyu H, Koike Y. Facial nerve palsy in children: clinical aspects of diagnosis and treatment. Acta Otolaryngol. 1994;(suppl 511):150-152.

9. Prescott CA. Idiopathic facial nerve palsy in children and the effect of treatment with steroids. Int J Pediatr Otorhinolaryngol. 1987;13:257-264.

10  Price T, Fife DG. Bilateral simultaneous facial nerve palsy. J Laryngol Otol. 2002;116:46-48.

11. May M, Fria TJ, Blumenthal F, Curtin H. Facial paralysis in children: differential diagnosis. Otolaryngol Head Neck Surg. 1981;89:8418.

12. Kay PP, Kinney SE, Levine H, Tucker HM. Rehabilitation of facial paralysis in children. Arch Otolaryngol. 1983;109:642-647.

13. Adour KK, Wingerd J, Bell DN, Manning JJ, Hurley JP. Prednisone treatment for idiopathic facial paralysis (Bell’s palsy). N Engl J Med. 1972;287:1268-1272.

14. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg. 1985;93:146-147.

15. Austin JR, Peskind SP, Austin SG, Rice DH. Idiopathic facial nerve paralysis: a randomized double blind controlled study of placebo versus prednisone. Laryngoscope. 1993;103:1326-1333.

16. De Diego JI, Prim MP, De Sarriá MJ, Madero R, Gavilán J. Idiopathic facial paralysis: a randomized, prospective, and controlled study using single-dose prednisone versus acyclovir three times daily. Laryngoscope. 1998;108:573-557.

17. Ünüvar E, Oguz F, Sidal M, Kiliç A. Corticosteroid treatment of childhood Bell’s palsy. Pediatr Neurol. 1999;21:814-816.

18. Jalaludin MA. Methylcobalamin treatment of Bell’s palsy. Methods Find Exp Clin Pharmacol. 1995;17:539-554.

19. Hu WL, Ross B, Nedzelski J. Reliability of the Sunnybrook Facial Grading System by novice users. J Otolaryngol. 2001;30:208-211.

20. Jemec B, Grobbelaar AO, Harrison DH. The abnormal nucleus as a cause of congenital facial palsy. Arch Dis Child. 2000;83:256-258.

21. Takahashi H, Nakamura H, Yui M, Mori H. Analysis of fifty cases of facial palsy due to otitis media. Arch Otorhinolaryngol. 1985;241:163-168.

22. Hydén D, Roberg M, Forsberg P, et al. Acute “idiopathic” peripheral facial palsy: clinical, serological, and cerebrospinal fluid findings and effects of corticosteroids. Am J Otolaryngol. 1993;14:179-186.

23. Hato N, Kisaki H, Honda N, Gyo K, Murakami S, Yanagihara N. Ramsay Hunt syndrome in children. Ann Neurol. 2000;48:254-256.

24. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry. 2001;71:149-154.

25. Bitsori M, Galanakis E, Papadakis CE, Sbyrakis S. Facial nerve palsy associated with Rickettsia conorii infection. Arch Dis Child. 2001;85:54-55.

26. Laeng RH, Stähelin J, Schaller P, Arnoux A. Pathological case of the month. Arch Pediatr Adolesc Med. 2002;156:191-192.

27. Atula T, Honkanen V, Tarkkanen J, Jero J. Otitis media as a sign of Wegener’s granulomatosis in childhood. Acta Otolaryngol. 2000;(suppl 543):48-50.

28. Poon LK, Lun KS, Ng YM. Facial nerve palsy and Kawasaki disease. Hong Kong Med J. 2000;6:224-226.

29. Lewis VE, Peat DS, Tizard EJ. Hypertension and facial palsy in middle aortic syndrome. Arch Dis Child. 2001;85:240-241.

30. Eidlitz-Markus T, Gilai A, Mimouni M, Shuper A. Recurrent facial nerve palsy in pediatric patients. Eur J Pediatr. 2001;160:659-663.

31. Adour KK, Byl FM, Hilsinger RL Jr., Kahn ZM, Sheldon MI. The true nature of Bell’s palsy: analysis of 1,000 consecutive patients. Laryngoscope. 1978;88:787-801.

32. Schuring AG, Gunter JP. Paralysis of the facial nerve in children. Clin Pediatr (Phila). 1970;9:105-109.

33. Williamson IG, Whelan TR. The clinical problem of Bell’s palsy: is treatment with steroids effective? Br J Gen Prac. 1996;46:743-747.

34. Ramsey MJ, DerSimonian R, Holter MR, Burgess LPA. Corticosteroid treatment for idiopathic facial nerve paralysis: a meta-analysis. Laryngoscope. 2000;110:335-341.

35. Anonymous. Database of Abstracts of Reviews of Effectiveness. NHS center for reviews and dissemination. York, United Kingdom: University of York; 2002:2.

36. Salinas RA, Alvarez G, Alvarez MI, Ferreira J. Corticosteroids for Bell’s Palsy(idiopathic facial paralysis). Cochrane Database of System Rev. 2001;2:CD001942.

37. Salman MS, MacGregor DL. Should children with Bell’s palsy be treated with corticosteroids? A systematic review. J Child Neurol. 2001;16:565-568.

38. Furuta Y, Ohtani F, Mesuda Y, Fukuda S, Inuyama Y. Early diagnosis of zoster sine herpete and antiviral therapy for the treatment of facial palsy. Neurol. 2000;55:708-710.

39. Sipe J, Dunn L. Aciclovir for Bell’s palsy (idiopathic facial paralysis). Cochrane Database System Rev. 2001;4:CD001869. (retracted)

40. Sipe J, Dunn L. Aciclovir for Bell’s palsy (idiopathic facial paralysis). Cochrane Database System Rev. 2001;2:CD001869. (addendum)

41. Mezzina C, De Grandis D, Calvani M, Marchionni A, Pomes A. Idiopathic facial paralysis: new therapeutic prospects with acetyl-L-canitine. Int J Clin Pharm Res. 1992;12:299-304.

42. Racic G, Denoble PJ, Sprem N, Bojic L, Bota B. Hyperbaric oxygen as a therapy of Bell’s palsy. Undersea Hyperbar Med. 1997;24:35-38.

43. Valenca MM, Valenca LP, Lima MC. [Idiopathic facial paralysis (Bell’s palsy): A study of 180 patients]. Portuguese Arq Neuropsiquiatr. 2001;59:733-739.

44. Furuta Y, Ohtani, Kawabata H, Fukuda S, Bergström T. High prevalence of varicella-zoster virus reactivation in herpes simplex virus-seronegative patients with acute peripheral facial palsy. Clin Inf Dis. 2000;30:529-533.

45. Morgan M, Moffat M, Ritchie L, Collacott I, Brown T. Is Bell’s palsy a reactivation of varicell zoster virus? J Inf. 1995;30:29-36.

46. Kinoshita T, Ishii K, Okitsu T, Okudera T, Ogawa T. Facial nerve palsy: evaluation by contrast-enhanced MR imaging. Clin Radiol. 2001;56:926-932.

47. Burgio DL, Siddique S, Haupert M, Meleca RJ. Magnetic resonance imaging of the facial nerve in children with idiopathic facial paralysis. Otolaryngol Head Neck Surg. 2000;122:556-559.



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David J. Hellerstein, MD, and Gregory B. Biedermann, MD

Primary Psychiatry. 2003;10(2):47-52


Dr. Hellerstein is clinical director at the New York State Psychiatric Institute in New York City.

Dr. Biedermann is a resident in the Department of Internal Medicine at Boston Medical Center in Massachusetts.

Acknowledgment: Dr. Biedermann would like to thank Project House, Inc.

Disclosure: This work was supported by an unrestricted educational grant from Cephalon, Inc. Dr. Hellerstein is on the speakers bureau for Forest Laboratories, Pfizer, and Bristol-Myers Squibb. Dr. Hellerstein receives grant funding from Forest, Pfizer, Eli Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Wyeth, Merck &?Co, the National Institute of Mental Health, and the National Insititute of Drug Abuse, and he is a consultant for Bristol-Myers Squibb

Please direct all correspondence to: David J. Hellerstein, MD, New York State Psychiatric Institute, 1051 Riverside Dr, Box 101, New York, NY 10032; Tel: 212-543-5790; Fax: 212-543-5674; E-mail:




Do scheduling restrictions influence the prescribing practices of physicians treating patients who require psychostimulants? Central nervous system (CNS) stimulants are beneficial for a variety of conditions, including attention-deficit/hyperactivity disorder (ADHD), narcolepsy, residual daytime sleepiness in sleep apnea, and fatigue. However, they are also associated with the potential for drug abuse, increased risk of addiction, a short half-life, possible toxicity, and prescription concerns associated with United States Drug Enforcement Agency (DEA) scheduling laws. This article presents results from a survey of family practice physicians conducted at the 1998 American Academy of Family Physicians meeting regarding scheduled CNS stimulants. The survey queried physicians about the conditions for which they prescribe CNS stimulants, the frequency with which they prescribe them, their concerns when prescribing them, and how those concerns affect their choice of prescribing a schedule IV drug over a schedule II drug. Of the 342 United States physicians surveyed, 266 currently prescribe CNS stimulants. The disorders for which the highest percentage of physicians reported prescribing CNS stimulants were ADHD (93%) and narcolepsy (49%). The drug prescribed most frequently by physicians was methylphenidate (95%). Dextroamphetamine (32%) and pemoline (24%) were prescribed less often than methylphenidate. Two concerns that were expressed more frequently for methylphenidate, a schedule II drug, than for pemoline, a schedule IV drug, were the logistical problems for patients and no allowance of refills. A large majority of the physicians (71%) expressed a preference for prescribing a less strictly controlled drug (schedule IV) before a more strictly controlled drug (schedule II). This survey suggests that concerns about the use of schedule II drugs and DEA scheduling in particular may influence prescribing behavior.


Central nervous system (CNS) stimulants may be beneficial for the pharmacologic treatment of neurobiological disorders affecting attention and sleep, such as attention-deficit/hyperactivity disorder (ADHD), narcolepsy, and fatigue. Drugs for the treatment of these disorders include methylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, and pemoline. Although the exact modes of action are not known for these stimulants, all of the compounds most likely exert their psychostimulant effects via interaction with dopaminergic systems.1 Methylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, and pemoline are approved by the United States Food and Drug Administration for the treatment of ADHD.2-5 For the treatment of narcolepsy, methylphenidate, dextroamphetamine, and dextroamphetamine/amphetamine have been approved.2,4,5 More recently, modafinil, a nonamphetamine wake-promoting agent, was approved for treatment of the excessive daytime sleepiness associated with narcolepsy.6

The potential benefits of CNS stimulants are compromised by a number of drawbacks. These drawbacks include potential for drug abuse, increased addiction risk, tolerance, short half-life, toxicity, and logistic difficulties in accessing the drug. The stimulatory and arousal effects that are mediated in the brain by these psychoactive agents increase their likelihood for physical and psychological dependence.7,8 Amphetamines have been extensively abused; patients tend to become tolerant to the drug and increase their dosage without the knowledge of their physicians.4 Methylphenidate has been shown to have an abuse pattern similar to that of cocaine, and the morbidity and mortality rates associated with methylphenidate abuse are greater than those usually observed for a group of patients involved in intravenous drug abuse.9

Despite numerous anecdotal reports of amphetamine abuse, CNS stimulants are widely prescribed. Nevertheless, the incidence of abuse of psychostimulants, such as methylphenidate, appears to be relatively low when appropriately prescribed by a physician.10-12 A recent study13 reviewed the available literature and found no hard data documenting abuse or diversion of prescribed methylphenidate. Admittedly, illegal use is, by its very nature, hard to document. Nonetheless, in efforts to prevent medication abuse and inappropriate dispensing of CNS stimulants, federal and state regulatory laws are in place to control drug prescription practices. At the federal level, the United States Drug Enforcement Agency (DEA) enforces the scheduling of drugs according to the Controlled Substances Act of 1970. Controlled drugs are divided into five schedules based on their potential for abuse, with schedule I drugs having the highest abuse potential and schedule V drugs the least (Table 1).

Some state regulatory policies impose stricter requirements than the federal government, such as the special triplicate prescription forms required in New York for all schedule II drugs and for benzodiazepines, which may be schedule IV drugs because of their potential to induce dependence.14 Following the addition of benzodiazepines to the New York State Department of Health Triplicate Prescription Program in January 1989, a statewide decrease in benzodiazepine prescribing was seen.14,15 Although the abuse of benzodiazepines appears to have been curtailed under these stricter regulations, many patients may have been denied access to needed medications for legitimate indications and may have received less appropriate drugs as substitutes due to the regulations.14,16

The restrictions imposed by federal and state policies, such as the Triplicate Prescription Program, may help explain why the nonbenzodiazepine schedule IV drug zolpidem tartrate is the most commonly prescribed hypnotic in the US.17 The question is whether negative perceptions and regulatory initiatives actually influence a physician’s prescribing behavior in any way.

We administered a survey in order to examine physicians’ attitudes that may influence their CNS stimulants prescribing practices. The survey determined the use of methylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, and pemoline for the treatment of ADHD, narcolepsy, sleep disorders (including sleep apnea), and fatigue. Physician concerns and difficulties regarding the prescription and dispensing of scheduled CNS stimulants (schedule II versus schedule IV) were analyzed.


A survey of current stimulant prescribing practices among physicians was administered at the American Academy of Family Physicians Scientific Assembly, September 17–19, 1998 in San Francisco, California. The survey was administered from a booth at the meeting by Project House, Inc. and 382 surveys were collected. Only surveys from US physicians (N=342) were used in data analysis. All non-US surveys (n=21) and surveys that did not specify the state in which the physician practiced (n=19) were excluded. Data analysis of two items (types of CNS stimulants currently prescribed and disorders for which CNS stimulants are currently prescribed) was based on 266 surveys of physicians who were current prescribers of CNS stimulants. A description of drug schedules according to the Controlled Substances Act of 1970 was provided for participating physicians. Survey information was entered and analyzed using Statistical Program for the Social Sciences 6.1 for Windows.


The survey queried US physicians about the conditions for which they prescribed CNS stimulants, the CNS stimulants they prescribed most often, and their concerns about prescribing the schedule II stimulant methylphenidate and the schedule IV stimulant pemoline (Table 2). Of the 342 physicians surveyed, 332 (97%) were family practitioners. The remaining 10 specified general practice, internal medicine, pediatrics, neurology, sports medicine, or public health as their specialty.

Among all physicians currently prescribing CNS stimulants, 93% reported that they prescribe CNS stimulants at least sometimes for the treatment of ADHD. They used a 5-point scale ranging from 1–5 (“never” to “always”). Nearly half (49%) reported that they at least sometimes prescribe stimulants for narcolepsy, 23% prescribe for sleep disorders, including sleep apnea, and 13% prescribe for fatigue. Eighteen percent reported that they prescribed stimulants at least sometimes for other conditions, including depression, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and migraine (Figure 1). Methylphenidate was prescribed at least sometimes by nearly all of the prescribing physicians (95%), while dextroamphetamine (32%), pemoline (24%), and dextroamphetamine/amphetamine (20%) were less often prescribed (Figure 2).

The survey examined concerns with prescribing the schedule II stimulant methylphenidate (Figure 3) and the schedule IV stimulant pemoline (Figure 4). Physicians were most concerned about side effects, efficacy, and abuse potential for both drugs. With regard to prescribing practices involving methylphenidate, physicians were also primarily concerned with the prohibition on refills and logistical problems for patients, such as requiring additional visits to obtain prescriptions. The exclusion of refills was even more of a concern than efficacy of the drug. However, these factors were not concerns associated with pemoline. Physicians reported liver toxicity as the primary concern when prescribing pemoline (Figure 4) with the exception of concerns about side effects and toxicity.

Figure 5 indicates a likely influence of scheduling restrictions on prescribing practices. Among all the physicians surveyed, a majority (71%) reported that they would prefer to prescribe a schedule IV agent rather than a schedule II agent. The investigators who administered the survey noted, however, that many physicians had to refer to the chart of scheduling definitions because they did not immediately recall the various scheduling assignments.


CNS stimulants are appropriately prescribed for conditions such as ADHD, narcolepsy, and fatigue. Yet, with the psychoactive nature of these agents comes the potential for abuse and addiction, and this has led to stringent control of these drugs under federally mandated scheduling regulations.

Although this strict regulatory control of scheduled medications has had positive effects in preventing drug abuse and discouraging improper prescription practices, unintended and unwanted effects have also ensued.14,18 Such unwanted results include prescribing scheduled medications in an overly cautious manner that may cause needless suffering; increased prescribing and use of less satisfactory alternative drugs; physician apprehension about potential legal consequences; and physician dissatisfaction with intrusive government regulations.14,18-20

The survey results presented here lend insight into the practices, attitudes, and concerns of physicians regarding the dispensing of scheduled CNS stimulant medications. Physicians cited logistical difficulties (ie, prohibition on refills, logistical problems for patients) as notable concerns specific only for the more strictly scheduled drug (schedule II but not schedule IV). Perhaps most importantly, physicians reported that they would prefer to prescribe a less strictly scheduled drug (schedule IV) before a more strictly scheduled one (schedule II).

Why then is methylphenidate, a schedule II drug, so much more widely prescribed than the less strictly controlled stimulant pemoline, a schedule IV drug?

The answer most likely lies in the efficacy and adverse effect profiles of the respective drugs. Pemoline is believed to be less effective than methylphenidate in the treatment of ADHD,21 and liver toxicity has been commonly reported with pemoline use, relegating it to second-line treatment.22-24 In the treatment of narcolepsy, compliance with pemoline has been shown to be better than that seen with methylphenidate and dextroamphetamine, two schedule II drugs.25 These observations thus suggest that a less strictly scheduled CNS stimulant with efficacy and toxicity equivalent to that of a more strictly scheduled agent may be of considerable usefulness for the physician treating ADHD, narcolepsy, or fatigue.

When reviewing the data from the survey, it must be kept in mind that state-to-state differences in physicians’ responses is likely a factor. Drug regulation policies can vary widely at the state level. This survey was conducted in California, and although the largest proportion of respondents (18%) was from California, responses covered 48 of the 50 United States. This coverage of almost the entire US may lend support to inferences that can be made from the data regarding regulatory practices at the federal level. State drug policies are also changing because some states are implementing, or planning to implement, computer-based electronic data transfer systems for tracking and regulating prescriptions.25,26 Such electronic data transfer databases can reduce the paperwork burden and misprescribing practices associated with current regulatory operations.25

The survey revealed a great deal of out-of-label prescribing of stimulants (eg, for fatigue, depression, cognitive disorders, and other nonapproved conditions). Notwithstanding their status as controlled substances, CNS stimulants may be prescribed in this manner because of patient pressure, lack of approved drugs for these indications, and general physician appreciation of the wake-promoting effects of such drugs, despite the lack of large, controlled trials confirming such clinical impressions. Several small studies in patients with refractory depression, cancer, and fatigue associated with human immunodeficiency virus infection have shown that treatment with CNS stimulants can safely ameliorate fatigue and depressive symptoms in these patient populations.27-29 Together with clinical observations in actual practice, these trials underscore the need for well-controlled formal studies that assess the safety and efficacy of this type of agent in fatigue and depression, thereby providing data to facilitate evaluations of risk-to-benefit ratios.

Continued education about CNS-related disorders and appropriate therapy options is important for the physician. Such education may reduce the underprescription of effective treatments because of drug-abuse concerns or as a result of inconvenient prescribing restrictions. Furthermore, insofar as FDA approval may not provide the optimal criterion for the use of psychotropic medications in certain patient populations, recommendations for off-label uses of such agents may require additional guidelines. In the case of scheduled drugs such as CNS stimulants, such guidelines may require the cooperation of several professional organizations, including patient advocacy groups and local authorities.


CNS stimulants are an important part of the pharmaceutical arsenal for the treatment of attention and sleep disorders. The strict regulation of these controlled substances can impose logistical obstacles for the physician and the patient, hindering access to medications in cases of legitimate need. Physicians can improve their prescribing practice by improving their understanding of which drugs are appropriate for each diagnosis, including an awareness of risk/benefit issues ensuing from choosing a schedule II over a schedule IV medication. Given the educational effort required to handle these substances appropriately in the treatment of CNS disorders, both physicians and patients would benefit from the advent of newer, less rigidly controlled psychoactive agents with lower abuse potential and improved efficacy and safety. Better data are needed on the efficacy and safety of these substances in indications that are currently not approved so that physicians can better assess the likely benefits to their patients relative to possible risks. PP


1. Koob GF. Stimulants: basic mechanisms and pharmacology. In: Kryger MH, Roth R, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders Co; 2000:419-428.

2. Ritalin [package insert]. Novartis:?East Hanover, NJ; 1999.

3. Cylert. [package insert]. Medical Economics Company, Inc.; 1999.

4. Dexedrine. [package insert]. Medical Economics Company, Inc.; 1999.

5. Adderall. [package insert].Shire Richwood, Inc.; 1998.

6. Provigil. [package insert].Cephalon, Inc; 2000.

7. Dackis CA, Gold MS. Addictiveness of central stimulants. Adv Alcohol Subst Abuse. 1990;9:9-26.

8. Wise RA, Bozarth MA. Brain mechanisms of drug reward and euphoria. Psychiatr Med. 1985;3:445-460.

9. Parran TV Jr, Jasinski DR. Intravenous methylphenidate abuse. Prototype for prescription drug abuse. Arch Intern Med. 1991;151:781-783.

10. Spier SA. Toxicity and abuse of prescribed stimulants. Int J Psychiatry Med. 1995;25:69-79.

11. Fernandez F, Adams F, Holmes VF, Levy JK, Neidhart M. Methylphenidate for depressive disorders in cancer patients. An alternative to standard antidepressants. Psychosomatics. 1987;28:455-461.

12. Woods SW, Tesar GE, Murray GB, Cassem NH. Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry. 1986;47:12-15.

13. Llana ME, Crismon ML. Methylphenidate: increased abuse or appropriate use? J Am Pharm Assoc (Wash). 1999;39:526-530.

14. Weintraub M, Singh S, Byrne L, Maharaj K, Guttmacher L. Consequences of the 1989 New York state triplicate benzodiazepine prescription regulations. JAMA. 1991;266:2392-2397.

15. Benzodiazepines: additional effects of the triplicate program. N Y State J Med. 1990;90:273-275.

16. Schwartz HI. Negative clinical consequences of triplicate prescription regulation of benzodiazepines. N Y State J Med. 1991;91:9S-12S.

17. List of top 200 drugs includes a few surprises. Drug Topics. 1999;143:30-33.

18. Jaffe JH. Impact of scheduling on the practice of medicine and biomedical research. Drug Alcohol Depend. 1985;14:403-418.

19. Clark HW. Legal implications of prescribing opioid controlled substances. Am J Orthop. 1998;27:29-32.

20. Glass RM. Benzodiazepine prescription regulation. Autonomy and outcome [editorial]. JAMA. 1991;266:2431-2433.

21. Gittelman R, Kanner A. Psychopharmacotherapy. In: Quay H, Werry J, eds. Psychopathological Disorders of Childhood. 3rd ed. New York, NY: John Wiley & Sons; 1986:455-494.

22. Berkovitch M, Pope E, Phillips J, Koren G. Pemoline-associated fulminant liver failure: testing the evidence for causation. Clin Pharmacol Ther. 1995;57:696-698.

23. Adcock KG, MacElroy DE, Wolford ET, Farrington EA. Pemoline therapy resulting in liver transplantation. Ann Pharmacother. 1998;32:422-425.

24. Stevenson RD, Wolraich ML. Stimulant medication therapy in the treatment of children with attention deficit hyperactivity disorder. Pediatr Clin North Am. 1989;36:1183-1197.

25. Clark HW. Policy and medical-legal issues in the prescribing of controlled substances. J Psychoactive Drugs. 1991;23:321-328.

26. Schiff GD, Rucker TD. Computerized prescribing. Building the electronic infrastructure for better medication usage. JAMA. 1998;279:1024-1029.

27. Masand PS, Anand VS, Tanquary JF. Psychostimulant augmentation of second generation antidepressants: a case series. Depress Anxiety. 1998;7:89-91.

28. Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J. A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med. 2001;161:411-420.

29. Olin J, Masand P. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics. 1996;37:57-62.


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Alison M. Kerr, FRCP
Primary Psychiatry. 2003;10(2):59-62


Dr. Kerr is senior lecturer and honorary consultant in pediatrics and learning disability at the academic centre in the Department of Psychological Medicine at Glasgow University in Scotland.

Acknowledgments: Dr. Kerr is pleased to acknowledge advice on the content of this paper from Anthony Charman, PhD, Fiona Knott, PhD, Bronwen Burford, PhD, and Jill Clayton-Smith, MD.

Disclosure: Dr. Kerr’s work has been supported by the Rett Syndrome Association United Kingdom, Rett Syndrome Association Scotland, International Rett Syndrome Association, RSRF, the University of Glasgow, and the families of people with Rett syndrome.

Please direct all correspondence to: Alison M. Kerr, FRCP, Gartnavel Hospital, Great Western Road, Glasgow, United Kingdom, G12 OXH; Tel: 011-44-141-211-0281; Fax: 011-44-141-357-4899; E-mail:



How should the physician provide for people with Rett disorder? From a newly described entity that was presumed to be rare in 1966, Rett disorder has become one of most characterized developmental disorders. Over 1 in 10,000 females are diagnosed with the disorder, which is among the most common genetic causes of combined profound intellectual and motor disability in women. Primary care practitioners, neurologists, and psychiatrists carry the responsibility of detecting the condition in infancy, offering support to the family, and monitoring the progress of the child and adult through a series of age- and stage-related difficulties. These difficulties include epilepsy, poor central cardiorespiratory regulation, movement disorder, nutritional problems, a tendency to joint contractures and scoliosis, severe intellectual disability, agitation, lack of speech, and evident enjoyment of non-speech communication and musical interaction. Discovery of the causative mutations in the methyl-CpG-binding protein-2 gene allows positive identification and has demonstrated a wide range in clinical severity. A unique combination of defects in control of both mind and movement provides fresh insights on the development of the brain. This article briefly reviews recent discoveries and their relation to behavior. A table compares possible early signs in Rett syndrome, Angelman, and autism.


Whereas some diseases destroy the brain, many developmental disorders impact specific functions and demonstrate vulnerabilities that depend on the characteristics of particular neural networks. Rettis a prime example of such a disorder and, as incomplete as our knowledge of the subject is, the present knowledge brings fresh insights to understanding the brain.

Andreas Rett1 distinguished the syndrome in 1966. Children with Rett disorder tend to be attractive and they love face-to-face contact. While personalities are most endearing, the unsteady posture, agitation, hand stereotypy, and color changes with abnormal breathing indicate severe problems in regulating movement, thought, and vital functions. Minimum estimated prevalence in the United Kingdom is 1 in 10,000 females at 14 years of age2 and the remarkably good survival (deaths are 1.2%/year)3 indicates that the disorder probably accounts for more than 1 in 10 women with profound disability.4

Genetics of Rett Disorder

The causative mutations on methyl-CpG-binding protein-2 (MECP2) usually arise in the male germ cell due to its numerous cell divisions.5,6 Offspring receiving a paternal X chromosome must be female. This explains why most cases are female but recurrences are rare. Since every female cell expresses only one of its two X chromosomes, the defective X is usually active in half the cells of the body. This causes typical/classic Rett disorder. If one X is used preferentially (skewed X inactivation) then the disorder may be exceptionally severe or mild. The risk to any offspring of a woman with a mutation is 50%. Severe XY male cases occur when the mutation affects every cell.7 In Klinefelter’s syndrome (XXY) the disorder can presents in its classic form.8 A mild male form may be seen if mutation occurs after fertilization, affecting a proportion of cells (somatic mosaic).9

The several types and many sites of mutation on MECP2 affect clinical severity, but in females the X-inactivation pattern chiefly determines outcome.10 A MECP2 mutation has been reported to cause a disabling neurologic disorder in a kindred’s males but not females.11 In about 15% of classic and 50% of atypical cases a mutation is not found.7,10 It is expected that still unidentified mutations may affect the same neural mechanisms. Initial diagnostic confusion with Rett disorder may occur in metabolic and brainstem disease.12 Rett disorder is often confused with Angelman’s syndrome and autistic disorder, causing particular diagnostic difficulty. Subtle differences in the early symptoms may distinguish these indicating differences in the neural mechanisms involved (Table).13,14

Pathogenesis of Rett Disorder

The MECP2 gene is believed to contribute to regulation of the activity of other genes15 with an important role in the development and maintenance of cortical connections.16-19

A recently developed mouse model for Rett disorder bears considerable likeness to human disease and is currently being used in research.17,18 Human brain growth is suboptimal, especially in the frontal, parietal, and temporal cortex where dendritic territories are reduced.19

From their study of disturbed sleep rhythms, Nomura and colleagues20 and Nomura and Segawa20,21 suggested that hypofunction of the monoamines, noradrenaline, and serotonin is present as early as 36 weeks of gestation.At 2 years of age, deficient brain-derived growth factor has been demonstrated22 and serotonin receptors are increased in the brainstem23 suggesting defective serotonin supply or activity. Throughout early childhood, levels of glutamate are raised24 and cortical receptors are increased, decreasing later.25 This period of increased excitatory neurotransmitter level coincides with a regressive, hyperactive period in the child.

Early Presentation and Diagnosis

A newborn child with Rett disorder appears well grown with a normal head circumference but is exceptionally placid. Experienced caregivers soon notice hypotonic or occasionally stiff posture, reduced mobility, and, as the year progresses, increasing repetitive movements and lack of exploration.26 However, there is real progress along with the early signs of developmental deviation, which explain some late diagnoses. Development usually plateaus around 10–12 months of age when confusion with Angelman’s syndrome is common (Table).

In most children 1–3 years of age there is a regressive period when hand use and communication decline. The child often becomes agitated with unexplained crying and hand use is replaced with stereotyped twisting or patting, frequently in the hair or mouth. At this stage confusion may arise with autism (Table). After some months the respiratory rhythm becomes erratic with spells of shallow, deep, and apneustic breathing, and breath holding. The electroencephalogram (EEG) becomes abnormal with bursts of slow large amplitude waves, sometimes with spikes, accentuated in sleep.26,27

Regression is a time of high stress for the brain and measures supportive of the neurones seem justified but there is no evidence that these affect the course or severity of the disease. Formal trials are now required using objective outcome measures.28 In severely affected males, the presentation is contracted into a few months, with death possibly due to cardiorespiratory arrest.29

Characteristics of Rett Disorder


Epilepsy occurs in over half of patients with Rett disorder.26 Their EEG is generally reported “normal” or “immature,” initially becoming abnormal towards the end of regression, with bursts of slow waves and spikes, increased during sleep.27 It may be difficult to distinguish atypical epileptic seizures from the much more frequent “vacant spells” due to poor autonomic regulation.27,30,31 Breathing rhythm is labile, with any one child showing several awake rhythms.30,31 Rhythms are grouped into those which are inadequate for gas exchange (feeble breathing); those which delay the onset of expiration common in the youngest girls (apneustic breathing); vigorous breathing often with hyperventilation, and Valsalva breathing where increased pressure in the chest interrupts venous return to the heart—common in older people.30,31 Non-epileptic vacant spells may occur during each type of breathing and may cause sudden deaths.3,30,31 Uncoordinated expiration causes aerophagy. Prolongation of the cardiac QT interval has been reported.32,33

Posture and Mobility

Many Rett disorder patients learn to walk independently, some quite late is life, and most walk with support. However, as initial hypotonia gives way to hypertonia and dystonia there is a tendency for the limbs to adopt dystonic postures. Without physiotherapy and careful positioning this leads to joint contractures with loss of mobility. Experience with the British cohort26 suggests that deterioration may be prevented in all but the most severe if there is due attention to therapy and the individual is encouraged to be active. Scoliosis is common and more difficult to prevent, progressing rapidly during growth spurts.34 Osteoporosis is common in young and active children.35

Nutrition and Growth

Nutritional and growth difficulties are implicated in half the deaths reported in the British survey.3 Most Rett disorder patients are dependent on others to feed them, posture may be awkward, chewing is either poor or absent, mouth closure is weak, and abnormal respiration makes timing of the swallow difficult. Gastro-oesophageal reflux is common and constipation almost universal.26,36 Habit toilet training is frequently possible26 and final stature is usually reduced.37

Hand Behavior, Communication, and Understanding

The marked hand stereotypy that aids in diagnosis is obligatory, repetitive, fixed, and exacerbated by agitation. Involuntary movements also affect the limbs, trunk, and face. Although voluntary hand use improves, after regression it remains poor. However, opportunities presented directly to touch, sight, and hearing such as wind, water, musical sounds, contact with responsive musical instruments, and close face-to-face “conversational” contact, seem to release useful movement (Figure).26,29 Poor voluntary control of movement and the confusion which is evident in Rett disorder patients makes it difficult to assess the level of understanding and many families feel that their daughters’ understanding is in advance of their ability to communicate.

Although 70% of girls in the British survey29 developed some speech initially, only 15% continued after regression. A few patients with mild Rett disorder can sign although speech is absent. Puberty and fertility in Rett disorder patients appear normal and the preference for human contact makes them vulnerable to physical and sexual abuse.26


With many questions still unanswered, it is known that in the Rett disorder patients, the genetic fault impacts on the autonomic, motor, and cognitive integrative systems in the brain. The neuronal differentiation on which these systems depend begins in the brainstem due to agents which may change their role or disappear later and the effects on dendritic and synaptic development continue to unfold as the infant grows. Investigation of the Rett mouse will be crucial to detection at the earliest stage of the disorder.17,18

The individual with Rett disorder is aware, interested, and involved yet deprived of means of expression. To this incapacity is added physiologically driven agitation and an involuntary movement disorder which mimics intentional movement. To serve patients with Rett disorder adequately, the physician must understand what is affected and what is spared by the disorder, tailoring assessments and care to particular needs. (See page 32 for a routine Rett disorder medical supervision checklist).

Further insight into the mind of the person with Rett disorder deserves close examination of behavior in the first year of life since the abilities displayed then seem eclipsed rather than destroyed by the subsequent regression.26 Sensitive and objective methods should be adopted to track the perceptions and responses of the individual. PP


1. Rett A. [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien Med Wochenschr. 1966;116:723-726. [German].

2. Kerr AM. Rett Syndrome British Longditudinal Study (1982-1990) and 1990 survey. In: JJ Roosendaal, eds. Mental Retardation and Medical Care. Zeist: Uitgeverij Kerckbosch: 1992:143-145.

3. Kerr AM, Armstrong DD, Prescott RJ, Doyle D, Kearney DL. Rett syndrome: analysis of deaths in the British survey. Eur Child Adolesc Psychiatry. 1997;6:71-74.

4. Kerr AM, Mitchell JM, Robertson PE. Short fourth toes in Rett syndrome: a biological indicator. Neuropediatrics. 1995;26:72-74.

5. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Franke U, Zoghbi HY. Rett Syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185-188.

6. Girard M, Couvert P, Carrie A, et al. Parental origin of de novo MECP2 mutations in Rett Syndrome. Eur J Hum Genet. 2001;9:231-236.

7. Shahbazian MD, Zoghbi HY. Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Curr Opin Neurol. 2001;14:171-176.

8. Salomao Schwartzman J, Zatz M, dos Reis Vasquez L, et al. Rett Syndrome in a boy with a 47, XXY karyotype. Am J Hum Genet. 1999;64:1781-1785.

9. Clayton-Smith J, Watson P, Ramsden S, Black GC. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet. 2000;356:830-832.

10. Amir RE, Van den Veyver IB, Schultz R, et al. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol. 2000;47:670-679.

11. Meloni I, Bruttini M, Longo I, et al. A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet. 2000;67:982-985.

12. Hagberg B, Witt-Engerstrom I. Early stages of the Rett syndrome and infantile neuronal ceroid lipofuscinosis—a difficult differential diagnosis. Brain Devel. 1990;12:20-22.

13. Maestro S, Muratori F, Cavallaro MC, et al. Attentional skills during the first 6 months of age in autistic spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2002;41:1239-1245.

14. Osterling JA, Dawson G, Munson JA. Early recognition of 1-year-old infants with autism spectrum disorder versus mental retardation. Dev Psychopathol. 2002;14:239-251.

15. Nan X, Campoy FJ, Bird A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88:471-481.

16. Kaufmann WE, Naidu S, Budden S. Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome. Neuropediatrics. 1995;26:109-113.

17. Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett Syndrome. Nat Genet. 2001;27:322-326.

18. Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001;27:327-331.

19. Armstrong D, Dunn JK, Antalffy B, Trivedi R. Selective dendritic alterations in the cortex of Rett syndrome. J Neuropathol Exp Neurol. 1995;54:195-201.

20. Nomura Y, Segawa M, Hasegawa M. Rett syndrome—clinical studies and pathophysiological considerations. Brain Devel. 1984;6:475-486.

21. Nomura Y, Segawa M. The monoamine hypothesis in Rett Syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:205-226.

22. Rikonnen R. Neurotrophic factors in the pathogenesis of Rett Syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:125-129.

23. Armstrong DA, Kinney H. The neuropathology of the Rett Disorder In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:57-84.

24. Lappalainen R, Rikonnen R. High levels of cerebrospinal fluid glutamate in Rett Syndrome. Pediatr Neurol. 1996;15:213-216.

25. Blue M, Johnson M. Amino acid receptor studies in Rett syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:115-118.

26. Kerr AM, Witt Engerstrom I. The clinical background to the Rett disorder In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:1-26.

27. Cooper R, Kerr AM, Amos P. Rett syndrome: critical examination of clinical features, serial EEG and video-monitoring in understanding and management. Eur J Pediatr Neurol. 1998;2:127-135.

28. Ellaway C, Williams K, Leonard H, Higgins G, Wilcken B, Christudoulou J. Rett syndrome: randomised controlled trial of L-carnitine. J Child Neurol. 1999;14:162-167

29. Kerr AM, Belichenko P, Woodcock T, Woodcock M. Mind and Brain in Rett disorder. Brain Dev. 2001;23:S44-S49.

30. Julu PO, Kerr AM, Apartopoulos F, et al. Characterisation of breathing and associated autonomic dysfunction in the Rett Disorder. Arch Dis Child. 2001;85:29-37.

31. Julu PO. The central autonomic disturbance in Rett Syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:131-181.

32. Ellaway CJ, Sholler G, Leonard H, et al. Prolonged QT in Rett Syndrome. Arch Dis Child. 1999;80:470-472.

33. Glaze DG, Schultz RJ. Autonomic dysfunction and sudden death in Rett Syndrome: prolonged QTc intervals and diminished heart rate variability In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:251-255.

34. Loder RT, Lee CL, Richards BS. Orthopaedic aspects of Rett Syndrome: a multicenter review. J Ped Orthop. 1989;9:557-562.

35. Leonard H, Thomson MR, Glasson EJ, et al. A population-based approach to the investigation of osteopenia in Rett Syndrome. Dev Med Child Neurol. 1999;41:323-328.

36. Morton RE, Bonas R, Minford J, Kerr A, Ellis RE. Feeding ability in Rett syndrome. Dev Med Child Neurol. 1997;39:331-335.

37. Holm VA. Physical Growth and development in patients with Rett Syndrome. Am J Med Genet. 1986;(suppl 1):119-126.