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A showdown with severe social phobia
History: Living in fear
Mr. I, 41, presents for an initial psychiatric evaluation. He saw a psychologist 8 years ago for a “mild depression,” which he described as a lack of motivation and difficulty concentrating. His mood has been chronically “flat” for the last 10 years. He complains of poor energy and decreased sleep because of irregular work hours, and admits to using over-the-counter caffeine pills to help him function.
The patient denies suicidal ideations, symptoms of guilt, psychotic symptoms, or crying spells, but has a history of alcoholism and cocaine abuse. (He has been sober for 5 years.) Significant recent stressors include a recent breakup with his girlfriend, which he adds “really hasn’t bothered me at all.”
Mr. I has been increasingly avoiding social situations. Though he denies having panic attacks, interaction with other people triggers shortness of breath and chest tight-ness, especially when speaking in public to strangers.
The fear of what others might think of him is dominating Mr. I’s life. For example, he would like to console a housemate whose mother died, but because he is afraid of how the friend will react, Mr. I has not approached him. He adds that he goes out of his way to avoid contact with his co-workers, working irregular hours and eating his lunch in his car rather than the office lounge—even in inclement weather.
Mr. I does attend Alcoholic Anonymous meetings, but often sits toward the back. He had led some meetings, but refused to even look up from the podium while doing so. His anxiety worsened, his heart rate increased, and his palms sweated while leading the group. He began attending different AA meetings so that others would not recognize him and volunteer him to lead.
He adds that he feels comfortable meeting and dating women, since these exchanges are “scripted.” As he gets to know his partner better, however, Mr. I becomes more self-conscious.
Which of Mr. I’s symptoms would you address first: the depressive or the phobic?
Drs. Yu’s, Gordon’s, and Maguire’s observations
Based on Mr. I’s presentation, one might at first diagnose major depressive disorder, but chronic avoidance patterns differentiate his illness from an endogenous depression. Mr. I was diagnosed as having social phobia, a disorder that has been gaining attention among researchers.
A phobia is defined as an irrational fear that produces conscious avoidance of the feared subject, activity, or situation. The presence or anticipation of the phobic entity elicits severe distress, though the affected person usually recognizes that the reaction is excessive. DSM-IV defines social phobia as a strong, persisting fear of potentially embarrassing situations (Box).1
Two peaks of onset have been described: one occurring before age 5, and the other between ages 11 and 17.2 The mean age of onset has been reported to be 15.2
- A marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing.
- Exposure to the feared social situation almost invariably provokes anxiety, which may take the form of a situational or predisposed panic attack.
- The person recognizes that the fear is excessive or unreasonable.
- The feared social or performance situations are avoided, or else endured with intense anxiety or distress.
- The avoidance, anxious anticipation, or distress in the feared social or performance situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships with others, or there is marked distress about having the phobia.
- In individuals younger than 18, the duration is at least 6 months.
- The fear or avoidance is not caused directly by a substance (e.g., a drug of abuse or medication) or general medical condition, and is not better accounted for by another mental disorder (e.g., panic disorder with or without agoraphobia, separation anxiety disorder, body dysmorphic disorder, a pervasive developmental disorder, or schizoid personality disorder).
- If a general medical condition or other mental disorder is present, the fear in criterion A is unrelated to it (e.g., the patient does not fear stuttering, trembling in Parkinson’s disease, or exhibiting abnormal eating behavior in anorexia nervosa or bulimia nervosa). Specify if:
SOURCE: DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000.
DSM-IV describes two types of social phobia: generalized social phobia and performance phobia. Normal fear and shyness should be differentiated from social phobia. Medical conditions—including CNS tumors and cerebrovascular diseases—and drugs typically bring about neurologic and mental status symptoms that can confound the diagnosis.
Symptoms of other anxiety disorders, including panic disorder and agoraphobia, may mimic social phobia. Fear in social phobia is not present outside of, or in anticipation of, the feared situation. Social phobia also can be misdiagnosed as an avoidant personality, schizoid personality, or major depressive disorder.1
At this point, one should consider diagnosing Mr. I with social phobia, as evinced by his excessive avoidance of social situations. Mr. I also recognizes that his avoidance is excessive and causes difficulty in his daily functioning.
Behavioral inhibition in childhood is suggested to be more common in children with parents who had panic disorder. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.5-7’
First treatment: Pharmacotherapy and psychotherapy
Mr. I is interested in trying an antidepressant, but noted that about 6 years ago a brief course of a selective serotonin reuptake inhibitor led to difficulty sleeping and decreased libido and orgasm. He agrees to take bupropion SR, 100 mg/d, titrated after 2 weeks to 100 mg bid.
He also begins cognitive-behavioral and supportive therapy, during which he reveals that his pattern of avoidance took root in grade school, where he was often a quiet sidekick to the popular kids. During therapy, he describes visitations with his daughters, both of whom live with his ex-wife, as extremely difficult.
“I really don’t know what to say,” Mr. I says. “We often stare at each other during dessert, and I want to get it over with and go home.”
After 1 month, his bupropion SR is increased to 150 mg bid. One month later, his feelings of depression are under control. He sleeps well, no longer feels fatigued, and can concentrate. Still he isolates himself, fearing others’ disapproval. He has become more resistant to psychotherapy. “I know my patterns. I know what I do, but I can’t change it,” he says.
How would you treat Mr. I’s persistent social phobia? Would you switch his medications or augment existing ones? Does psychotherapy still have a role in treatment?
Drs. Yu’s, Gordon’s, and Maguire’s observations
Pharmacologic treatment of social phobia has spawned several neurochemical hypotheses. As beta-adrenergic antagonists have been proven efficacious in treating performance phobia, an adrenergic hypothesis suggests patients with performance phobia release more norepinephrine and epinephrine or are more sensitive to normal levels of these neuro-transmitters.8
The success of monoamine oxidase inhibitors in generalized social phobia suggests that dopamine plays a role in treating this form of the disorder. Central dopamine activity has been associated with positive emotions or extraversion.9
SSRIs have also demonstrated efficacy against generalized social phobia.10 Researchers have associated higher serotonin levels with increased social dominance11 and suggest that abnormal dopamine and serotonin levels contribute to the disorder’s pathogenesis.
Current treatments include psychotherapy and pharmacotherapy, and studies suggest that a combination of the two may be more efficacious than either alone.8 Venlafaxine, phenelzine, buspirone, benzodiazepines, and SSRIs have all demonstrated effectiveness and tolerability in generalized social phobia. Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol) are commonly administered to treat performance phobia shortly before exposure to the phobic stimulus.
An adequate time frame for psychopharmacologic treatment of social phobia has not been defined. In depression therapy, medications should be maintained for at least 4 to 5 weeks before considering the regimen unsuccessful.1
While Mr. I’s depression responded well to bupropion SR, a medication whose mechanism involves dopamine and norepinephrine reuptake, use of a medication that augments his serotonin may further improve his condition.
Cognitive and behavioral therapies also are indicated for both generalized social phobia and performance phobia. These should be considered along with medication therapy for Mr. I to treat his social phobia and prevent a relapse.
Despite the available evidence, however, the course and prognosis of social phobia are not clear. Data are still forthcoming on this recently recognized disorder.
Further treatment: Another neurotransmitter
Again cautious of potential adverse sexual effects, Mr. I agrees to try mirtazapine, 30 mg at bedtime, in addition to bupropion SR. He initially complains of sedation and lowered energy, but is willing to continue the mirtazapine, hoping that it will help his social phobia.
Two months after starting mirtazapine, Mr. I is still fearful at work and home, and his relationship with his order. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.5-7’ daughters has not improved. After another month, he reports that his sedation has resolved, but complains of increased fatigue and difficulty concentrating. He suspects that the bupropion SR has stopped working.
After another month, Mr. I self-discontinues the mirtazapine. Though he tries to participate in social situations, his anxiety has worsened. He goes to a country music club once a week but is afraid to ask anyone to dance.
Should you focus on Mr. I’s depression rather than his social phobia? If so, how do you change his treatment?
Drs. Yu’s, Gordon’s, and Maguire’s observations
The severity of Mr. I’s social phobia may be causing his depression. Both trials of bupropion SR and mirtazapine have been adequate for his depression but have not alleviated his social phobia.
Medications that affect gamma-aminobutyric acid (GABA) levels, specifically benzodiazepines, have not been tried. Benzodiazepines provide rapid relief with little risk in short-term treatment, but dependence/withdrawal risks increase greatly when given more than 4 to 6 months.8 Because of Mr. I’s chronic anxiety in social phobia and his history of alcoholism, benzodiazepines are not recommended.
The novel compound tiagabine has been shown to increase GABA in the synaptic cleft.12 GABA increases chloride conduction through its ligand-gated channels, creating a potential antianxiety effect similar to that produced by benzodiazepines.8,13,14 GAT-1, the predominant transporter, removes excess GABA.
Just as SSRIs inhibit serotonin reuptake and allow the neurotransmitter to act on its receptors to alleviate depression and anxiety, so does tiagabine inhibit GAT-1. Theoretically, tiagabine may relieve anxiety by increasing synaptic concentrations of GABA.
Tiagabine also has been shown to be well-tolerated without a known abuse or dependence potential.12 Possible adverse effects include impaired concentration, somnolence, fatigue, nausea, and dizziness. To avoid adverse effects, slow titration (about 4 mg per week) is recommended.
Changing treatment: Looking up
Tiagabine, 4 mg at bedtime, is added to help with Mr. I’s anxiety; he is instructed to increase the dosage by 4 mg every 5 days in divided doses. He began to sense improvement during the second week, at 4 mg bid, and 2 weeks later his anxiety has been greatly reduced. He can now sit quietly with his co-workers during coffee breaks and has begun training a co-worker, which he never dared to attempt before. At this point, he was tolerating tiagabine at 8 mg bid.
One month later, tiagabine is increased to 16 mg bid. Mr. I has noticed mild dizziness with each dosage increase, but each time it subsided within a day. He has been maintained on 16 mg bid.
Saying that his anxiety is now well-controlled, Mr. I enjoys at least one dance each week at the country music club he frequents. One week later, he led an Alcoholics Anonymous meeting—while looking up to his audience for the first time. He continues these activities and his therapy sessions, which are geared toward developing stronger skills to minimize his anxiety. He is considering lowering his medication dosages (though he is wary of a possible relapse) and furthering his therapy.
Related resources
- Anxiety Disorders Association of America www.adaa.org
- National Institute of Mental Health: Phobias from NLM’s MEDLINEplus http://www.nlm.nih.gov/medlineplus/phobias.html
Author affiliations
Dr. Yu is a fellow in child and adolescent psychiatry, Dr. Gordon is a resident physician; and Dr. Maguire is assistant dean for continuing medical education, director of resident training, and associate clinical professor, department of psychiatry, University of California, Irvine.
Drug brand names
- Bupropion • Wellbutrin
- Buspirone • BuSpar
- Mirtazapine • Remeron
- Phenelzine • Nardil
- Tiagabine • Gabitril
- Venlafaxine • Effexor
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc., Novartis Pharmaceuticals Corp., and Pfizer Inc., and receives research/grant support from and serves as a consultant to Eli Lilly and Co.
Dr. Gordon reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly and Co., is on the speaker’s bureau of Pfizer Inc., and receives research/grant support from Forest Laboratories and GlaxoSmithKline.
1. Sadock BJ, Sadock VA. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry (7th ed). Philadelphia: Lippincott Williams & Wilkins, 2000.
2. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia: comorbidity and morbidity in an epidemiological sample. Arch Gen Psychiatry 1992;49:282-8.
3. Wacker HR, Mhllejans R, Klein KH, Battegay R. Identification of cases of anxiety disorders and affective disorders in the community according to ICD-10 and DSM-III-R using the composite international diagnostic interview (CIDI). Int J Methods Psychiatr Res 1992;2:91-100.
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed), text revision. Washington, DC: American Psychiatric Association, 2000.
5. Van Ameringen M, Mancini C, Oakman JM. The relationship of behavioral inhibition and shyness to anxiety disorder. J Nerv Ment Dis 1998;186:425-31.
6. Schwartz CE, Snidman N, Kagan J. Adolescent social anxiety as an outcome of inhibited temperament in childhood. J Am Acad Child Adolesc Psychiatry 1999;38:1008-15.
7. Turner SM, Beidel DC, Townsley RM. Social phobia: relationship to shyness. Behav Res Ther 1990;28:497-505.
8. Stahl SM. Essential psychopharmacology: neuroscientific basis and practical application (2nd ed). Cambridge University Press, Cambridge, 2000.
9. Depue RA, Luciana M, Arbisi P, Collins P, Leon A. Dopamine and the structure of personality: relation of agonist induced dopamine activity to positive emotionality. J Pers Soc Psychol 1994;67:485-98.
10. Van Ameringen M, Mancini C, Oakman JM, Farvolden P. Selective serotonin reuptake inhibitors in the treatment of social phobia: the emerging gold standard. CNS Drugs 1999;11:307-15.
11. Knutson B, Wolkowitz OM, Cole SW, et al. Selective alteration of personality and social behavior by serotonergic intervention. Am J Psychiatry 1998;155:373-9.
12. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
13. Bowery NG. Pharmacology of mammalian GABAB receptors. In: Enna SJ, Bowery NG (eds). The GABA receptors (2nd ed). Totowa, NJ: Humana Press, 1997;209-36.
14. Johnston GAR. Molecular biology, pharmacology, and physiology of GABAC receptors. In: Enna SJ, Bowery NG (eds). The GABA receptors (2nd ed). Totowa, NJ: Humana Press, 1997;297-323.
History: Living in fear
Mr. I, 41, presents for an initial psychiatric evaluation. He saw a psychologist 8 years ago for a “mild depression,” which he described as a lack of motivation and difficulty concentrating. His mood has been chronically “flat” for the last 10 years. He complains of poor energy and decreased sleep because of irregular work hours, and admits to using over-the-counter caffeine pills to help him function.
The patient denies suicidal ideations, symptoms of guilt, psychotic symptoms, or crying spells, but has a history of alcoholism and cocaine abuse. (He has been sober for 5 years.) Significant recent stressors include a recent breakup with his girlfriend, which he adds “really hasn’t bothered me at all.”
Mr. I has been increasingly avoiding social situations. Though he denies having panic attacks, interaction with other people triggers shortness of breath and chest tight-ness, especially when speaking in public to strangers.
The fear of what others might think of him is dominating Mr. I’s life. For example, he would like to console a housemate whose mother died, but because he is afraid of how the friend will react, Mr. I has not approached him. He adds that he goes out of his way to avoid contact with his co-workers, working irregular hours and eating his lunch in his car rather than the office lounge—even in inclement weather.
Mr. I does attend Alcoholic Anonymous meetings, but often sits toward the back. He had led some meetings, but refused to even look up from the podium while doing so. His anxiety worsened, his heart rate increased, and his palms sweated while leading the group. He began attending different AA meetings so that others would not recognize him and volunteer him to lead.
He adds that he feels comfortable meeting and dating women, since these exchanges are “scripted.” As he gets to know his partner better, however, Mr. I becomes more self-conscious.
Which of Mr. I’s symptoms would you address first: the depressive or the phobic?
Drs. Yu’s, Gordon’s, and Maguire’s observations
Based on Mr. I’s presentation, one might at first diagnose major depressive disorder, but chronic avoidance patterns differentiate his illness from an endogenous depression. Mr. I was diagnosed as having social phobia, a disorder that has been gaining attention among researchers.
A phobia is defined as an irrational fear that produces conscious avoidance of the feared subject, activity, or situation. The presence or anticipation of the phobic entity elicits severe distress, though the affected person usually recognizes that the reaction is excessive. DSM-IV defines social phobia as a strong, persisting fear of potentially embarrassing situations (Box).1
Two peaks of onset have been described: one occurring before age 5, and the other between ages 11 and 17.2 The mean age of onset has been reported to be 15.2
- A marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing.
- Exposure to the feared social situation almost invariably provokes anxiety, which may take the form of a situational or predisposed panic attack.
- The person recognizes that the fear is excessive or unreasonable.
- The feared social or performance situations are avoided, or else endured with intense anxiety or distress.
- The avoidance, anxious anticipation, or distress in the feared social or performance situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships with others, or there is marked distress about having the phobia.
- In individuals younger than 18, the duration is at least 6 months.
- The fear or avoidance is not caused directly by a substance (e.g., a drug of abuse or medication) or general medical condition, and is not better accounted for by another mental disorder (e.g., panic disorder with or without agoraphobia, separation anxiety disorder, body dysmorphic disorder, a pervasive developmental disorder, or schizoid personality disorder).
- If a general medical condition or other mental disorder is present, the fear in criterion A is unrelated to it (e.g., the patient does not fear stuttering, trembling in Parkinson’s disease, or exhibiting abnormal eating behavior in anorexia nervosa or bulimia nervosa). Specify if:
SOURCE: DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000.
DSM-IV describes two types of social phobia: generalized social phobia and performance phobia. Normal fear and shyness should be differentiated from social phobia. Medical conditions—including CNS tumors and cerebrovascular diseases—and drugs typically bring about neurologic and mental status symptoms that can confound the diagnosis.
Symptoms of other anxiety disorders, including panic disorder and agoraphobia, may mimic social phobia. Fear in social phobia is not present outside of, or in anticipation of, the feared situation. Social phobia also can be misdiagnosed as an avoidant personality, schizoid personality, or major depressive disorder.1
At this point, one should consider diagnosing Mr. I with social phobia, as evinced by his excessive avoidance of social situations. Mr. I also recognizes that his avoidance is excessive and causes difficulty in his daily functioning.
Behavioral inhibition in childhood is suggested to be more common in children with parents who had panic disorder. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.5-7’
First treatment: Pharmacotherapy and psychotherapy
Mr. I is interested in trying an antidepressant, but noted that about 6 years ago a brief course of a selective serotonin reuptake inhibitor led to difficulty sleeping and decreased libido and orgasm. He agrees to take bupropion SR, 100 mg/d, titrated after 2 weeks to 100 mg bid.
He also begins cognitive-behavioral and supportive therapy, during which he reveals that his pattern of avoidance took root in grade school, where he was often a quiet sidekick to the popular kids. During therapy, he describes visitations with his daughters, both of whom live with his ex-wife, as extremely difficult.
“I really don’t know what to say,” Mr. I says. “We often stare at each other during dessert, and I want to get it over with and go home.”
After 1 month, his bupropion SR is increased to 150 mg bid. One month later, his feelings of depression are under control. He sleeps well, no longer feels fatigued, and can concentrate. Still he isolates himself, fearing others’ disapproval. He has become more resistant to psychotherapy. “I know my patterns. I know what I do, but I can’t change it,” he says.
How would you treat Mr. I’s persistent social phobia? Would you switch his medications or augment existing ones? Does psychotherapy still have a role in treatment?
Drs. Yu’s, Gordon’s, and Maguire’s observations
Pharmacologic treatment of social phobia has spawned several neurochemical hypotheses. As beta-adrenergic antagonists have been proven efficacious in treating performance phobia, an adrenergic hypothesis suggests patients with performance phobia release more norepinephrine and epinephrine or are more sensitive to normal levels of these neuro-transmitters.8
The success of monoamine oxidase inhibitors in generalized social phobia suggests that dopamine plays a role in treating this form of the disorder. Central dopamine activity has been associated with positive emotions or extraversion.9
SSRIs have also demonstrated efficacy against generalized social phobia.10 Researchers have associated higher serotonin levels with increased social dominance11 and suggest that abnormal dopamine and serotonin levels contribute to the disorder’s pathogenesis.
Current treatments include psychotherapy and pharmacotherapy, and studies suggest that a combination of the two may be more efficacious than either alone.8 Venlafaxine, phenelzine, buspirone, benzodiazepines, and SSRIs have all demonstrated effectiveness and tolerability in generalized social phobia. Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol) are commonly administered to treat performance phobia shortly before exposure to the phobic stimulus.
An adequate time frame for psychopharmacologic treatment of social phobia has not been defined. In depression therapy, medications should be maintained for at least 4 to 5 weeks before considering the regimen unsuccessful.1
While Mr. I’s depression responded well to bupropion SR, a medication whose mechanism involves dopamine and norepinephrine reuptake, use of a medication that augments his serotonin may further improve his condition.
Cognitive and behavioral therapies also are indicated for both generalized social phobia and performance phobia. These should be considered along with medication therapy for Mr. I to treat his social phobia and prevent a relapse.
Despite the available evidence, however, the course and prognosis of social phobia are not clear. Data are still forthcoming on this recently recognized disorder.
Further treatment: Another neurotransmitter
Again cautious of potential adverse sexual effects, Mr. I agrees to try mirtazapine, 30 mg at bedtime, in addition to bupropion SR. He initially complains of sedation and lowered energy, but is willing to continue the mirtazapine, hoping that it will help his social phobia.
Two months after starting mirtazapine, Mr. I is still fearful at work and home, and his relationship with his order. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.5-7’ daughters has not improved. After another month, he reports that his sedation has resolved, but complains of increased fatigue and difficulty concentrating. He suspects that the bupropion SR has stopped working.
After another month, Mr. I self-discontinues the mirtazapine. Though he tries to participate in social situations, his anxiety has worsened. He goes to a country music club once a week but is afraid to ask anyone to dance.
Should you focus on Mr. I’s depression rather than his social phobia? If so, how do you change his treatment?
Drs. Yu’s, Gordon’s, and Maguire’s observations
The severity of Mr. I’s social phobia may be causing his depression. Both trials of bupropion SR and mirtazapine have been adequate for his depression but have not alleviated his social phobia.
Medications that affect gamma-aminobutyric acid (GABA) levels, specifically benzodiazepines, have not been tried. Benzodiazepines provide rapid relief with little risk in short-term treatment, but dependence/withdrawal risks increase greatly when given more than 4 to 6 months.8 Because of Mr. I’s chronic anxiety in social phobia and his history of alcoholism, benzodiazepines are not recommended.
The novel compound tiagabine has been shown to increase GABA in the synaptic cleft.12 GABA increases chloride conduction through its ligand-gated channels, creating a potential antianxiety effect similar to that produced by benzodiazepines.8,13,14 GAT-1, the predominant transporter, removes excess GABA.
Just as SSRIs inhibit serotonin reuptake and allow the neurotransmitter to act on its receptors to alleviate depression and anxiety, so does tiagabine inhibit GAT-1. Theoretically, tiagabine may relieve anxiety by increasing synaptic concentrations of GABA.
Tiagabine also has been shown to be well-tolerated without a known abuse or dependence potential.12 Possible adverse effects include impaired concentration, somnolence, fatigue, nausea, and dizziness. To avoid adverse effects, slow titration (about 4 mg per week) is recommended.
Changing treatment: Looking up
Tiagabine, 4 mg at bedtime, is added to help with Mr. I’s anxiety; he is instructed to increase the dosage by 4 mg every 5 days in divided doses. He began to sense improvement during the second week, at 4 mg bid, and 2 weeks later his anxiety has been greatly reduced. He can now sit quietly with his co-workers during coffee breaks and has begun training a co-worker, which he never dared to attempt before. At this point, he was tolerating tiagabine at 8 mg bid.
One month later, tiagabine is increased to 16 mg bid. Mr. I has noticed mild dizziness with each dosage increase, but each time it subsided within a day. He has been maintained on 16 mg bid.
Saying that his anxiety is now well-controlled, Mr. I enjoys at least one dance each week at the country music club he frequents. One week later, he led an Alcoholics Anonymous meeting—while looking up to his audience for the first time. He continues these activities and his therapy sessions, which are geared toward developing stronger skills to minimize his anxiety. He is considering lowering his medication dosages (though he is wary of a possible relapse) and furthering his therapy.
Related resources
- Anxiety Disorders Association of America www.adaa.org
- National Institute of Mental Health: Phobias from NLM’s MEDLINEplus http://www.nlm.nih.gov/medlineplus/phobias.html
Author affiliations
Dr. Yu is a fellow in child and adolescent psychiatry, Dr. Gordon is a resident physician; and Dr. Maguire is assistant dean for continuing medical education, director of resident training, and associate clinical professor, department of psychiatry, University of California, Irvine.
Drug brand names
- Bupropion • Wellbutrin
- Buspirone • BuSpar
- Mirtazapine • Remeron
- Phenelzine • Nardil
- Tiagabine • Gabitril
- Venlafaxine • Effexor
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc., Novartis Pharmaceuticals Corp., and Pfizer Inc., and receives research/grant support from and serves as a consultant to Eli Lilly and Co.
Dr. Gordon reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly and Co., is on the speaker’s bureau of Pfizer Inc., and receives research/grant support from Forest Laboratories and GlaxoSmithKline.
History: Living in fear
Mr. I, 41, presents for an initial psychiatric evaluation. He saw a psychologist 8 years ago for a “mild depression,” which he described as a lack of motivation and difficulty concentrating. His mood has been chronically “flat” for the last 10 years. He complains of poor energy and decreased sleep because of irregular work hours, and admits to using over-the-counter caffeine pills to help him function.
The patient denies suicidal ideations, symptoms of guilt, psychotic symptoms, or crying spells, but has a history of alcoholism and cocaine abuse. (He has been sober for 5 years.) Significant recent stressors include a recent breakup with his girlfriend, which he adds “really hasn’t bothered me at all.”
Mr. I has been increasingly avoiding social situations. Though he denies having panic attacks, interaction with other people triggers shortness of breath and chest tight-ness, especially when speaking in public to strangers.
The fear of what others might think of him is dominating Mr. I’s life. For example, he would like to console a housemate whose mother died, but because he is afraid of how the friend will react, Mr. I has not approached him. He adds that he goes out of his way to avoid contact with his co-workers, working irregular hours and eating his lunch in his car rather than the office lounge—even in inclement weather.
Mr. I does attend Alcoholic Anonymous meetings, but often sits toward the back. He had led some meetings, but refused to even look up from the podium while doing so. His anxiety worsened, his heart rate increased, and his palms sweated while leading the group. He began attending different AA meetings so that others would not recognize him and volunteer him to lead.
He adds that he feels comfortable meeting and dating women, since these exchanges are “scripted.” As he gets to know his partner better, however, Mr. I becomes more self-conscious.
Which of Mr. I’s symptoms would you address first: the depressive or the phobic?
Drs. Yu’s, Gordon’s, and Maguire’s observations
Based on Mr. I’s presentation, one might at first diagnose major depressive disorder, but chronic avoidance patterns differentiate his illness from an endogenous depression. Mr. I was diagnosed as having social phobia, a disorder that has been gaining attention among researchers.
A phobia is defined as an irrational fear that produces conscious avoidance of the feared subject, activity, or situation. The presence or anticipation of the phobic entity elicits severe distress, though the affected person usually recognizes that the reaction is excessive. DSM-IV defines social phobia as a strong, persisting fear of potentially embarrassing situations (Box).1
Two peaks of onset have been described: one occurring before age 5, and the other between ages 11 and 17.2 The mean age of onset has been reported to be 15.2
- A marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing.
- Exposure to the feared social situation almost invariably provokes anxiety, which may take the form of a situational or predisposed panic attack.
- The person recognizes that the fear is excessive or unreasonable.
- The feared social or performance situations are avoided, or else endured with intense anxiety or distress.
- The avoidance, anxious anticipation, or distress in the feared social or performance situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships with others, or there is marked distress about having the phobia.
- In individuals younger than 18, the duration is at least 6 months.
- The fear or avoidance is not caused directly by a substance (e.g., a drug of abuse or medication) or general medical condition, and is not better accounted for by another mental disorder (e.g., panic disorder with or without agoraphobia, separation anxiety disorder, body dysmorphic disorder, a pervasive developmental disorder, or schizoid personality disorder).
- If a general medical condition or other mental disorder is present, the fear in criterion A is unrelated to it (e.g., the patient does not fear stuttering, trembling in Parkinson’s disease, or exhibiting abnormal eating behavior in anorexia nervosa or bulimia nervosa). Specify if:
SOURCE: DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000.
DSM-IV describes two types of social phobia: generalized social phobia and performance phobia. Normal fear and shyness should be differentiated from social phobia. Medical conditions—including CNS tumors and cerebrovascular diseases—and drugs typically bring about neurologic and mental status symptoms that can confound the diagnosis.
Symptoms of other anxiety disorders, including panic disorder and agoraphobia, may mimic social phobia. Fear in social phobia is not present outside of, or in anticipation of, the feared situation. Social phobia also can be misdiagnosed as an avoidant personality, schizoid personality, or major depressive disorder.1
At this point, one should consider diagnosing Mr. I with social phobia, as evinced by his excessive avoidance of social situations. Mr. I also recognizes that his avoidance is excessive and causes difficulty in his daily functioning.
Behavioral inhibition in childhood is suggested to be more common in children with parents who had panic disorder. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.5-7’
First treatment: Pharmacotherapy and psychotherapy
Mr. I is interested in trying an antidepressant, but noted that about 6 years ago a brief course of a selective serotonin reuptake inhibitor led to difficulty sleeping and decreased libido and orgasm. He agrees to take bupropion SR, 100 mg/d, titrated after 2 weeks to 100 mg bid.
He also begins cognitive-behavioral and supportive therapy, during which he reveals that his pattern of avoidance took root in grade school, where he was often a quiet sidekick to the popular kids. During therapy, he describes visitations with his daughters, both of whom live with his ex-wife, as extremely difficult.
“I really don’t know what to say,” Mr. I says. “We often stare at each other during dessert, and I want to get it over with and go home.”
After 1 month, his bupropion SR is increased to 150 mg bid. One month later, his feelings of depression are under control. He sleeps well, no longer feels fatigued, and can concentrate. Still he isolates himself, fearing others’ disapproval. He has become more resistant to psychotherapy. “I know my patterns. I know what I do, but I can’t change it,” he says.
How would you treat Mr. I’s persistent social phobia? Would you switch his medications or augment existing ones? Does psychotherapy still have a role in treatment?
Drs. Yu’s, Gordon’s, and Maguire’s observations
Pharmacologic treatment of social phobia has spawned several neurochemical hypotheses. As beta-adrenergic antagonists have been proven efficacious in treating performance phobia, an adrenergic hypothesis suggests patients with performance phobia release more norepinephrine and epinephrine or are more sensitive to normal levels of these neuro-transmitters.8
The success of monoamine oxidase inhibitors in generalized social phobia suggests that dopamine plays a role in treating this form of the disorder. Central dopamine activity has been associated with positive emotions or extraversion.9
SSRIs have also demonstrated efficacy against generalized social phobia.10 Researchers have associated higher serotonin levels with increased social dominance11 and suggest that abnormal dopamine and serotonin levels contribute to the disorder’s pathogenesis.
Current treatments include psychotherapy and pharmacotherapy, and studies suggest that a combination of the two may be more efficacious than either alone.8 Venlafaxine, phenelzine, buspirone, benzodiazepines, and SSRIs have all demonstrated effectiveness and tolerability in generalized social phobia. Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol) are commonly administered to treat performance phobia shortly before exposure to the phobic stimulus.
An adequate time frame for psychopharmacologic treatment of social phobia has not been defined. In depression therapy, medications should be maintained for at least 4 to 5 weeks before considering the regimen unsuccessful.1
While Mr. I’s depression responded well to bupropion SR, a medication whose mechanism involves dopamine and norepinephrine reuptake, use of a medication that augments his serotonin may further improve his condition.
Cognitive and behavioral therapies also are indicated for both generalized social phobia and performance phobia. These should be considered along with medication therapy for Mr. I to treat his social phobia and prevent a relapse.
Despite the available evidence, however, the course and prognosis of social phobia are not clear. Data are still forthcoming on this recently recognized disorder.
Further treatment: Another neurotransmitter
Again cautious of potential adverse sexual effects, Mr. I agrees to try mirtazapine, 30 mg at bedtime, in addition to bupropion SR. He initially complains of sedation and lowered energy, but is willing to continue the mirtazapine, hoping that it will help his social phobia.
Two months after starting mirtazapine, Mr. I is still fearful at work and home, and his relationship with his order. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.5-7’ daughters has not improved. After another month, he reports that his sedation has resolved, but complains of increased fatigue and difficulty concentrating. He suspects that the bupropion SR has stopped working.
After another month, Mr. I self-discontinues the mirtazapine. Though he tries to participate in social situations, his anxiety has worsened. He goes to a country music club once a week but is afraid to ask anyone to dance.
Should you focus on Mr. I’s depression rather than his social phobia? If so, how do you change his treatment?
Drs. Yu’s, Gordon’s, and Maguire’s observations
The severity of Mr. I’s social phobia may be causing his depression. Both trials of bupropion SR and mirtazapine have been adequate for his depression but have not alleviated his social phobia.
Medications that affect gamma-aminobutyric acid (GABA) levels, specifically benzodiazepines, have not been tried. Benzodiazepines provide rapid relief with little risk in short-term treatment, but dependence/withdrawal risks increase greatly when given more than 4 to 6 months.8 Because of Mr. I’s chronic anxiety in social phobia and his history of alcoholism, benzodiazepines are not recommended.
The novel compound tiagabine has been shown to increase GABA in the synaptic cleft.12 GABA increases chloride conduction through its ligand-gated channels, creating a potential antianxiety effect similar to that produced by benzodiazepines.8,13,14 GAT-1, the predominant transporter, removes excess GABA.
Just as SSRIs inhibit serotonin reuptake and allow the neurotransmitter to act on its receptors to alleviate depression and anxiety, so does tiagabine inhibit GAT-1. Theoretically, tiagabine may relieve anxiety by increasing synaptic concentrations of GABA.
Tiagabine also has been shown to be well-tolerated without a known abuse or dependence potential.12 Possible adverse effects include impaired concentration, somnolence, fatigue, nausea, and dizziness. To avoid adverse effects, slow titration (about 4 mg per week) is recommended.
Changing treatment: Looking up
Tiagabine, 4 mg at bedtime, is added to help with Mr. I’s anxiety; he is instructed to increase the dosage by 4 mg every 5 days in divided doses. He began to sense improvement during the second week, at 4 mg bid, and 2 weeks later his anxiety has been greatly reduced. He can now sit quietly with his co-workers during coffee breaks and has begun training a co-worker, which he never dared to attempt before. At this point, he was tolerating tiagabine at 8 mg bid.
One month later, tiagabine is increased to 16 mg bid. Mr. I has noticed mild dizziness with each dosage increase, but each time it subsided within a day. He has been maintained on 16 mg bid.
Saying that his anxiety is now well-controlled, Mr. I enjoys at least one dance each week at the country music club he frequents. One week later, he led an Alcoholics Anonymous meeting—while looking up to his audience for the first time. He continues these activities and his therapy sessions, which are geared toward developing stronger skills to minimize his anxiety. He is considering lowering his medication dosages (though he is wary of a possible relapse) and furthering his therapy.
Related resources
- Anxiety Disorders Association of America www.adaa.org
- National Institute of Mental Health: Phobias from NLM’s MEDLINEplus http://www.nlm.nih.gov/medlineplus/phobias.html
Author affiliations
Dr. Yu is a fellow in child and adolescent psychiatry, Dr. Gordon is a resident physician; and Dr. Maguire is assistant dean for continuing medical education, director of resident training, and associate clinical professor, department of psychiatry, University of California, Irvine.
Drug brand names
- Bupropion • Wellbutrin
- Buspirone • BuSpar
- Mirtazapine • Remeron
- Phenelzine • Nardil
- Tiagabine • Gabitril
- Venlafaxine • Effexor
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc., Novartis Pharmaceuticals Corp., and Pfizer Inc., and receives research/grant support from and serves as a consultant to Eli Lilly and Co.
Dr. Gordon reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly and Co., is on the speaker’s bureau of Pfizer Inc., and receives research/grant support from Forest Laboratories and GlaxoSmithKline.
1. Sadock BJ, Sadock VA. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry (7th ed). Philadelphia: Lippincott Williams & Wilkins, 2000.
2. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia: comorbidity and morbidity in an epidemiological sample. Arch Gen Psychiatry 1992;49:282-8.
3. Wacker HR, Mhllejans R, Klein KH, Battegay R. Identification of cases of anxiety disorders and affective disorders in the community according to ICD-10 and DSM-III-R using the composite international diagnostic interview (CIDI). Int J Methods Psychiatr Res 1992;2:91-100.
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed), text revision. Washington, DC: American Psychiatric Association, 2000.
5. Van Ameringen M, Mancini C, Oakman JM. The relationship of behavioral inhibition and shyness to anxiety disorder. J Nerv Ment Dis 1998;186:425-31.
6. Schwartz CE, Snidman N, Kagan J. Adolescent social anxiety as an outcome of inhibited temperament in childhood. J Am Acad Child Adolesc Psychiatry 1999;38:1008-15.
7. Turner SM, Beidel DC, Townsley RM. Social phobia: relationship to shyness. Behav Res Ther 1990;28:497-505.
8. Stahl SM. Essential psychopharmacology: neuroscientific basis and practical application (2nd ed). Cambridge University Press, Cambridge, 2000.
9. Depue RA, Luciana M, Arbisi P, Collins P, Leon A. Dopamine and the structure of personality: relation of agonist induced dopamine activity to positive emotionality. J Pers Soc Psychol 1994;67:485-98.
10. Van Ameringen M, Mancini C, Oakman JM, Farvolden P. Selective serotonin reuptake inhibitors in the treatment of social phobia: the emerging gold standard. CNS Drugs 1999;11:307-15.
11. Knutson B, Wolkowitz OM, Cole SW, et al. Selective alteration of personality and social behavior by serotonergic intervention. Am J Psychiatry 1998;155:373-9.
12. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
13. Bowery NG. Pharmacology of mammalian GABAB receptors. In: Enna SJ, Bowery NG (eds). The GABA receptors (2nd ed). Totowa, NJ: Humana Press, 1997;209-36.
14. Johnston GAR. Molecular biology, pharmacology, and physiology of GABAC receptors. In: Enna SJ, Bowery NG (eds). The GABA receptors (2nd ed). Totowa, NJ: Humana Press, 1997;297-323.
1. Sadock BJ, Sadock VA. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry (7th ed). Philadelphia: Lippincott Williams & Wilkins, 2000.
2. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia: comorbidity and morbidity in an epidemiological sample. Arch Gen Psychiatry 1992;49:282-8.
3. Wacker HR, Mhllejans R, Klein KH, Battegay R. Identification of cases of anxiety disorders and affective disorders in the community according to ICD-10 and DSM-III-R using the composite international diagnostic interview (CIDI). Int J Methods Psychiatr Res 1992;2:91-100.
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed), text revision. Washington, DC: American Psychiatric Association, 2000.
5. Van Ameringen M, Mancini C, Oakman JM. The relationship of behavioral inhibition and shyness to anxiety disorder. J Nerv Ment Dis 1998;186:425-31.
6. Schwartz CE, Snidman N, Kagan J. Adolescent social anxiety as an outcome of inhibited temperament in childhood. J Am Acad Child Adolesc Psychiatry 1999;38:1008-15.
7. Turner SM, Beidel DC, Townsley RM. Social phobia: relationship to shyness. Behav Res Ther 1990;28:497-505.
8. Stahl SM. Essential psychopharmacology: neuroscientific basis and practical application (2nd ed). Cambridge University Press, Cambridge, 2000.
9. Depue RA, Luciana M, Arbisi P, Collins P, Leon A. Dopamine and the structure of personality: relation of agonist induced dopamine activity to positive emotionality. J Pers Soc Psychol 1994;67:485-98.
10. Van Ameringen M, Mancini C, Oakman JM, Farvolden P. Selective serotonin reuptake inhibitors in the treatment of social phobia: the emerging gold standard. CNS Drugs 1999;11:307-15.
11. Knutson B, Wolkowitz OM, Cole SW, et al. Selective alteration of personality and social behavior by serotonergic intervention. Am J Psychiatry 1998;155:373-9.
12. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
13. Bowery NG. Pharmacology of mammalian GABAB receptors. In: Enna SJ, Bowery NG (eds). The GABA receptors (2nd ed). Totowa, NJ: Humana Press, 1997;209-36.
14. Johnston GAR. Molecular biology, pharmacology, and physiology of GABAC receptors. In: Enna SJ, Bowery NG (eds). The GABA receptors (2nd ed). Totowa, NJ: Humana Press, 1997;297-323.
Can a wakefulness-promoting agent augment schizophrenia treatment?
History: A long, losing battle
Mr. X, 41, has had schizophrenia, paranoid type, since age 24. Unable to work, keep house, or even groom himself, he has lived his entire life with his mother, his principal advocate and caretaker. He has been hospitalized 11 times for persecutory delusions, most recently 2 years ago at our medical center..
Numerous antipsychotics, including risperidone, haloperidol, quetiapine, clozapine, and thiothixene, did not work. He has responded best to olanzapine, but some mild paranoid symptoms and significant negative symptoms (alogia, anhedonia, amotivation, hypersomnia, restricted affect) persist.
He gained 30 pounds within 6 months after starting olanzapine. He was keeping his weight at 230 pounds and his body mass index (BMI) at 31.3. (A normal BMI is <25; a BMI >30 is considered obese.)
The patient was maintained on olanzapine 20 mg/d, but higher dosages caused oversedation. At the hospital, he would sleep through breakfast, get up late in the morning, then lie around until bedtime.
As an outpatient, he had no social contact outside the home. While hospitalized, Mr. X attended a therapy group on his ward, but never participated in the discussion. His speech was profoundly deficient; he never volunteered information and never responded to questions with anything more than a barely audible “yes” or “ no ”
How would you help Mr. X? Would you augment the olanzapine therapy or consider another antipsychotic, even one that failed the first time? Which negative symptom would you address first?
Drs. Yu’s and Maguire’s observations
Compared with the older antipsychotic agents, specifically haloperidol and thiothixene in this case, the newer antipsychotics (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) have demonstrated the ability to comprehensively treat schizophrenia.1-4 But these novel agents sometimes fail to remedy the negative symptoms. Thus, as is the case with Mr. X, many patients with schizophrenia whose positive symptoms are controlled realize little or no improvement in quality of life.
Olanzapine and risperidone have more effectively reduced the negative symptoms of schizophrenia than have the older antipsychotics,1-4 but—as we see with Mr. X—their record in treating negative symptoms is far from perfect. Additionally, sedation secondary to the antipsychotic may worsen the negative symptoms.
What’s more, the newer agents are associated with potential weight gain.5-7 Mr. X’s weight will need to be addressed, but with much caution. Many agents prescribed for weight loss, notably amphetamines, are avoided in psychotic patients because of the potential for abuse and worsening psychosis.8
Augmentation with modafinil, a wakefulness-promoting agent, is being considered for Mr. X. Although modafinil’s efficacy against obesity has not specifically been tested, studies have shown that this agent, which has actions similar to those of sympathomimetic agents, offers a lower abuse potential. Gold and Balster found that the medication was 250 times less potent than amphetamine and 15 times less potent than ephedrine in producing cocaine-like discriminative stimulus effects in rats.9 Single oral doses of modafinil did not cause elation or euphoria in healthy volunteers or those with substance abuse disorders.10,11 And compared with amphetamines, modafinil has a limited side-effect profile, with weak peripheral sympathomimetic activity and minimal effects on hemodynamics.12
Though it is best to minimize both the number of medications and the dosage for each patient, augmentation is still needed in some cases.13-15
Treatment augmentation: An agent is added
Mr. X’s olanzapine was increased to 30 mg/d. Modafinil, 100 mg/d, was then added to reduce the sedation associated with the higher olanzapine dosage.
Within a week, Mr. X’s negative symptoms had begun to improve. He started to speak more often and more clearly; his previously monotone voice exhibited a small degree of intonation and inflection. His fatigue decreased, and he was able to stay awake through breakfast and throughout the day.
That first week, he exhibited a brightened affect and more energy. He began to socialize to some extent with other patients in the hospital therapy group and was less isolated than before.
This slight but sudden improvement encouraged us. While he still showed slight paranoid ideations, he looked forward to a safe discharge and returning home to his family.
At this point, would you increase the dosage of either modafinil or olanzapine, or stay the course and monitor the patient’s improvement?
Drs. Yu’s and Maguire’s observations
Modafinil is a novel compound indicated for narcolepsy treatment. Though its precise mechanism is unknown, modafinil is neither a direct- nor indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity.16 Therefore, the agent’s pharmacologic profile may be favorable for off-label use in treating negative symptoms of schizophrenia. Modafinil also has been shown to be effective as an augmentation therapy in depression, especially with treating fatigue symptoms.17
Continued treatment: Improving symptoms
After 1 month, we increased Mr. X’s modafinil dosage to 200 mg/d and olanzapine to 40 mg/d. Both were well tolerated. No extrapyramidal symptoms were noted.
Over the next 4 months, his negative symptoms improved to the point where he had some concept of self-image. He was more alert, less isolated, and better groomed.
Once too sleepy to even eat breakfast, Mr. X began to participate in an exercise program, performing aerobic exercise including regular use of a treadmill, at a local gymnasium 3 days a week. This may have contributed to his loss of 20 pounds across 4 months. Over the next 6 months, the patient maintained his weight at 210 pounds, with a resultant BMI of 28.5. (He has lost slightly more weight since then.)
His socialization skills, while still far from mainstream levels, also improved. His mother began taking him to support group meetings at the local office of the National Alliance for the Mentally Ill (NAMI). There, he interacted with persons with schizophrenia and other psychiatric disorders.
During this time, his psychiatric condition remained stable, and his paranoia showed a mild improvement. Whereas Mr. X once required hospitalization every 6 months to 2 years, he has now been an outpatient for more than 2 years.
The modafinil dosage was titrated to 400 mg/d to further improve his negative symptoms and prevent antipsychotic-associated sedation. Mr. X has noted a continued increase in his alertness. He is still exercising, remains well groomed, and has begun taking vacations with his family. His mother, an active NAMI member, has continued to be his advocate and encourage his improvement.
Overall, we estimate that Mr. X is now functioning at about 65% of normal human capacity. When we began olanzapine with modafinil augmentation 2 years ago, he was functioning at barely one-half that level.
In your view, what should be the next step toward reintegration for Mr. X?
Drs. Yu’s and Maguire’s observations
The olanzapine/modafinil regimen brought about great improvement, but pharmacologic therapy only goes so far. As of this writing, Mr. X has never held a job or lived independently. Also, socialization beyond the family and NAMI support group meetings remains nonexistent.
Behavioral strategies may be just as important as medication treatment for patients with schizophrenia. We would consider behavioral therapy for Mr. X, employing token economies and social skills training to increase social abilities, self-sufficiency, practical skills, and interpersonal communication—skills that may further improve his negative symptoms and lessen the chance of relapse. Social skills training through the use of videotapes, role playing in therapy, and homework assignments to practice specific skills may allow Mr. X to improve his maladaptive behaviors.
Educating the patient and his family would help them understand what to expect in the course of his illness and can enhance treatment. NAMI is one useful referral source. NAMI and similar organizations offer emotional and practical advice about obtaining care in today’s complex health care delivery system.
A case manager also plays an invaluable role, ensuring that efforts are coordinated and that the patient keeps appointments and complies with treatment plans. The case manager may make home visits and even accompany the patient to work. The program’s success depends on the educational background, training, and qualifications of the case manager, which are variable.
Other behavioral strategies that could help Mr. X and other patients with schizophrenia include:
- Group therapy, which focuses on real-life plans, problems, and relationships. Group therapy effectively reduces social isolation, increases cohesiveness, and improves reality testing. Groups led in a supportive rather than interpretative manner appear to be most helpful in schizophrenia.
- Cognitive-behavioral therapy, which has been used in schizophrenia to improve cognitive distortions, reduce distractibility, and correct errors in judgment.
- Individual psychotherapy, which has been shown to effectively complement pharmacologic treatment.18
As patients’ symptoms improve, we as psychiatrists can help by encouraging them to gradually reintegrate into society, often by offering resources such as NAMI or referrals to appropriate rehabilitation programs.
We plan to continue Mr. X’s olanzapine/modafinil regimen to keep positive and negative symptoms at bay while improving his chances at reintegration. Careful monitoring of medications during reintegration is key to preventing relapse. We will continue to see Mr. X once a month.
Related resources
- National Alliance for the Mentally Ill. www.nami.org
- The Center for Reintegration. www.reintegration.com
- National Alliance for Research on Schizophrenia and Depression. www.mhsource.com/narsad/ or www.narsad.org
Drug brand names
- Clozapine • Clozaril
- Ephedrine • Rynatuss
- Haloperidol • Haldol
- Modafinil • Provigil
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Author affiliations
Benjamin P. Yu, MD
Resident physician
Gerald A. Maguire, MD
Assistant dean for continuing medical education, Director of residency training,
Associate clinical professor
Department of psychiatry and human behavior
University of California-Irvine Medical Center
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly & Co.
1. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538-46.
2. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42:233-46.
3. Tollefson GD, Sanger TM, Lu Y, et al. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 1998;55:250-8.
4. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
5. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60(6):358-63.
6. Beasley CM, Jr, Hamilton SH, Crawford AM, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7(2):125-37.
7. Blackburn GL. Weight gain and antipsychotic medication. J Clin Psychiatry 2000;61(suppl 8):36-41.
8. Gawin FH, Khalsa ME, Ellinwood E. Stimulants. In: Galanter M, Kleber HD, eds. The American Psychiatric Press textbook of substance abuse treatment. Washington, DC: American Psychiatric Press, 1994.
9. Gold LH, Balster RL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology (Berl) 1996;126(4):286-92.
10. Warot D, Coruble E, Payan C, et al. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 1993;8:201-8.
11. Duteil J, Rambert FA, Pessonnier J, et al. Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effects of modafinil: studies with experimental animals. Eur J Pharmacol 1990;180:49-58.
12. Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999;39:30-40.
13. Purdon SE. Cognitive improvement in schizophrenia with novel antipsychotic medications. Schizophr Res 1999;35(suppl):S51-S60.
14. Beasley CM, Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacol 1996;124(1-2):159-67.
15. Marder SR. Management of treatment-resistant patients with schizophrenia. J Clin Psychiatry 1996;57(suppl 11):26-30.
16. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
17. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61(5):378-81.
18. Maguire GA. CNS News. Supplement August 2001;6-10.
History: A long, losing battle
Mr. X, 41, has had schizophrenia, paranoid type, since age 24. Unable to work, keep house, or even groom himself, he has lived his entire life with his mother, his principal advocate and caretaker. He has been hospitalized 11 times for persecutory delusions, most recently 2 years ago at our medical center..
Numerous antipsychotics, including risperidone, haloperidol, quetiapine, clozapine, and thiothixene, did not work. He has responded best to olanzapine, but some mild paranoid symptoms and significant negative symptoms (alogia, anhedonia, amotivation, hypersomnia, restricted affect) persist.
He gained 30 pounds within 6 months after starting olanzapine. He was keeping his weight at 230 pounds and his body mass index (BMI) at 31.3. (A normal BMI is <25; a BMI >30 is considered obese.)
The patient was maintained on olanzapine 20 mg/d, but higher dosages caused oversedation. At the hospital, he would sleep through breakfast, get up late in the morning, then lie around until bedtime.
As an outpatient, he had no social contact outside the home. While hospitalized, Mr. X attended a therapy group on his ward, but never participated in the discussion. His speech was profoundly deficient; he never volunteered information and never responded to questions with anything more than a barely audible “yes” or “ no ”
How would you help Mr. X? Would you augment the olanzapine therapy or consider another antipsychotic, even one that failed the first time? Which negative symptom would you address first?
Drs. Yu’s and Maguire’s observations
Compared with the older antipsychotic agents, specifically haloperidol and thiothixene in this case, the newer antipsychotics (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) have demonstrated the ability to comprehensively treat schizophrenia.1-4 But these novel agents sometimes fail to remedy the negative symptoms. Thus, as is the case with Mr. X, many patients with schizophrenia whose positive symptoms are controlled realize little or no improvement in quality of life.
Olanzapine and risperidone have more effectively reduced the negative symptoms of schizophrenia than have the older antipsychotics,1-4 but—as we see with Mr. X—their record in treating negative symptoms is far from perfect. Additionally, sedation secondary to the antipsychotic may worsen the negative symptoms.
What’s more, the newer agents are associated with potential weight gain.5-7 Mr. X’s weight will need to be addressed, but with much caution. Many agents prescribed for weight loss, notably amphetamines, are avoided in psychotic patients because of the potential for abuse and worsening psychosis.8
Augmentation with modafinil, a wakefulness-promoting agent, is being considered for Mr. X. Although modafinil’s efficacy against obesity has not specifically been tested, studies have shown that this agent, which has actions similar to those of sympathomimetic agents, offers a lower abuse potential. Gold and Balster found that the medication was 250 times less potent than amphetamine and 15 times less potent than ephedrine in producing cocaine-like discriminative stimulus effects in rats.9 Single oral doses of modafinil did not cause elation or euphoria in healthy volunteers or those with substance abuse disorders.10,11 And compared with amphetamines, modafinil has a limited side-effect profile, with weak peripheral sympathomimetic activity and minimal effects on hemodynamics.12
Though it is best to minimize both the number of medications and the dosage for each patient, augmentation is still needed in some cases.13-15
Treatment augmentation: An agent is added
Mr. X’s olanzapine was increased to 30 mg/d. Modafinil, 100 mg/d, was then added to reduce the sedation associated with the higher olanzapine dosage.
Within a week, Mr. X’s negative symptoms had begun to improve. He started to speak more often and more clearly; his previously monotone voice exhibited a small degree of intonation and inflection. His fatigue decreased, and he was able to stay awake through breakfast and throughout the day.
That first week, he exhibited a brightened affect and more energy. He began to socialize to some extent with other patients in the hospital therapy group and was less isolated than before.
This slight but sudden improvement encouraged us. While he still showed slight paranoid ideations, he looked forward to a safe discharge and returning home to his family.
At this point, would you increase the dosage of either modafinil or olanzapine, or stay the course and monitor the patient’s improvement?
Drs. Yu’s and Maguire’s observations
Modafinil is a novel compound indicated for narcolepsy treatment. Though its precise mechanism is unknown, modafinil is neither a direct- nor indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity.16 Therefore, the agent’s pharmacologic profile may be favorable for off-label use in treating negative symptoms of schizophrenia. Modafinil also has been shown to be effective as an augmentation therapy in depression, especially with treating fatigue symptoms.17
Continued treatment: Improving symptoms
After 1 month, we increased Mr. X’s modafinil dosage to 200 mg/d and olanzapine to 40 mg/d. Both were well tolerated. No extrapyramidal symptoms were noted.
Over the next 4 months, his negative symptoms improved to the point where he had some concept of self-image. He was more alert, less isolated, and better groomed.
Once too sleepy to even eat breakfast, Mr. X began to participate in an exercise program, performing aerobic exercise including regular use of a treadmill, at a local gymnasium 3 days a week. This may have contributed to his loss of 20 pounds across 4 months. Over the next 6 months, the patient maintained his weight at 210 pounds, with a resultant BMI of 28.5. (He has lost slightly more weight since then.)
His socialization skills, while still far from mainstream levels, also improved. His mother began taking him to support group meetings at the local office of the National Alliance for the Mentally Ill (NAMI). There, he interacted with persons with schizophrenia and other psychiatric disorders.
During this time, his psychiatric condition remained stable, and his paranoia showed a mild improvement. Whereas Mr. X once required hospitalization every 6 months to 2 years, he has now been an outpatient for more than 2 years.
The modafinil dosage was titrated to 400 mg/d to further improve his negative symptoms and prevent antipsychotic-associated sedation. Mr. X has noted a continued increase in his alertness. He is still exercising, remains well groomed, and has begun taking vacations with his family. His mother, an active NAMI member, has continued to be his advocate and encourage his improvement.
Overall, we estimate that Mr. X is now functioning at about 65% of normal human capacity. When we began olanzapine with modafinil augmentation 2 years ago, he was functioning at barely one-half that level.
In your view, what should be the next step toward reintegration for Mr. X?
Drs. Yu’s and Maguire’s observations
The olanzapine/modafinil regimen brought about great improvement, but pharmacologic therapy only goes so far. As of this writing, Mr. X has never held a job or lived independently. Also, socialization beyond the family and NAMI support group meetings remains nonexistent.
Behavioral strategies may be just as important as medication treatment for patients with schizophrenia. We would consider behavioral therapy for Mr. X, employing token economies and social skills training to increase social abilities, self-sufficiency, practical skills, and interpersonal communication—skills that may further improve his negative symptoms and lessen the chance of relapse. Social skills training through the use of videotapes, role playing in therapy, and homework assignments to practice specific skills may allow Mr. X to improve his maladaptive behaviors.
Educating the patient and his family would help them understand what to expect in the course of his illness and can enhance treatment. NAMI is one useful referral source. NAMI and similar organizations offer emotional and practical advice about obtaining care in today’s complex health care delivery system.
A case manager also plays an invaluable role, ensuring that efforts are coordinated and that the patient keeps appointments and complies with treatment plans. The case manager may make home visits and even accompany the patient to work. The program’s success depends on the educational background, training, and qualifications of the case manager, which are variable.
Other behavioral strategies that could help Mr. X and other patients with schizophrenia include:
- Group therapy, which focuses on real-life plans, problems, and relationships. Group therapy effectively reduces social isolation, increases cohesiveness, and improves reality testing. Groups led in a supportive rather than interpretative manner appear to be most helpful in schizophrenia.
- Cognitive-behavioral therapy, which has been used in schizophrenia to improve cognitive distortions, reduce distractibility, and correct errors in judgment.
- Individual psychotherapy, which has been shown to effectively complement pharmacologic treatment.18
As patients’ symptoms improve, we as psychiatrists can help by encouraging them to gradually reintegrate into society, often by offering resources such as NAMI or referrals to appropriate rehabilitation programs.
We plan to continue Mr. X’s olanzapine/modafinil regimen to keep positive and negative symptoms at bay while improving his chances at reintegration. Careful monitoring of medications during reintegration is key to preventing relapse. We will continue to see Mr. X once a month.
Related resources
- National Alliance for the Mentally Ill. www.nami.org
- The Center for Reintegration. www.reintegration.com
- National Alliance for Research on Schizophrenia and Depression. www.mhsource.com/narsad/ or www.narsad.org
Drug brand names
- Clozapine • Clozaril
- Ephedrine • Rynatuss
- Haloperidol • Haldol
- Modafinil • Provigil
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Author affiliations
Benjamin P. Yu, MD
Resident physician
Gerald A. Maguire, MD
Assistant dean for continuing medical education, Director of residency training,
Associate clinical professor
Department of psychiatry and human behavior
University of California-Irvine Medical Center
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly & Co.
History: A long, losing battle
Mr. X, 41, has had schizophrenia, paranoid type, since age 24. Unable to work, keep house, or even groom himself, he has lived his entire life with his mother, his principal advocate and caretaker. He has been hospitalized 11 times for persecutory delusions, most recently 2 years ago at our medical center..
Numerous antipsychotics, including risperidone, haloperidol, quetiapine, clozapine, and thiothixene, did not work. He has responded best to olanzapine, but some mild paranoid symptoms and significant negative symptoms (alogia, anhedonia, amotivation, hypersomnia, restricted affect) persist.
He gained 30 pounds within 6 months after starting olanzapine. He was keeping his weight at 230 pounds and his body mass index (BMI) at 31.3. (A normal BMI is <25; a BMI >30 is considered obese.)
The patient was maintained on olanzapine 20 mg/d, but higher dosages caused oversedation. At the hospital, he would sleep through breakfast, get up late in the morning, then lie around until bedtime.
As an outpatient, he had no social contact outside the home. While hospitalized, Mr. X attended a therapy group on his ward, but never participated in the discussion. His speech was profoundly deficient; he never volunteered information and never responded to questions with anything more than a barely audible “yes” or “ no ”
How would you help Mr. X? Would you augment the olanzapine therapy or consider another antipsychotic, even one that failed the first time? Which negative symptom would you address first?
Drs. Yu’s and Maguire’s observations
Compared with the older antipsychotic agents, specifically haloperidol and thiothixene in this case, the newer antipsychotics (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) have demonstrated the ability to comprehensively treat schizophrenia.1-4 But these novel agents sometimes fail to remedy the negative symptoms. Thus, as is the case with Mr. X, many patients with schizophrenia whose positive symptoms are controlled realize little or no improvement in quality of life.
Olanzapine and risperidone have more effectively reduced the negative symptoms of schizophrenia than have the older antipsychotics,1-4 but—as we see with Mr. X—their record in treating negative symptoms is far from perfect. Additionally, sedation secondary to the antipsychotic may worsen the negative symptoms.
What’s more, the newer agents are associated with potential weight gain.5-7 Mr. X’s weight will need to be addressed, but with much caution. Many agents prescribed for weight loss, notably amphetamines, are avoided in psychotic patients because of the potential for abuse and worsening psychosis.8
Augmentation with modafinil, a wakefulness-promoting agent, is being considered for Mr. X. Although modafinil’s efficacy against obesity has not specifically been tested, studies have shown that this agent, which has actions similar to those of sympathomimetic agents, offers a lower abuse potential. Gold and Balster found that the medication was 250 times less potent than amphetamine and 15 times less potent than ephedrine in producing cocaine-like discriminative stimulus effects in rats.9 Single oral doses of modafinil did not cause elation or euphoria in healthy volunteers or those with substance abuse disorders.10,11 And compared with amphetamines, modafinil has a limited side-effect profile, with weak peripheral sympathomimetic activity and minimal effects on hemodynamics.12
Though it is best to minimize both the number of medications and the dosage for each patient, augmentation is still needed in some cases.13-15
Treatment augmentation: An agent is added
Mr. X’s olanzapine was increased to 30 mg/d. Modafinil, 100 mg/d, was then added to reduce the sedation associated with the higher olanzapine dosage.
Within a week, Mr. X’s negative symptoms had begun to improve. He started to speak more often and more clearly; his previously monotone voice exhibited a small degree of intonation and inflection. His fatigue decreased, and he was able to stay awake through breakfast and throughout the day.
That first week, he exhibited a brightened affect and more energy. He began to socialize to some extent with other patients in the hospital therapy group and was less isolated than before.
This slight but sudden improvement encouraged us. While he still showed slight paranoid ideations, he looked forward to a safe discharge and returning home to his family.
At this point, would you increase the dosage of either modafinil or olanzapine, or stay the course and monitor the patient’s improvement?
Drs. Yu’s and Maguire’s observations
Modafinil is a novel compound indicated for narcolepsy treatment. Though its precise mechanism is unknown, modafinil is neither a direct- nor indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity.16 Therefore, the agent’s pharmacologic profile may be favorable for off-label use in treating negative symptoms of schizophrenia. Modafinil also has been shown to be effective as an augmentation therapy in depression, especially with treating fatigue symptoms.17
Continued treatment: Improving symptoms
After 1 month, we increased Mr. X’s modafinil dosage to 200 mg/d and olanzapine to 40 mg/d. Both were well tolerated. No extrapyramidal symptoms were noted.
Over the next 4 months, his negative symptoms improved to the point where he had some concept of self-image. He was more alert, less isolated, and better groomed.
Once too sleepy to even eat breakfast, Mr. X began to participate in an exercise program, performing aerobic exercise including regular use of a treadmill, at a local gymnasium 3 days a week. This may have contributed to his loss of 20 pounds across 4 months. Over the next 6 months, the patient maintained his weight at 210 pounds, with a resultant BMI of 28.5. (He has lost slightly more weight since then.)
His socialization skills, while still far from mainstream levels, also improved. His mother began taking him to support group meetings at the local office of the National Alliance for the Mentally Ill (NAMI). There, he interacted with persons with schizophrenia and other psychiatric disorders.
During this time, his psychiatric condition remained stable, and his paranoia showed a mild improvement. Whereas Mr. X once required hospitalization every 6 months to 2 years, he has now been an outpatient for more than 2 years.
The modafinil dosage was titrated to 400 mg/d to further improve his negative symptoms and prevent antipsychotic-associated sedation. Mr. X has noted a continued increase in his alertness. He is still exercising, remains well groomed, and has begun taking vacations with his family. His mother, an active NAMI member, has continued to be his advocate and encourage his improvement.
Overall, we estimate that Mr. X is now functioning at about 65% of normal human capacity. When we began olanzapine with modafinil augmentation 2 years ago, he was functioning at barely one-half that level.
In your view, what should be the next step toward reintegration for Mr. X?
Drs. Yu’s and Maguire’s observations
The olanzapine/modafinil regimen brought about great improvement, but pharmacologic therapy only goes so far. As of this writing, Mr. X has never held a job or lived independently. Also, socialization beyond the family and NAMI support group meetings remains nonexistent.
Behavioral strategies may be just as important as medication treatment for patients with schizophrenia. We would consider behavioral therapy for Mr. X, employing token economies and social skills training to increase social abilities, self-sufficiency, practical skills, and interpersonal communication—skills that may further improve his negative symptoms and lessen the chance of relapse. Social skills training through the use of videotapes, role playing in therapy, and homework assignments to practice specific skills may allow Mr. X to improve his maladaptive behaviors.
Educating the patient and his family would help them understand what to expect in the course of his illness and can enhance treatment. NAMI is one useful referral source. NAMI and similar organizations offer emotional and practical advice about obtaining care in today’s complex health care delivery system.
A case manager also plays an invaluable role, ensuring that efforts are coordinated and that the patient keeps appointments and complies with treatment plans. The case manager may make home visits and even accompany the patient to work. The program’s success depends on the educational background, training, and qualifications of the case manager, which are variable.
Other behavioral strategies that could help Mr. X and other patients with schizophrenia include:
- Group therapy, which focuses on real-life plans, problems, and relationships. Group therapy effectively reduces social isolation, increases cohesiveness, and improves reality testing. Groups led in a supportive rather than interpretative manner appear to be most helpful in schizophrenia.
- Cognitive-behavioral therapy, which has been used in schizophrenia to improve cognitive distortions, reduce distractibility, and correct errors in judgment.
- Individual psychotherapy, which has been shown to effectively complement pharmacologic treatment.18
As patients’ symptoms improve, we as psychiatrists can help by encouraging them to gradually reintegrate into society, often by offering resources such as NAMI or referrals to appropriate rehabilitation programs.
We plan to continue Mr. X’s olanzapine/modafinil regimen to keep positive and negative symptoms at bay while improving his chances at reintegration. Careful monitoring of medications during reintegration is key to preventing relapse. We will continue to see Mr. X once a month.
Related resources
- National Alliance for the Mentally Ill. www.nami.org
- The Center for Reintegration. www.reintegration.com
- National Alliance for Research on Schizophrenia and Depression. www.mhsource.com/narsad/ or www.narsad.org
Drug brand names
- Clozapine • Clozaril
- Ephedrine • Rynatuss
- Haloperidol • Haldol
- Modafinil • Provigil
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Author affiliations
Benjamin P. Yu, MD
Resident physician
Gerald A. Maguire, MD
Assistant dean for continuing medical education, Director of residency training,
Associate clinical professor
Department of psychiatry and human behavior
University of California-Irvine Medical Center
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly & Co.
1. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538-46.
2. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42:233-46.
3. Tollefson GD, Sanger TM, Lu Y, et al. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 1998;55:250-8.
4. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
5. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60(6):358-63.
6. Beasley CM, Jr, Hamilton SH, Crawford AM, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7(2):125-37.
7. Blackburn GL. Weight gain and antipsychotic medication. J Clin Psychiatry 2000;61(suppl 8):36-41.
8. Gawin FH, Khalsa ME, Ellinwood E. Stimulants. In: Galanter M, Kleber HD, eds. The American Psychiatric Press textbook of substance abuse treatment. Washington, DC: American Psychiatric Press, 1994.
9. Gold LH, Balster RL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology (Berl) 1996;126(4):286-92.
10. Warot D, Coruble E, Payan C, et al. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 1993;8:201-8.
11. Duteil J, Rambert FA, Pessonnier J, et al. Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effects of modafinil: studies with experimental animals. Eur J Pharmacol 1990;180:49-58.
12. Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999;39:30-40.
13. Purdon SE. Cognitive improvement in schizophrenia with novel antipsychotic medications. Schizophr Res 1999;35(suppl):S51-S60.
14. Beasley CM, Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacol 1996;124(1-2):159-67.
15. Marder SR. Management of treatment-resistant patients with schizophrenia. J Clin Psychiatry 1996;57(suppl 11):26-30.
16. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
17. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61(5):378-81.
18. Maguire GA. CNS News. Supplement August 2001;6-10.
1. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538-46.
2. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42:233-46.
3. Tollefson GD, Sanger TM, Lu Y, et al. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 1998;55:250-8.
4. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
5. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60(6):358-63.
6. Beasley CM, Jr, Hamilton SH, Crawford AM, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7(2):125-37.
7. Blackburn GL. Weight gain and antipsychotic medication. J Clin Psychiatry 2000;61(suppl 8):36-41.
8. Gawin FH, Khalsa ME, Ellinwood E. Stimulants. In: Galanter M, Kleber HD, eds. The American Psychiatric Press textbook of substance abuse treatment. Washington, DC: American Psychiatric Press, 1994.
9. Gold LH, Balster RL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology (Berl) 1996;126(4):286-92.
10. Warot D, Coruble E, Payan C, et al. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 1993;8:201-8.
11. Duteil J, Rambert FA, Pessonnier J, et al. Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effects of modafinil: studies with experimental animals. Eur J Pharmacol 1990;180:49-58.
12. Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999;39:30-40.
13. Purdon SE. Cognitive improvement in schizophrenia with novel antipsychotic medications. Schizophr Res 1999;35(suppl):S51-S60.
14. Beasley CM, Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacol 1996;124(1-2):159-67.
15. Marder SR. Management of treatment-resistant patients with schizophrenia. J Clin Psychiatry 1996;57(suppl 11):26-30.
16. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
17. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61(5):378-81.
18. Maguire GA. CNS News. Supplement August 2001;6-10.
Can a wakefulness-promoting agent augment schizophrenia treatment?
History: A long, losing battle
Mr. X, 41, has had schizophrenia, paranoid type, since age 24. Unable to work, keep house, or even groom himself, he has lived his entire life with his mother, his principal advocate and caretaker. He has been hospitalized 11 times for persecutory delusions, most recently 2 years ago at our medical center..
Numerous antipsychotics, including risperidone, haloperidol, quetiapine, clozapine, and thiothixene, did not work. He has responded best to olanzapine, but some mild paranoid symptoms and significant negative symptoms (alogia, anhedonia, amotivation, hypersomnia, restricted affect) persist.
He gained 30 pounds within 6 months after starting olanzapine. He was keeping his weight at 230 pounds and his body mass index (BMI) at 31.3. (A normal BMI is <25; a BMI >30 is considered obese.)
The patient was maintained on olanzapine 20 mg/d, but higher dosages caused oversedation. At the hospital, he would sleep through breakfast, get up late in the morning, then lie around until bedtime.
As an outpatient, he had no social contact outside the home. While hospitalized, Mr. X attended a therapy group on his ward, but never participated in the discussion. His speech was profoundly deficient; he never volunteered information and never responded to questions with anything more than a barely audible “yes” or “ no ”
How would you help Mr. X? Would you augment the olanzapine therapy or consider another antipsychotic, even one that failed the first time? Which negative symptom would you address first?
Drs. Yu’s and Maguire’s observations
Compared with the older antipsychotic agents, specifically haloperidol and thiothixene in this case, the newer antipsychotics (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) have demonstrated the ability to comprehensively treat schizophrenia.1-4 But these novel agents sometimes fail to remedy the negative symptoms. Thus, as is the case with Mr. X, many patients with schizophrenia whose positive symptoms are controlled realize little or no improvement in quality of life.
Olanzapine and risperidone have more effectively reduced the negative symptoms of schizophrenia than have the older antipsychotics,1-4 but—as we see with Mr. X—their record in treating negative symptoms is far from perfect. Additionally, sedation secondary to the antipsychotic may worsen the negative symptoms.
What’s more, the newer agents are associated with potential weight gain.5-7 Mr. X’s weight will need to be addressed, but with much caution. Many agents prescribed for weight loss, notably amphetamines, are avoided in psychotic patients because of the potential for abuse and worsening psychosis.8
Augmentation with modafinil, a wakefulness-promoting agent, is being considered for Mr. X. Although modafinil’s efficacy against obesity has not specifically been tested, studies have shown that this agent, which has actions similar to those of sympathomimetic agents, offers a lower abuse potential. Gold and Balster found that the medication was 250 times less potent than amphetamine and 15 times less potent than ephedrine in producing cocaine-like discriminative stimulus effects in rats.9 Single oral doses of modafinil did not cause elation or euphoria in healthy volunteers or those with substance abuse disorders.10,11 And compared with amphetamines, modafinil has a limited side-effect profile, with weak peripheral sympathomimetic activity and minimal effects on hemodynamics.12
Though it is best to minimize both the number of medications and the dosage for each patient, augmentation is still needed in some cases.13-15
Treatment augmentation: An agent is added
Mr. X’s olanzapine was increased to 30 mg/d. Modafinil, 100 mg/d, was then added to reduce the sedation associated with the higher olanzapine dosage.
Within a week, Mr. X’s negative symptoms had begun to improve. He started to speak more often and more clearly; his previously monotone voice exhibited a small degree of intonation and inflection. His fatigue decreased, and he was able to stay awake through breakfast and throughout the day.
That first week, he exhibited a brightened affect and more energy. He began to socialize to some extent with other patients in the hospital therapy group and was less isolated than before.
This slight but sudden improvement encouraged us. While he still showed slight paranoid ideations, he looked forward to a safe discharge and returning home to his family.
At this point, would you increase the dosage of either modafinil or olanzapine, or stay the course and monitor the patient’s improvement?
Drs. Yu’s and Maguire’s observations
Modafinil is a novel compound indicated for narcolepsy treatment. Though its precise mechanism is unknown, modafinil is neither a direct- nor indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity.16 Therefore, the agent’s pharmacologic profile may be favorable for off-label use in treating negative symptoms of schizophrenia. Modafinil also has been shown to be effective as an augmentation therapy in depression, especially with treating fatigue symptoms.17
Continued treatment: Improving symptoms
After 1 month, we increased Mr. X’s modafinil dosage to 200 mg/d and olanzapine to 40 mg/d. Both were well tolerated. No extrapyramidal symptoms were noted.
Over the next 4 months, his negative symptoms improved to the point where he had some concept of self-image. He was more alert, less isolated, and better groomed.
Once too sleepy to even eat breakfast, Mr. X began to participate in an exercise program, performing aerobic exercise including regular use of a treadmill, at a local gymnasium 3 days a week. This may have contributed to his loss of 20 pounds across 4 months. Over the next 6 months, the patient maintained his weight at 210 pounds, with a resultant BMI of 28.5. (He has lost slightly more weight since then.)
His socialization skills, while still far from mainstream levels, also improved. His mother began taking him to support group meetings at the local office of the National Alliance for the Mentally Ill (NAMI). There, he interacted with persons with schizophrenia and other psychiatric disorders.
During this time, his psychiatric condition remained stable, and his paranoia showed a mild improvement. Whereas Mr. X once required hospitalization every 6 months to 2 years, he has now been an outpatient for more than 2 years.
The modafinil dosage was titrated to 400 mg/d to further improve his negative symptoms and prevent antipsychotic-associated sedation. Mr. X has noted a continued increase in his alertness. He is still exercising, remains well groomed, and has begun taking vacations with his family. His mother, an active NAMI member, has continued to be his advocate and encourage his improvement.
Overall, we estimate that Mr. X is now functioning at about 65% of normal human capacity. When we began olanzapine with modafinil augmentation 2 years ago, he was functioning at barely one-half that level.
In your view, what should be the next step toward reintegration for Mr. X?
Drs. Yu’s and Maguire’s observations
The olanzapine/modafinil regimen brought about great improvement, but pharmacologic therapy only goes so far. As of this writing, Mr. X has never held a job or lived independently. Also, socialization beyond the family and NAMI support group meetings remains nonexistent.
Behavioral strategies may be just as important as medication treatment for patients with schizophrenia. We would consider behavioral therapy for Mr. X, employing token economies and social skills training to increase social abilities, self-sufficiency, practical skills, and interpersonal communication—skills that may further improve his negative symptoms and lessen the chance of relapse. Social skills training through the use of videotapes, role playing in therapy, and homework assignments to practice specific skills may allow Mr. X to improve his maladaptive behaviors.
Educating the patient and his family would help them understand what to expect in the course of his illness and can enhance treatment. NAMI is one useful referral source. NAMI and similar organizations offer emotional and practical advice about obtaining care in today’s complex health care delivery system.
A case manager also plays an invaluable role, ensuring that efforts are coordinated and that the patient keeps appointments and complies with treatment plans. The case manager may make home visits and even accompany the patient to work. The program’s success depends on the educational background, training, and qualifications of the case manager, which are variable.
Other behavioral strategies that could help Mr. X and other patients with schizophrenia include:
- Group therapy, which focuses on real-life plans, problems, and relationships. Group therapy effectively reduces social isolation, increases cohesiveness, and improves reality testing. Groups led in a supportive rather than interpretative manner appear to be most helpful in schizophrenia.
- Cognitive-behavioral therapy, which has been used in schizophrenia to improve cognitive distortions, reduce distractibility, and correct errors in judgment.
- Individual psychotherapy, which has been shown to effectively complement pharmacologic treatment.18
As patients’ symptoms improve, we as psychiatrists can help by encouraging them to gradually reintegrate into society, often by offering resources such as NAMI or referrals to appropriate rehabilitation programs.
We plan to continue Mr. X’s olanzapine/modafinil regimen to keep positive and negative symptoms at bay while improving his chances at reintegration. Careful monitoring of medications during reintegration is key to preventing relapse. We will continue to see Mr. X once a month.
Related resources
- National Alliance for the Mentally Ill. www.nami.org
- The Center for Reintegration. www.reintegration.com
- National Alliance for Research on Schizophrenia and Depression. www.mhsource.com/narsad/ or www.narsad.org
Drug brand names
- Clozapine • Clozaril
- Ephedrine • Rynatuss
- Haloperidol • Haldol
- Modafinil • Provigil
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Author affiliations
Benjamin P. Yu, MD
Resident physician
Gerald A. Maguire, MD
Assistant dean for continuing medical education, Director of residency training,
Associate clinical professor
Department of psychiatry and human behavior
University of California-Irvine Medical Center
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly & Co.
1. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538-46.
2. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42:233-46.
3. Tollefson GD, Sanger TM, Lu Y, et al. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 1998;55:250-8.
4. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
5. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60(6):358-63.
6. Beasley CM, Jr, Hamilton SH, Crawford AM, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7(2):125-37.
7. Blackburn GL. Weight gain and antipsychotic medication. J Clin Psychiatry 2000;61(suppl 8):36-41.
8. Gawin FH, Khalsa ME, Ellinwood E. Stimulants. In: Galanter M, Kleber HD, eds. The American Psychiatric Press textbook of substance abuse treatment. Washington, DC: American Psychiatric Press, 1994.
9. Gold LH, Balster RL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology (Berl) 1996;126(4):286-92.
10. Warot D, Coruble E, Payan C, et al. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 1993;8:201-8.
11. Duteil J, Rambert FA, Pessonnier J, et al. Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effects of modafinil: studies with experimental animals. Eur J Pharmacol 1990;180:49-58.
12. Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999;39:30-40.
13. Purdon SE. Cognitive improvement in schizophrenia with novel antipsychotic medications. Schizophr Res 1999;35(suppl):S51-S60.
14. Beasley CM, Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacol 1996;124(1-2):159-67.
15. Marder SR. Management of treatment-resistant patients with schizophrenia. J Clin Psychiatry 1996;57(suppl 11):26-30.
16. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
17. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61(5):378-81.
18. Maguire GA. CNS News. Supplement August 2001;6-10.
History: A long, losing battle
Mr. X, 41, has had schizophrenia, paranoid type, since age 24. Unable to work, keep house, or even groom himself, he has lived his entire life with his mother, his principal advocate and caretaker. He has been hospitalized 11 times for persecutory delusions, most recently 2 years ago at our medical center..
Numerous antipsychotics, including risperidone, haloperidol, quetiapine, clozapine, and thiothixene, did not work. He has responded best to olanzapine, but some mild paranoid symptoms and significant negative symptoms (alogia, anhedonia, amotivation, hypersomnia, restricted affect) persist.
He gained 30 pounds within 6 months after starting olanzapine. He was keeping his weight at 230 pounds and his body mass index (BMI) at 31.3. (A normal BMI is <25; a BMI >30 is considered obese.)
The patient was maintained on olanzapine 20 mg/d, but higher dosages caused oversedation. At the hospital, he would sleep through breakfast, get up late in the morning, then lie around until bedtime.
As an outpatient, he had no social contact outside the home. While hospitalized, Mr. X attended a therapy group on his ward, but never participated in the discussion. His speech was profoundly deficient; he never volunteered information and never responded to questions with anything more than a barely audible “yes” or “ no ”
How would you help Mr. X? Would you augment the olanzapine therapy or consider another antipsychotic, even one that failed the first time? Which negative symptom would you address first?
Drs. Yu’s and Maguire’s observations
Compared with the older antipsychotic agents, specifically haloperidol and thiothixene in this case, the newer antipsychotics (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) have demonstrated the ability to comprehensively treat schizophrenia.1-4 But these novel agents sometimes fail to remedy the negative symptoms. Thus, as is the case with Mr. X, many patients with schizophrenia whose positive symptoms are controlled realize little or no improvement in quality of life.
Olanzapine and risperidone have more effectively reduced the negative symptoms of schizophrenia than have the older antipsychotics,1-4 but—as we see with Mr. X—their record in treating negative symptoms is far from perfect. Additionally, sedation secondary to the antipsychotic may worsen the negative symptoms.
What’s more, the newer agents are associated with potential weight gain.5-7 Mr. X’s weight will need to be addressed, but with much caution. Many agents prescribed for weight loss, notably amphetamines, are avoided in psychotic patients because of the potential for abuse and worsening psychosis.8
Augmentation with modafinil, a wakefulness-promoting agent, is being considered for Mr. X. Although modafinil’s efficacy against obesity has not specifically been tested, studies have shown that this agent, which has actions similar to those of sympathomimetic agents, offers a lower abuse potential. Gold and Balster found that the medication was 250 times less potent than amphetamine and 15 times less potent than ephedrine in producing cocaine-like discriminative stimulus effects in rats.9 Single oral doses of modafinil did not cause elation or euphoria in healthy volunteers or those with substance abuse disorders.10,11 And compared with amphetamines, modafinil has a limited side-effect profile, with weak peripheral sympathomimetic activity and minimal effects on hemodynamics.12
Though it is best to minimize both the number of medications and the dosage for each patient, augmentation is still needed in some cases.13-15
Treatment augmentation: An agent is added
Mr. X’s olanzapine was increased to 30 mg/d. Modafinil, 100 mg/d, was then added to reduce the sedation associated with the higher olanzapine dosage.
Within a week, Mr. X’s negative symptoms had begun to improve. He started to speak more often and more clearly; his previously monotone voice exhibited a small degree of intonation and inflection. His fatigue decreased, and he was able to stay awake through breakfast and throughout the day.
That first week, he exhibited a brightened affect and more energy. He began to socialize to some extent with other patients in the hospital therapy group and was less isolated than before.
This slight but sudden improvement encouraged us. While he still showed slight paranoid ideations, he looked forward to a safe discharge and returning home to his family.
At this point, would you increase the dosage of either modafinil or olanzapine, or stay the course and monitor the patient’s improvement?
Drs. Yu’s and Maguire’s observations
Modafinil is a novel compound indicated for narcolepsy treatment. Though its precise mechanism is unknown, modafinil is neither a direct- nor indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity.16 Therefore, the agent’s pharmacologic profile may be favorable for off-label use in treating negative symptoms of schizophrenia. Modafinil also has been shown to be effective as an augmentation therapy in depression, especially with treating fatigue symptoms.17
Continued treatment: Improving symptoms
After 1 month, we increased Mr. X’s modafinil dosage to 200 mg/d and olanzapine to 40 mg/d. Both were well tolerated. No extrapyramidal symptoms were noted.
Over the next 4 months, his negative symptoms improved to the point where he had some concept of self-image. He was more alert, less isolated, and better groomed.
Once too sleepy to even eat breakfast, Mr. X began to participate in an exercise program, performing aerobic exercise including regular use of a treadmill, at a local gymnasium 3 days a week. This may have contributed to his loss of 20 pounds across 4 months. Over the next 6 months, the patient maintained his weight at 210 pounds, with a resultant BMI of 28.5. (He has lost slightly more weight since then.)
His socialization skills, while still far from mainstream levels, also improved. His mother began taking him to support group meetings at the local office of the National Alliance for the Mentally Ill (NAMI). There, he interacted with persons with schizophrenia and other psychiatric disorders.
During this time, his psychiatric condition remained stable, and his paranoia showed a mild improvement. Whereas Mr. X once required hospitalization every 6 months to 2 years, he has now been an outpatient for more than 2 years.
The modafinil dosage was titrated to 400 mg/d to further improve his negative symptoms and prevent antipsychotic-associated sedation. Mr. X has noted a continued increase in his alertness. He is still exercising, remains well groomed, and has begun taking vacations with his family. His mother, an active NAMI member, has continued to be his advocate and encourage his improvement.
Overall, we estimate that Mr. X is now functioning at about 65% of normal human capacity. When we began olanzapine with modafinil augmentation 2 years ago, he was functioning at barely one-half that level.
In your view, what should be the next step toward reintegration for Mr. X?
Drs. Yu’s and Maguire’s observations
The olanzapine/modafinil regimen brought about great improvement, but pharmacologic therapy only goes so far. As of this writing, Mr. X has never held a job or lived independently. Also, socialization beyond the family and NAMI support group meetings remains nonexistent.
Behavioral strategies may be just as important as medication treatment for patients with schizophrenia. We would consider behavioral therapy for Mr. X, employing token economies and social skills training to increase social abilities, self-sufficiency, practical skills, and interpersonal communication—skills that may further improve his negative symptoms and lessen the chance of relapse. Social skills training through the use of videotapes, role playing in therapy, and homework assignments to practice specific skills may allow Mr. X to improve his maladaptive behaviors.
Educating the patient and his family would help them understand what to expect in the course of his illness and can enhance treatment. NAMI is one useful referral source. NAMI and similar organizations offer emotional and practical advice about obtaining care in today’s complex health care delivery system.
A case manager also plays an invaluable role, ensuring that efforts are coordinated and that the patient keeps appointments and complies with treatment plans. The case manager may make home visits and even accompany the patient to work. The program’s success depends on the educational background, training, and qualifications of the case manager, which are variable.
Other behavioral strategies that could help Mr. X and other patients with schizophrenia include:
- Group therapy, which focuses on real-life plans, problems, and relationships. Group therapy effectively reduces social isolation, increases cohesiveness, and improves reality testing. Groups led in a supportive rather than interpretative manner appear to be most helpful in schizophrenia.
- Cognitive-behavioral therapy, which has been used in schizophrenia to improve cognitive distortions, reduce distractibility, and correct errors in judgment.
- Individual psychotherapy, which has been shown to effectively complement pharmacologic treatment.18
As patients’ symptoms improve, we as psychiatrists can help by encouraging them to gradually reintegrate into society, often by offering resources such as NAMI or referrals to appropriate rehabilitation programs.
We plan to continue Mr. X’s olanzapine/modafinil regimen to keep positive and negative symptoms at bay while improving his chances at reintegration. Careful monitoring of medications during reintegration is key to preventing relapse. We will continue to see Mr. X once a month.
Related resources
- National Alliance for the Mentally Ill. www.nami.org
- The Center for Reintegration. www.reintegration.com
- National Alliance for Research on Schizophrenia and Depression. www.mhsource.com/narsad/ or www.narsad.org
Drug brand names
- Clozapine • Clozaril
- Ephedrine • Rynatuss
- Haloperidol • Haldol
- Modafinil • Provigil
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Author affiliations
Benjamin P. Yu, MD
Resident physician
Gerald A. Maguire, MD
Assistant dean for continuing medical education, Director of residency training,
Associate clinical professor
Department of psychiatry and human behavior
University of California-Irvine Medical Center
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly & Co.
History: A long, losing battle
Mr. X, 41, has had schizophrenia, paranoid type, since age 24. Unable to work, keep house, or even groom himself, he has lived his entire life with his mother, his principal advocate and caretaker. He has been hospitalized 11 times for persecutory delusions, most recently 2 years ago at our medical center..
Numerous antipsychotics, including risperidone, haloperidol, quetiapine, clozapine, and thiothixene, did not work. He has responded best to olanzapine, but some mild paranoid symptoms and significant negative symptoms (alogia, anhedonia, amotivation, hypersomnia, restricted affect) persist.
He gained 30 pounds within 6 months after starting olanzapine. He was keeping his weight at 230 pounds and his body mass index (BMI) at 31.3. (A normal BMI is <25; a BMI >30 is considered obese.)
The patient was maintained on olanzapine 20 mg/d, but higher dosages caused oversedation. At the hospital, he would sleep through breakfast, get up late in the morning, then lie around until bedtime.
As an outpatient, he had no social contact outside the home. While hospitalized, Mr. X attended a therapy group on his ward, but never participated in the discussion. His speech was profoundly deficient; he never volunteered information and never responded to questions with anything more than a barely audible “yes” or “ no ”
How would you help Mr. X? Would you augment the olanzapine therapy or consider another antipsychotic, even one that failed the first time? Which negative symptom would you address first?
Drs. Yu’s and Maguire’s observations
Compared with the older antipsychotic agents, specifically haloperidol and thiothixene in this case, the newer antipsychotics (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) have demonstrated the ability to comprehensively treat schizophrenia.1-4 But these novel agents sometimes fail to remedy the negative symptoms. Thus, as is the case with Mr. X, many patients with schizophrenia whose positive symptoms are controlled realize little or no improvement in quality of life.
Olanzapine and risperidone have more effectively reduced the negative symptoms of schizophrenia than have the older antipsychotics,1-4 but—as we see with Mr. X—their record in treating negative symptoms is far from perfect. Additionally, sedation secondary to the antipsychotic may worsen the negative symptoms.
What’s more, the newer agents are associated with potential weight gain.5-7 Mr. X’s weight will need to be addressed, but with much caution. Many agents prescribed for weight loss, notably amphetamines, are avoided in psychotic patients because of the potential for abuse and worsening psychosis.8
Augmentation with modafinil, a wakefulness-promoting agent, is being considered for Mr. X. Although modafinil’s efficacy against obesity has not specifically been tested, studies have shown that this agent, which has actions similar to those of sympathomimetic agents, offers a lower abuse potential. Gold and Balster found that the medication was 250 times less potent than amphetamine and 15 times less potent than ephedrine in producing cocaine-like discriminative stimulus effects in rats.9 Single oral doses of modafinil did not cause elation or euphoria in healthy volunteers or those with substance abuse disorders.10,11 And compared with amphetamines, modafinil has a limited side-effect profile, with weak peripheral sympathomimetic activity and minimal effects on hemodynamics.12
Though it is best to minimize both the number of medications and the dosage for each patient, augmentation is still needed in some cases.13-15
Treatment augmentation: An agent is added
Mr. X’s olanzapine was increased to 30 mg/d. Modafinil, 100 mg/d, was then added to reduce the sedation associated with the higher olanzapine dosage.
Within a week, Mr. X’s negative symptoms had begun to improve. He started to speak more often and more clearly; his previously monotone voice exhibited a small degree of intonation and inflection. His fatigue decreased, and he was able to stay awake through breakfast and throughout the day.
That first week, he exhibited a brightened affect and more energy. He began to socialize to some extent with other patients in the hospital therapy group and was less isolated than before.
This slight but sudden improvement encouraged us. While he still showed slight paranoid ideations, he looked forward to a safe discharge and returning home to his family.
At this point, would you increase the dosage of either modafinil or olanzapine, or stay the course and monitor the patient’s improvement?
Drs. Yu’s and Maguire’s observations
Modafinil is a novel compound indicated for narcolepsy treatment. Though its precise mechanism is unknown, modafinil is neither a direct- nor indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity.16 Therefore, the agent’s pharmacologic profile may be favorable for off-label use in treating negative symptoms of schizophrenia. Modafinil also has been shown to be effective as an augmentation therapy in depression, especially with treating fatigue symptoms.17
Continued treatment: Improving symptoms
After 1 month, we increased Mr. X’s modafinil dosage to 200 mg/d and olanzapine to 40 mg/d. Both were well tolerated. No extrapyramidal symptoms were noted.
Over the next 4 months, his negative symptoms improved to the point where he had some concept of self-image. He was more alert, less isolated, and better groomed.
Once too sleepy to even eat breakfast, Mr. X began to participate in an exercise program, performing aerobic exercise including regular use of a treadmill, at a local gymnasium 3 days a week. This may have contributed to his loss of 20 pounds across 4 months. Over the next 6 months, the patient maintained his weight at 210 pounds, with a resultant BMI of 28.5. (He has lost slightly more weight since then.)
His socialization skills, while still far from mainstream levels, also improved. His mother began taking him to support group meetings at the local office of the National Alliance for the Mentally Ill (NAMI). There, he interacted with persons with schizophrenia and other psychiatric disorders.
During this time, his psychiatric condition remained stable, and his paranoia showed a mild improvement. Whereas Mr. X once required hospitalization every 6 months to 2 years, he has now been an outpatient for more than 2 years.
The modafinil dosage was titrated to 400 mg/d to further improve his negative symptoms and prevent antipsychotic-associated sedation. Mr. X has noted a continued increase in his alertness. He is still exercising, remains well groomed, and has begun taking vacations with his family. His mother, an active NAMI member, has continued to be his advocate and encourage his improvement.
Overall, we estimate that Mr. X is now functioning at about 65% of normal human capacity. When we began olanzapine with modafinil augmentation 2 years ago, he was functioning at barely one-half that level.
In your view, what should be the next step toward reintegration for Mr. X?
Drs. Yu’s and Maguire’s observations
The olanzapine/modafinil regimen brought about great improvement, but pharmacologic therapy only goes so far. As of this writing, Mr. X has never held a job or lived independently. Also, socialization beyond the family and NAMI support group meetings remains nonexistent.
Behavioral strategies may be just as important as medication treatment for patients with schizophrenia. We would consider behavioral therapy for Mr. X, employing token economies and social skills training to increase social abilities, self-sufficiency, practical skills, and interpersonal communication—skills that may further improve his negative symptoms and lessen the chance of relapse. Social skills training through the use of videotapes, role playing in therapy, and homework assignments to practice specific skills may allow Mr. X to improve his maladaptive behaviors.
Educating the patient and his family would help them understand what to expect in the course of his illness and can enhance treatment. NAMI is one useful referral source. NAMI and similar organizations offer emotional and practical advice about obtaining care in today’s complex health care delivery system.
A case manager also plays an invaluable role, ensuring that efforts are coordinated and that the patient keeps appointments and complies with treatment plans. The case manager may make home visits and even accompany the patient to work. The program’s success depends on the educational background, training, and qualifications of the case manager, which are variable.
Other behavioral strategies that could help Mr. X and other patients with schizophrenia include:
- Group therapy, which focuses on real-life plans, problems, and relationships. Group therapy effectively reduces social isolation, increases cohesiveness, and improves reality testing. Groups led in a supportive rather than interpretative manner appear to be most helpful in schizophrenia.
- Cognitive-behavioral therapy, which has been used in schizophrenia to improve cognitive distortions, reduce distractibility, and correct errors in judgment.
- Individual psychotherapy, which has been shown to effectively complement pharmacologic treatment.18
As patients’ symptoms improve, we as psychiatrists can help by encouraging them to gradually reintegrate into society, often by offering resources such as NAMI or referrals to appropriate rehabilitation programs.
We plan to continue Mr. X’s olanzapine/modafinil regimen to keep positive and negative symptoms at bay while improving his chances at reintegration. Careful monitoring of medications during reintegration is key to preventing relapse. We will continue to see Mr. X once a month.
Related resources
- National Alliance for the Mentally Ill. www.nami.org
- The Center for Reintegration. www.reintegration.com
- National Alliance for Research on Schizophrenia and Depression. www.mhsource.com/narsad/ or www.narsad.org
Drug brand names
- Clozapine • Clozaril
- Ephedrine • Rynatuss
- Haloperidol • Haldol
- Modafinil • Provigil
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Author affiliations
Benjamin P. Yu, MD
Resident physician
Gerald A. Maguire, MD
Assistant dean for continuing medical education, Director of residency training,
Associate clinical professor
Department of psychiatry and human behavior
University of California-Irvine Medical Center
Disclosure
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly & Co.
1. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538-46.
2. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42:233-46.
3. Tollefson GD, Sanger TM, Lu Y, et al. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 1998;55:250-8.
4. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
5. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60(6):358-63.
6. Beasley CM, Jr, Hamilton SH, Crawford AM, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7(2):125-37.
7. Blackburn GL. Weight gain and antipsychotic medication. J Clin Psychiatry 2000;61(suppl 8):36-41.
8. Gawin FH, Khalsa ME, Ellinwood E. Stimulants. In: Galanter M, Kleber HD, eds. The American Psychiatric Press textbook of substance abuse treatment. Washington, DC: American Psychiatric Press, 1994.
9. Gold LH, Balster RL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology (Berl) 1996;126(4):286-92.
10. Warot D, Coruble E, Payan C, et al. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 1993;8:201-8.
11. Duteil J, Rambert FA, Pessonnier J, et al. Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effects of modafinil: studies with experimental animals. Eur J Pharmacol 1990;180:49-58.
12. Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999;39:30-40.
13. Purdon SE. Cognitive improvement in schizophrenia with novel antipsychotic medications. Schizophr Res 1999;35(suppl):S51-S60.
14. Beasley CM, Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacol 1996;124(1-2):159-67.
15. Marder SR. Management of treatment-resistant patients with schizophrenia. J Clin Psychiatry 1996;57(suppl 11):26-30.
16. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
17. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61(5):378-81.
18. Maguire GA. CNS News. Supplement August 2001;6-10.
1. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538-46.
2. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42:233-46.
3. Tollefson GD, Sanger TM, Lu Y, et al. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 1998;55:250-8.
4. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
5. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60(6):358-63.
6. Beasley CM, Jr, Hamilton SH, Crawford AM, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7(2):125-37.
7. Blackburn GL. Weight gain and antipsychotic medication. J Clin Psychiatry 2000;61(suppl 8):36-41.
8. Gawin FH, Khalsa ME, Ellinwood E. Stimulants. In: Galanter M, Kleber HD, eds. The American Psychiatric Press textbook of substance abuse treatment. Washington, DC: American Psychiatric Press, 1994.
9. Gold LH, Balster RL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology (Berl) 1996;126(4):286-92.
10. Warot D, Coruble E, Payan C, et al. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry 1993;8:201-8.
11. Duteil J, Rambert FA, Pessonnier J, et al. Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effects of modafinil: studies with experimental animals. Eur J Pharmacol 1990;180:49-58.
12. Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999;39:30-40.
13. Purdon SE. Cognitive improvement in schizophrenia with novel antipsychotic medications. Schizophr Res 1999;35(suppl):S51-S60.
14. Beasley CM, Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacol 1996;124(1-2):159-67.
15. Marder SR. Management of treatment-resistant patients with schizophrenia. J Clin Psychiatry 1996;57(suppl 11):26-30.
16. Physician’s Desk Reference (55th ed). Montvale, NJ: Medical Economics, 2001.
17. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61(5):378-81.
18. Maguire GA. CNS News. Supplement August 2001;6-10.
New therapies can help patients who stŭťtər
Despite its prevalence, stuttering has not received as much attention as other psychiatric disorders from patients or psychiatrists—with good reason. Until recently, little was known about the neurophysiology of stuttering, and treatment was generally ineffective especially in adults (Box 1). Despite their own personal struggles with the disorder, patients have questioned the need for psychiatric treatment.
That has now changed. We know now that stuttering is likely a disorder of brain chemistry. Studies suggests that olanzapine, a novel dopamine antagonist, is a useful, well-tolerated medication for the treatment of stuttering. As a result, psychiatrists are now equipped to play an important role in its management.
Furthermore, we can give patients the therapeutic opportunity to discuss what often has been a lifetime of frustration with stuttering. We can enable them to understand the course and treatment of this disorder and encourage them to take advantage of the opportunities to lessen the symptoms of stuttering and, ultimately, improve their quality of life.
How stuttering develops
Stuttering is a speech disorder characterized by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables. A common disorder affecting 1% of adults and 4% of children, stuttering is classified in DSM-IV as an Axis I disorder (Box 2).1
Stuttering has occurred throughout history, with descriptions from the ancient Egyptians and Greeks. For centuries, theories on its etiology involved abnormalities in the tongue or larynx, and the treatments addressed such ideology. Even today, some stuttering treatments involve such archaic methods as cauterizing or cutting the tongue. Treatments focused on the tongue or larynx have not demonstrated consistent efficacy.
The pioneering work of Orton21 and Travis22 signaled a significant change in the understanding of stuttering. They postulated that stuttering may arise from abnormal cerebral activity, signaling a significant change in the theories of the etiology of stuttering. Unfortunately, stuttering treatments did not reflect this new understanding until fairly recently.
Psychoanalytic theorists believed that stuttering arose from the individual’s attempt to fulfill some type of unconscious neurotic need, usually resulting from disturbed early parent-child interaction.23 Psychoanalytic therapy was largely ineffective, however.
Most stuttering treatment practiced today involves speech therapy utilizing cognitive and behavioral methods. Such methods are often limited in their efficacy, especially in adults.24 Some forms of therapy involving speech motor training have been shown effective in young children while the brain is still in development.25 The pharmacologic treatment of stuttering is not widespread today, but new and recent research identifying certain cerebral abnormalities is providing clues for pharmacologic interventions.
Stuttering usually begins in childhood and is likely a developmental disorder. Rare cases of acquired stuttering begin in adulthood but are related to secondary causes such as medications, brain trauma, or stroke.3 Some 80% to 90% of developmental stuttering begins by age 6; onset after age 9 is likely to have some psychogenic or neurogenic basis.4 In approximately 60% of the children who stutter, the symptoms will remit by age 16. Children who stutter require early intervention, given the importance of communication in a child’s development.5
Stuttering shares many similarities with Tourette syndrome. Both begin in childhood, follow a waxing or waning course, have a 4:1 male-to-female ratio, are made worse by anxiety, involve abnormalities in the basal ganglia, and respond to dopamine antagonist therapy.6 Persons who stutter often exhibit tic motions, similar to those seen in Tourette syndrome, which are associated with the struggles to produce speech. Genetic studies have shown possible high additive genetic effects; pair-wise concordance for stuttering was significantly higher in identical twins (63%) than it was in fraternal same-sex twins (19%).7,8 Researchers are investigating potential molecular genetic markers for stuttering.
Functional brain imaging studies suggest that stuttering is associated with abnormal cerebral activation primarily involving abnormally low metabolism of the cortical speech areas and the striatum. The defects in stuttering occur primarily in the timing and initiation of spontaneous speech, with such tasks as singing and reading in chorus being spared. A clue to understanding stuttering lies with these “induced fluency” tasks.
Functional positron emission tomography studies utilizing18 F-deoxyglucose showed that stuttering is associated with abnormally low metabolism of speech cortical areas (Wernicke’s and Broca’s) and low metabolism of the basal ganglia, notably the striatum. During the induced fluency, Wernicke’s and Broca’s areas normalize but the striatum remains abnormally low.
Riley postulates two “loops” of speech, an inner or medial system and an outer or lateral system.9 The lateral system is preserved in stuttering and can be activated through singing, rhythmic speech, etc., but the inner loop, as mediated by the striatum and influenced by dopamine, remains impaired. Once a person who stutters initiates speech, he or she often avoids taking a breath as the whole system must again be jump-started. The low striatal metabolism may be the common-state phenomenon underlying this timing.
- Disturbance in normal fluency and time patterning of speech (inappropriate for the individual’s age), characterized by frequent occurrences of one or more of the following:
- Sound and syllable repetitions
- Sound prolongations
- Interjections
- Broken words (e.g., pauses within a word)
- Audible or silent blocking (filled or unfilled pauses in speech)
- Circumlocutions (word substitutions to avoid problematic words)
- Words produced with an excess of physical tension
- Monosyllabic whole-word repetitions (e.g., “I-I-I-I see him”)
- Sound and syllable repetitions
- The disturbance in fluency interferes with academic or occupational achievement or with social communications
- If a speech-motor or sensory deficit is present, the speech difficulties are in excess of those usually associated with these problems.
Coding note: If a speech-motor or sensory deficit or a neurological condition is present, code the condition on Axis III.
The dopamine hypothesis of stuttering
Stuttering is likely related to abnormal elevations of cerebral dopamine activity. Stimulant medications, which increase dopamine activity, have been shown to increase stuttering symptoms.10 As will be reviewed later, dopamine antagonist medications have been shown to improve the symptoms of stuttering. Also, the striatal hypometabolism in stuttering seen in PET imaging may be a result of a hyperdopaminergic state.
To investigate this dopamine hypothesis of stuttering, Wu et al measured presynaptic dopamine levels in individuals who stutter.11 These were found to have 50% to 200% higher levels of dopamine activity than did the controls. Dopamine is inhibitory to striatal metabolism, providing an explanation for the striatal hypometabolism seen in stuttering. Also, risperidone was found to increase striatal metabolism in those whose stuttering improved on this medication.12
Evaluating the patient
One should begin with a comprehensive psychiatric history. Because many patients began stuttering in childhood and have had difficulty dealing with their disorder, other psychiatric disorders such as social phobia may be present. Moreover, other medical etiologies (e.g., stroke) may cause a speech disorder that resembles stuttering.
Stuttering involves abnormalities in fluency as well as tic motions and cognitive avoidances. Inquiries should be made as to the patient’s fluency of speech during work, during introductions, speaking in front of an audience, with family, etc.; the level of stuttering can vary depending on the particular environment.
Stuttering fluency can be rated through an objective scale known as the Riley SSI-3.13 This scale measures the duration of each stuttering event, the percentage of syllables stuttered versus syllables spoken, the severity of associated tic motions, and a global score of the aforementioned components. Because most psychiatrists cannot routinely perform this scale to assess the patient’s progress, it is best to partner with a speech-language pathologist who can also assist the patient through speech therapy.
Nonetheless, you may assess the progress of treatment by relying on your own “ear,” the patient’s own assessment, and the input of a significant other or family member.
In addition to considering DSM-IV criteria, comprehensive treatment should address all aspects of this disorder, including not only the fluency enhancement but improvement in social avoidances and cognitive restructuring. Be aware that stuttering waxes and wanes over time. You should expect to see some “dips” in efficacy during the course of therapy. A longitudinal assessment over several months is needed to determine if the stuttering treatment is efficacious.
What we’ve learned about drug therapy
Many medications have been tried to treat stuttering but few have shown efficacy in well-controlled trials. Most pharmacologic studies did not include a placebo control or employ objective measures of stuttering severity, nor did they provide multiple baseline and treatment measures.
The critical new knowledge is this: Medications that lower dopamine activity have shown replicated efficacy in improving stuttering. The benzodiazepines have been shown to reduce anxiety short-term but have not been shown to improve fluency in stuttering. Limited studies of serotonergic antidepressants suggest a possible role in reducing the social anxiety of stuttering but have not been shown in well-controlled trials to improve stuttering fluency directly.
Multiple studies of haloperidol in the 1970s showed that this medication improved fluency in individuals who stutter. Long-term compliance with this medication, however, was poor given its dysphoric side effects, sexual dysfunction, extrapyramidal concerns, and risks of tardive dyskinesia. Limited research with calcium-channel-blocking medications (e.g., verapamil, nimodipine) showed limited efficacy in stuttering.14,15 Calcium-channel blockers, however, may exert a mild antidopamine effect.
Further supporting dopamine hyperactivity in the pathology of stuttering, Stager et al compared pimozide (n = 6), a selective dopamine (D2) antagonist, paroxetine (n = 5), a highly selective serotonin reuptake inhibitor, and placebo (n = 6). The researchers found a positive clinical response in those on pimozide compared with those taking placebo, whereas the paroxetine group exhibited no clinical response.16 Although small, such a study supports the hypothesis that dopamine may be a principal transmitter involved in stuttering pathology, and serotonin may play a minor role, if any.
Risperidone, a newer-generation dopamine antagonist with a side-effect profile more favorable than haloperidol, has been shown in a well-controlled, double-blind, placebo-controlled study to improve stuttering symptoms (0.5 mg to 2 mg/d). Although generally well tolerated, long-term compliance was hindered by prolactin-related side effects such as sexual dysfunction, galactorrhea, amenorrhea, and dysphoria.17 Dysphoria with risperidone has also recently been reported to occur with its use in Tourette disorder.18
Olanzapine is a novel psychotropic medication that possesses dopamine-blocking qualities but is not associated as much with prolactin-related side effects or dysphoria. A preliminary open-label study suggests that it too improves the symptoms of stuttering.19
A multicenter study of olanzapine in the treatment of adult developmental stuttering involved 23 adults in a 3-month, double-blind, placebo-controlled trial preceded by a 1-month baseline rating period. At the end of the double-blind phase, subjects were followed for 1 year. Olanzapine (2.5 mg titrated to 5 mg/d) was shown to exert a statistically significant improvement over placebo in multiple objective measures of stuttering severity. The medication was well tolerated without prolactin-associated side effects. Concerns of appetite increase and weight gain with olanzapine were minimized through simple education. The average weight gain was 4 lb in the treatment group, compared with 1 lb in the placebo group. Compliance was also high. All subjects elected to enter the open-label phase of the protocol.
In many patients in the study, stuttering symptoms have continued to improve over 6 months to 1 year or even longer, suggesting that an adequate treatment trial should be measured not in days or even weeks, but possibly months. Also, some individuals in the open-label phase have shown even further efficacy with dose escalation to 7.5 mg to 10 mg/d or higher of olanzapine.20
It is likely, however, that pharmacologic treatment will not be the total answer. In the studies cited earlier, the novel dopamine antagonists led to significant—yet only partial—reductions in stuttering symptoms. The future of optimal stuttering treatment will likely involve the active collaboration between a speech language pathologist and a psychiatrist, using speech therapy to enhance the positive benefits of the medication.
Related resources
- National Stuttering Association http://www.nsastutter.org
- University of California-Irvine Medical Center: Facts About Stuttering. http://www.ucihealth.com/News/UCI%20Health/stutter2.htm
- Hulstijn W, Peters HFM, Van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam, Netherlands: Excerpta Medica, 1997.
- Haloperidol • Haldol
- Nimodipine • Nimotop
- Olanzapine • Zyprexa
- Paroxetine • Paxil
- Pimozide • Orap
- Risperidone • Risperdal
Drs. Maguire and Franklin report that they receive grant/research support from, serve as consultants to, and are on the speaker’s bureau of Eli Lilly &Co.
Dr. Maguire also reports that he receives grant/research support from Johnson & Johnson, and serves on the speaker’s bureau of Pfizer Inc. and GlaxoSmithKline.
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Drs. Riley and Ortiz report no financial relationship with any company whose products are mentioned in this article.
1. American Psychiatric Association. DSM-IV-R. Washington, DC: American Psychiatric Association, 2000.
2. Maguire GA, Riley GD, Franklin DL, Wu JC, et al. The dopamine hypothesis of stuttering and its treatment implications. Intern J Neuropsychopharmacology 2000;3(1):
3. Ludlow CL, Dooman AG. Genetic aspects of idiopathic speech and language disorders. Otolaryngol Clin N Am 1992;25(5):979-94.
4. Manning WH. Clinical decision making in fluency disorders. 2nd ed. San Diego, Calif: Singular, 2001;107-8.
5. Riley G, Ingham J. Acoustic duration changes associated with two types of treatment for children who stutter. J Speech Language Hearing 2000;43:965-78.
6. Wu JC, Maguire GA, et al. A positron emission tomography [18F] deoxyglucose study of developmental stuttering. Neuroreport 1995;6:501-5.
7. Felsenfeld S, Kirk KM, Zhu G, et al. A study of the genetic and environmental etiology of stuttering in a selected twin sample. Behav Gen 2000;30(5):359-66.
8. Howie PM. Concordance for stuttering in monozygotic and dizygotic twin pairs. J Speech Hearing Research 1981;24(3):317-21.
9. Riley GD, Wu JC, Maguire GA. Pet scan evidence of parallel cerebral systems related to treatment effects. In Hulstijn W, Peters HFM, Van Lieshout PHHM (eds.), Speech Production: Motor Control, Brain Research and Fluency Disorders. Amsterdam: Excerpta Medica, 1997.
10. Burd, Kerbeshian J. Stuttering and stimulants [letter]. J Clin Psychopharmacology 1991;11(1):72-3.
11. Wu JC, Maguire G, Riley G, et al. Increased dopamine activity associated with stuttering. Neuroreport 1997;8(3):767-70.
12. Maguire GA. The Dopamine Hypothesis of Stuttering and its Treatment Implications. Presented at Collegium Internationale Neuro-Psychopharmacologicum. Brussels, Belgium, July 2000.
13. Riley G. Stuttering Severity Instrument. 3rd ed. Austin, Tex: ProEd, 1994.
14. Brady JP, McAllister TW, Price TR. Verapamil in stuttering [letter]. Biol Psychiatry 1990;27(6):680-1.
15. Maguire G, Riley G, Hahn R, Plon L. Nimodipine in the treatment of stuttering. ASHA Journal 1994;36:51.-
16. Stager S, Calis K, Grothe D, et al. A double-blind trial of pimozide and paroxetine for stuttering. In: Hulstijn W, Peters HRM, van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam: Excerpta Medica, 1997;379-82.
17. Maguire GA, Riley GD, Franklin DL, Gottshalk LA. Risperidone for the Treatment of Stuttering. J Clin Psychopharmacology 2000-20:479-82.
18. Margolese HC, Annabel L, Dion Y. Depression and dysphoria in adult and adolescent patients with Tourette syndrome treated with risperidone. Presented at the American College of Neuropsychopharmacology, Waikoloa, Hawaii Dec. 10, 2001.
19. Lavid N, Franklin DL, Maguire GA. Management of Child and Adolescent Stuttering with Olanzapine: Three Case Reports. Ann Clin Psychiatry 1999;11(4):233-36.
20. Maguire GA, et al. Olanzapine in the Treatment of Adult Developmental Stuttering. Presented at the American College of Neuropsychopharmacology, Waikoloa, Hawaii Dec. 10, 2001.
21. Orton ST. Studies in stuttering. Arch Neurology Psychiatry 1927;18:671-2.
22. Travis LE. Speech Pathology. New York: Appleton-Century-Crofts, 1931.
23. Sadock BJ, Sadock VA. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 7th ed. Baltimore, Md: Lippincott Williams & Wilkins, 2000.
24. Manning WH. Clinical Decision Making in Fluency Disorders. 2nd ed. San Diego, Calif: Singular Publishing, 2001;311-14.
25. Riley G, Ingham J. Acoustic duration changes associated with two types of treatment for children who stutter. J Speech Language Hearing 2000;43:965-78.
Despite its prevalence, stuttering has not received as much attention as other psychiatric disorders from patients or psychiatrists—with good reason. Until recently, little was known about the neurophysiology of stuttering, and treatment was generally ineffective especially in adults (Box 1). Despite their own personal struggles with the disorder, patients have questioned the need for psychiatric treatment.
That has now changed. We know now that stuttering is likely a disorder of brain chemistry. Studies suggests that olanzapine, a novel dopamine antagonist, is a useful, well-tolerated medication for the treatment of stuttering. As a result, psychiatrists are now equipped to play an important role in its management.
Furthermore, we can give patients the therapeutic opportunity to discuss what often has been a lifetime of frustration with stuttering. We can enable them to understand the course and treatment of this disorder and encourage them to take advantage of the opportunities to lessen the symptoms of stuttering and, ultimately, improve their quality of life.
How stuttering develops
Stuttering is a speech disorder characterized by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables. A common disorder affecting 1% of adults and 4% of children, stuttering is classified in DSM-IV as an Axis I disorder (Box 2).1
Stuttering has occurred throughout history, with descriptions from the ancient Egyptians and Greeks. For centuries, theories on its etiology involved abnormalities in the tongue or larynx, and the treatments addressed such ideology. Even today, some stuttering treatments involve such archaic methods as cauterizing or cutting the tongue. Treatments focused on the tongue or larynx have not demonstrated consistent efficacy.
The pioneering work of Orton21 and Travis22 signaled a significant change in the understanding of stuttering. They postulated that stuttering may arise from abnormal cerebral activity, signaling a significant change in the theories of the etiology of stuttering. Unfortunately, stuttering treatments did not reflect this new understanding until fairly recently.
Psychoanalytic theorists believed that stuttering arose from the individual’s attempt to fulfill some type of unconscious neurotic need, usually resulting from disturbed early parent-child interaction.23 Psychoanalytic therapy was largely ineffective, however.
Most stuttering treatment practiced today involves speech therapy utilizing cognitive and behavioral methods. Such methods are often limited in their efficacy, especially in adults.24 Some forms of therapy involving speech motor training have been shown effective in young children while the brain is still in development.25 The pharmacologic treatment of stuttering is not widespread today, but new and recent research identifying certain cerebral abnormalities is providing clues for pharmacologic interventions.
Stuttering usually begins in childhood and is likely a developmental disorder. Rare cases of acquired stuttering begin in adulthood but are related to secondary causes such as medications, brain trauma, or stroke.3 Some 80% to 90% of developmental stuttering begins by age 6; onset after age 9 is likely to have some psychogenic or neurogenic basis.4 In approximately 60% of the children who stutter, the symptoms will remit by age 16. Children who stutter require early intervention, given the importance of communication in a child’s development.5
Stuttering shares many similarities with Tourette syndrome. Both begin in childhood, follow a waxing or waning course, have a 4:1 male-to-female ratio, are made worse by anxiety, involve abnormalities in the basal ganglia, and respond to dopamine antagonist therapy.6 Persons who stutter often exhibit tic motions, similar to those seen in Tourette syndrome, which are associated with the struggles to produce speech. Genetic studies have shown possible high additive genetic effects; pair-wise concordance for stuttering was significantly higher in identical twins (63%) than it was in fraternal same-sex twins (19%).7,8 Researchers are investigating potential molecular genetic markers for stuttering.
Functional brain imaging studies suggest that stuttering is associated with abnormal cerebral activation primarily involving abnormally low metabolism of the cortical speech areas and the striatum. The defects in stuttering occur primarily in the timing and initiation of spontaneous speech, with such tasks as singing and reading in chorus being spared. A clue to understanding stuttering lies with these “induced fluency” tasks.
Functional positron emission tomography studies utilizing18 F-deoxyglucose showed that stuttering is associated with abnormally low metabolism of speech cortical areas (Wernicke’s and Broca’s) and low metabolism of the basal ganglia, notably the striatum. During the induced fluency, Wernicke’s and Broca’s areas normalize but the striatum remains abnormally low.
Riley postulates two “loops” of speech, an inner or medial system and an outer or lateral system.9 The lateral system is preserved in stuttering and can be activated through singing, rhythmic speech, etc., but the inner loop, as mediated by the striatum and influenced by dopamine, remains impaired. Once a person who stutters initiates speech, he or she often avoids taking a breath as the whole system must again be jump-started. The low striatal metabolism may be the common-state phenomenon underlying this timing.
- Disturbance in normal fluency and time patterning of speech (inappropriate for the individual’s age), characterized by frequent occurrences of one or more of the following:
- Sound and syllable repetitions
- Sound prolongations
- Interjections
- Broken words (e.g., pauses within a word)
- Audible or silent blocking (filled or unfilled pauses in speech)
- Circumlocutions (word substitutions to avoid problematic words)
- Words produced with an excess of physical tension
- Monosyllabic whole-word repetitions (e.g., “I-I-I-I see him”)
- Sound and syllable repetitions
- The disturbance in fluency interferes with academic or occupational achievement or with social communications
- If a speech-motor or sensory deficit is present, the speech difficulties are in excess of those usually associated with these problems.
Coding note: If a speech-motor or sensory deficit or a neurological condition is present, code the condition on Axis III.
The dopamine hypothesis of stuttering
Stuttering is likely related to abnormal elevations of cerebral dopamine activity. Stimulant medications, which increase dopamine activity, have been shown to increase stuttering symptoms.10 As will be reviewed later, dopamine antagonist medications have been shown to improve the symptoms of stuttering. Also, the striatal hypometabolism in stuttering seen in PET imaging may be a result of a hyperdopaminergic state.
To investigate this dopamine hypothesis of stuttering, Wu et al measured presynaptic dopamine levels in individuals who stutter.11 These were found to have 50% to 200% higher levels of dopamine activity than did the controls. Dopamine is inhibitory to striatal metabolism, providing an explanation for the striatal hypometabolism seen in stuttering. Also, risperidone was found to increase striatal metabolism in those whose stuttering improved on this medication.12
Evaluating the patient
One should begin with a comprehensive psychiatric history. Because many patients began stuttering in childhood and have had difficulty dealing with their disorder, other psychiatric disorders such as social phobia may be present. Moreover, other medical etiologies (e.g., stroke) may cause a speech disorder that resembles stuttering.
Stuttering involves abnormalities in fluency as well as tic motions and cognitive avoidances. Inquiries should be made as to the patient’s fluency of speech during work, during introductions, speaking in front of an audience, with family, etc.; the level of stuttering can vary depending on the particular environment.
Stuttering fluency can be rated through an objective scale known as the Riley SSI-3.13 This scale measures the duration of each stuttering event, the percentage of syllables stuttered versus syllables spoken, the severity of associated tic motions, and a global score of the aforementioned components. Because most psychiatrists cannot routinely perform this scale to assess the patient’s progress, it is best to partner with a speech-language pathologist who can also assist the patient through speech therapy.
Nonetheless, you may assess the progress of treatment by relying on your own “ear,” the patient’s own assessment, and the input of a significant other or family member.
In addition to considering DSM-IV criteria, comprehensive treatment should address all aspects of this disorder, including not only the fluency enhancement but improvement in social avoidances and cognitive restructuring. Be aware that stuttering waxes and wanes over time. You should expect to see some “dips” in efficacy during the course of therapy. A longitudinal assessment over several months is needed to determine if the stuttering treatment is efficacious.
What we’ve learned about drug therapy
Many medications have been tried to treat stuttering but few have shown efficacy in well-controlled trials. Most pharmacologic studies did not include a placebo control or employ objective measures of stuttering severity, nor did they provide multiple baseline and treatment measures.
The critical new knowledge is this: Medications that lower dopamine activity have shown replicated efficacy in improving stuttering. The benzodiazepines have been shown to reduce anxiety short-term but have not been shown to improve fluency in stuttering. Limited studies of serotonergic antidepressants suggest a possible role in reducing the social anxiety of stuttering but have not been shown in well-controlled trials to improve stuttering fluency directly.
Multiple studies of haloperidol in the 1970s showed that this medication improved fluency in individuals who stutter. Long-term compliance with this medication, however, was poor given its dysphoric side effects, sexual dysfunction, extrapyramidal concerns, and risks of tardive dyskinesia. Limited research with calcium-channel-blocking medications (e.g., verapamil, nimodipine) showed limited efficacy in stuttering.14,15 Calcium-channel blockers, however, may exert a mild antidopamine effect.
Further supporting dopamine hyperactivity in the pathology of stuttering, Stager et al compared pimozide (n = 6), a selective dopamine (D2) antagonist, paroxetine (n = 5), a highly selective serotonin reuptake inhibitor, and placebo (n = 6). The researchers found a positive clinical response in those on pimozide compared with those taking placebo, whereas the paroxetine group exhibited no clinical response.16 Although small, such a study supports the hypothesis that dopamine may be a principal transmitter involved in stuttering pathology, and serotonin may play a minor role, if any.
Risperidone, a newer-generation dopamine antagonist with a side-effect profile more favorable than haloperidol, has been shown in a well-controlled, double-blind, placebo-controlled study to improve stuttering symptoms (0.5 mg to 2 mg/d). Although generally well tolerated, long-term compliance was hindered by prolactin-related side effects such as sexual dysfunction, galactorrhea, amenorrhea, and dysphoria.17 Dysphoria with risperidone has also recently been reported to occur with its use in Tourette disorder.18
Olanzapine is a novel psychotropic medication that possesses dopamine-blocking qualities but is not associated as much with prolactin-related side effects or dysphoria. A preliminary open-label study suggests that it too improves the symptoms of stuttering.19
A multicenter study of olanzapine in the treatment of adult developmental stuttering involved 23 adults in a 3-month, double-blind, placebo-controlled trial preceded by a 1-month baseline rating period. At the end of the double-blind phase, subjects were followed for 1 year. Olanzapine (2.5 mg titrated to 5 mg/d) was shown to exert a statistically significant improvement over placebo in multiple objective measures of stuttering severity. The medication was well tolerated without prolactin-associated side effects. Concerns of appetite increase and weight gain with olanzapine were minimized through simple education. The average weight gain was 4 lb in the treatment group, compared with 1 lb in the placebo group. Compliance was also high. All subjects elected to enter the open-label phase of the protocol.
In many patients in the study, stuttering symptoms have continued to improve over 6 months to 1 year or even longer, suggesting that an adequate treatment trial should be measured not in days or even weeks, but possibly months. Also, some individuals in the open-label phase have shown even further efficacy with dose escalation to 7.5 mg to 10 mg/d or higher of olanzapine.20
It is likely, however, that pharmacologic treatment will not be the total answer. In the studies cited earlier, the novel dopamine antagonists led to significant—yet only partial—reductions in stuttering symptoms. The future of optimal stuttering treatment will likely involve the active collaboration between a speech language pathologist and a psychiatrist, using speech therapy to enhance the positive benefits of the medication.
Related resources
- National Stuttering Association http://www.nsastutter.org
- University of California-Irvine Medical Center: Facts About Stuttering. http://www.ucihealth.com/News/UCI%20Health/stutter2.htm
- Hulstijn W, Peters HFM, Van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam, Netherlands: Excerpta Medica, 1997.
- Haloperidol • Haldol
- Nimodipine • Nimotop
- Olanzapine • Zyprexa
- Paroxetine • Paxil
- Pimozide • Orap
- Risperidone • Risperdal
Drs. Maguire and Franklin report that they receive grant/research support from, serve as consultants to, and are on the speaker’s bureau of Eli Lilly &Co.
Dr. Maguire also reports that he receives grant/research support from Johnson & Johnson, and serves on the speaker’s bureau of Pfizer Inc. and GlaxoSmithKline.
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Drs. Riley and Ortiz report no financial relationship with any company whose products are mentioned in this article.
Despite its prevalence, stuttering has not received as much attention as other psychiatric disorders from patients or psychiatrists—with good reason. Until recently, little was known about the neurophysiology of stuttering, and treatment was generally ineffective especially in adults (Box 1). Despite their own personal struggles with the disorder, patients have questioned the need for psychiatric treatment.
That has now changed. We know now that stuttering is likely a disorder of brain chemistry. Studies suggests that olanzapine, a novel dopamine antagonist, is a useful, well-tolerated medication for the treatment of stuttering. As a result, psychiatrists are now equipped to play an important role in its management.
Furthermore, we can give patients the therapeutic opportunity to discuss what often has been a lifetime of frustration with stuttering. We can enable them to understand the course and treatment of this disorder and encourage them to take advantage of the opportunities to lessen the symptoms of stuttering and, ultimately, improve their quality of life.
How stuttering develops
Stuttering is a speech disorder characterized by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables. A common disorder affecting 1% of adults and 4% of children, stuttering is classified in DSM-IV as an Axis I disorder (Box 2).1
Stuttering has occurred throughout history, with descriptions from the ancient Egyptians and Greeks. For centuries, theories on its etiology involved abnormalities in the tongue or larynx, and the treatments addressed such ideology. Even today, some stuttering treatments involve such archaic methods as cauterizing or cutting the tongue. Treatments focused on the tongue or larynx have not demonstrated consistent efficacy.
The pioneering work of Orton21 and Travis22 signaled a significant change in the understanding of stuttering. They postulated that stuttering may arise from abnormal cerebral activity, signaling a significant change in the theories of the etiology of stuttering. Unfortunately, stuttering treatments did not reflect this new understanding until fairly recently.
Psychoanalytic theorists believed that stuttering arose from the individual’s attempt to fulfill some type of unconscious neurotic need, usually resulting from disturbed early parent-child interaction.23 Psychoanalytic therapy was largely ineffective, however.
Most stuttering treatment practiced today involves speech therapy utilizing cognitive and behavioral methods. Such methods are often limited in their efficacy, especially in adults.24 Some forms of therapy involving speech motor training have been shown effective in young children while the brain is still in development.25 The pharmacologic treatment of stuttering is not widespread today, but new and recent research identifying certain cerebral abnormalities is providing clues for pharmacologic interventions.
Stuttering usually begins in childhood and is likely a developmental disorder. Rare cases of acquired stuttering begin in adulthood but are related to secondary causes such as medications, brain trauma, or stroke.3 Some 80% to 90% of developmental stuttering begins by age 6; onset after age 9 is likely to have some psychogenic or neurogenic basis.4 In approximately 60% of the children who stutter, the symptoms will remit by age 16. Children who stutter require early intervention, given the importance of communication in a child’s development.5
Stuttering shares many similarities with Tourette syndrome. Both begin in childhood, follow a waxing or waning course, have a 4:1 male-to-female ratio, are made worse by anxiety, involve abnormalities in the basal ganglia, and respond to dopamine antagonist therapy.6 Persons who stutter often exhibit tic motions, similar to those seen in Tourette syndrome, which are associated with the struggles to produce speech. Genetic studies have shown possible high additive genetic effects; pair-wise concordance for stuttering was significantly higher in identical twins (63%) than it was in fraternal same-sex twins (19%).7,8 Researchers are investigating potential molecular genetic markers for stuttering.
Functional brain imaging studies suggest that stuttering is associated with abnormal cerebral activation primarily involving abnormally low metabolism of the cortical speech areas and the striatum. The defects in stuttering occur primarily in the timing and initiation of spontaneous speech, with such tasks as singing and reading in chorus being spared. A clue to understanding stuttering lies with these “induced fluency” tasks.
Functional positron emission tomography studies utilizing18 F-deoxyglucose showed that stuttering is associated with abnormally low metabolism of speech cortical areas (Wernicke’s and Broca’s) and low metabolism of the basal ganglia, notably the striatum. During the induced fluency, Wernicke’s and Broca’s areas normalize but the striatum remains abnormally low.
Riley postulates two “loops” of speech, an inner or medial system and an outer or lateral system.9 The lateral system is preserved in stuttering and can be activated through singing, rhythmic speech, etc., but the inner loop, as mediated by the striatum and influenced by dopamine, remains impaired. Once a person who stutters initiates speech, he or she often avoids taking a breath as the whole system must again be jump-started. The low striatal metabolism may be the common-state phenomenon underlying this timing.
- Disturbance in normal fluency and time patterning of speech (inappropriate for the individual’s age), characterized by frequent occurrences of one or more of the following:
- Sound and syllable repetitions
- Sound prolongations
- Interjections
- Broken words (e.g., pauses within a word)
- Audible or silent blocking (filled or unfilled pauses in speech)
- Circumlocutions (word substitutions to avoid problematic words)
- Words produced with an excess of physical tension
- Monosyllabic whole-word repetitions (e.g., “I-I-I-I see him”)
- Sound and syllable repetitions
- The disturbance in fluency interferes with academic or occupational achievement or with social communications
- If a speech-motor or sensory deficit is present, the speech difficulties are in excess of those usually associated with these problems.
Coding note: If a speech-motor or sensory deficit or a neurological condition is present, code the condition on Axis III.
The dopamine hypothesis of stuttering
Stuttering is likely related to abnormal elevations of cerebral dopamine activity. Stimulant medications, which increase dopamine activity, have been shown to increase stuttering symptoms.10 As will be reviewed later, dopamine antagonist medications have been shown to improve the symptoms of stuttering. Also, the striatal hypometabolism in stuttering seen in PET imaging may be a result of a hyperdopaminergic state.
To investigate this dopamine hypothesis of stuttering, Wu et al measured presynaptic dopamine levels in individuals who stutter.11 These were found to have 50% to 200% higher levels of dopamine activity than did the controls. Dopamine is inhibitory to striatal metabolism, providing an explanation for the striatal hypometabolism seen in stuttering. Also, risperidone was found to increase striatal metabolism in those whose stuttering improved on this medication.12
Evaluating the patient
One should begin with a comprehensive psychiatric history. Because many patients began stuttering in childhood and have had difficulty dealing with their disorder, other psychiatric disorders such as social phobia may be present. Moreover, other medical etiologies (e.g., stroke) may cause a speech disorder that resembles stuttering.
Stuttering involves abnormalities in fluency as well as tic motions and cognitive avoidances. Inquiries should be made as to the patient’s fluency of speech during work, during introductions, speaking in front of an audience, with family, etc.; the level of stuttering can vary depending on the particular environment.
Stuttering fluency can be rated through an objective scale known as the Riley SSI-3.13 This scale measures the duration of each stuttering event, the percentage of syllables stuttered versus syllables spoken, the severity of associated tic motions, and a global score of the aforementioned components. Because most psychiatrists cannot routinely perform this scale to assess the patient’s progress, it is best to partner with a speech-language pathologist who can also assist the patient through speech therapy.
Nonetheless, you may assess the progress of treatment by relying on your own “ear,” the patient’s own assessment, and the input of a significant other or family member.
In addition to considering DSM-IV criteria, comprehensive treatment should address all aspects of this disorder, including not only the fluency enhancement but improvement in social avoidances and cognitive restructuring. Be aware that stuttering waxes and wanes over time. You should expect to see some “dips” in efficacy during the course of therapy. A longitudinal assessment over several months is needed to determine if the stuttering treatment is efficacious.
What we’ve learned about drug therapy
Many medications have been tried to treat stuttering but few have shown efficacy in well-controlled trials. Most pharmacologic studies did not include a placebo control or employ objective measures of stuttering severity, nor did they provide multiple baseline and treatment measures.
The critical new knowledge is this: Medications that lower dopamine activity have shown replicated efficacy in improving stuttering. The benzodiazepines have been shown to reduce anxiety short-term but have not been shown to improve fluency in stuttering. Limited studies of serotonergic antidepressants suggest a possible role in reducing the social anxiety of stuttering but have not been shown in well-controlled trials to improve stuttering fluency directly.
Multiple studies of haloperidol in the 1970s showed that this medication improved fluency in individuals who stutter. Long-term compliance with this medication, however, was poor given its dysphoric side effects, sexual dysfunction, extrapyramidal concerns, and risks of tardive dyskinesia. Limited research with calcium-channel-blocking medications (e.g., verapamil, nimodipine) showed limited efficacy in stuttering.14,15 Calcium-channel blockers, however, may exert a mild antidopamine effect.
Further supporting dopamine hyperactivity in the pathology of stuttering, Stager et al compared pimozide (n = 6), a selective dopamine (D2) antagonist, paroxetine (n = 5), a highly selective serotonin reuptake inhibitor, and placebo (n = 6). The researchers found a positive clinical response in those on pimozide compared with those taking placebo, whereas the paroxetine group exhibited no clinical response.16 Although small, such a study supports the hypothesis that dopamine may be a principal transmitter involved in stuttering pathology, and serotonin may play a minor role, if any.
Risperidone, a newer-generation dopamine antagonist with a side-effect profile more favorable than haloperidol, has been shown in a well-controlled, double-blind, placebo-controlled study to improve stuttering symptoms (0.5 mg to 2 mg/d). Although generally well tolerated, long-term compliance was hindered by prolactin-related side effects such as sexual dysfunction, galactorrhea, amenorrhea, and dysphoria.17 Dysphoria with risperidone has also recently been reported to occur with its use in Tourette disorder.18
Olanzapine is a novel psychotropic medication that possesses dopamine-blocking qualities but is not associated as much with prolactin-related side effects or dysphoria. A preliminary open-label study suggests that it too improves the symptoms of stuttering.19
A multicenter study of olanzapine in the treatment of adult developmental stuttering involved 23 adults in a 3-month, double-blind, placebo-controlled trial preceded by a 1-month baseline rating period. At the end of the double-blind phase, subjects were followed for 1 year. Olanzapine (2.5 mg titrated to 5 mg/d) was shown to exert a statistically significant improvement over placebo in multiple objective measures of stuttering severity. The medication was well tolerated without prolactin-associated side effects. Concerns of appetite increase and weight gain with olanzapine were minimized through simple education. The average weight gain was 4 lb in the treatment group, compared with 1 lb in the placebo group. Compliance was also high. All subjects elected to enter the open-label phase of the protocol.
In many patients in the study, stuttering symptoms have continued to improve over 6 months to 1 year or even longer, suggesting that an adequate treatment trial should be measured not in days or even weeks, but possibly months. Also, some individuals in the open-label phase have shown even further efficacy with dose escalation to 7.5 mg to 10 mg/d or higher of olanzapine.20
It is likely, however, that pharmacologic treatment will not be the total answer. In the studies cited earlier, the novel dopamine antagonists led to significant—yet only partial—reductions in stuttering symptoms. The future of optimal stuttering treatment will likely involve the active collaboration between a speech language pathologist and a psychiatrist, using speech therapy to enhance the positive benefits of the medication.
Related resources
- National Stuttering Association http://www.nsastutter.org
- University of California-Irvine Medical Center: Facts About Stuttering. http://www.ucihealth.com/News/UCI%20Health/stutter2.htm
- Hulstijn W, Peters HFM, Van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam, Netherlands: Excerpta Medica, 1997.
- Haloperidol • Haldol
- Nimodipine • Nimotop
- Olanzapine • Zyprexa
- Paroxetine • Paxil
- Pimozide • Orap
- Risperidone • Risperdal
Drs. Maguire and Franklin report that they receive grant/research support from, serve as consultants to, and are on the speaker’s bureau of Eli Lilly &Co.
Dr. Maguire also reports that he receives grant/research support from Johnson & Johnson, and serves on the speaker’s bureau of Pfizer Inc. and GlaxoSmithKline.
Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.
Drs. Riley and Ortiz report no financial relationship with any company whose products are mentioned in this article.
1. American Psychiatric Association. DSM-IV-R. Washington, DC: American Psychiatric Association, 2000.
2. Maguire GA, Riley GD, Franklin DL, Wu JC, et al. The dopamine hypothesis of stuttering and its treatment implications. Intern J Neuropsychopharmacology 2000;3(1):
3. Ludlow CL, Dooman AG. Genetic aspects of idiopathic speech and language disorders. Otolaryngol Clin N Am 1992;25(5):979-94.
4. Manning WH. Clinical decision making in fluency disorders. 2nd ed. San Diego, Calif: Singular, 2001;107-8.
5. Riley G, Ingham J. Acoustic duration changes associated with two types of treatment for children who stutter. J Speech Language Hearing 2000;43:965-78.
6. Wu JC, Maguire GA, et al. A positron emission tomography [18F] deoxyglucose study of developmental stuttering. Neuroreport 1995;6:501-5.
7. Felsenfeld S, Kirk KM, Zhu G, et al. A study of the genetic and environmental etiology of stuttering in a selected twin sample. Behav Gen 2000;30(5):359-66.
8. Howie PM. Concordance for stuttering in monozygotic and dizygotic twin pairs. J Speech Hearing Research 1981;24(3):317-21.
9. Riley GD, Wu JC, Maguire GA. Pet scan evidence of parallel cerebral systems related to treatment effects. In Hulstijn W, Peters HFM, Van Lieshout PHHM (eds.), Speech Production: Motor Control, Brain Research and Fluency Disorders. Amsterdam: Excerpta Medica, 1997.
10. Burd, Kerbeshian J. Stuttering and stimulants [letter]. J Clin Psychopharmacology 1991;11(1):72-3.
11. Wu JC, Maguire G, Riley G, et al. Increased dopamine activity associated with stuttering. Neuroreport 1997;8(3):767-70.
12. Maguire GA. The Dopamine Hypothesis of Stuttering and its Treatment Implications. Presented at Collegium Internationale Neuro-Psychopharmacologicum. Brussels, Belgium, July 2000.
13. Riley G. Stuttering Severity Instrument. 3rd ed. Austin, Tex: ProEd, 1994.
14. Brady JP, McAllister TW, Price TR. Verapamil in stuttering [letter]. Biol Psychiatry 1990;27(6):680-1.
15. Maguire G, Riley G, Hahn R, Plon L. Nimodipine in the treatment of stuttering. ASHA Journal 1994;36:51.-
16. Stager S, Calis K, Grothe D, et al. A double-blind trial of pimozide and paroxetine for stuttering. In: Hulstijn W, Peters HRM, van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam: Excerpta Medica, 1997;379-82.
17. Maguire GA, Riley GD, Franklin DL, Gottshalk LA. Risperidone for the Treatment of Stuttering. J Clin Psychopharmacology 2000-20:479-82.
18. Margolese HC, Annabel L, Dion Y. Depression and dysphoria in adult and adolescent patients with Tourette syndrome treated with risperidone. Presented at the American College of Neuropsychopharmacology, Waikoloa, Hawaii Dec. 10, 2001.
19. Lavid N, Franklin DL, Maguire GA. Management of Child and Adolescent Stuttering with Olanzapine: Three Case Reports. Ann Clin Psychiatry 1999;11(4):233-36.
20. Maguire GA, et al. Olanzapine in the Treatment of Adult Developmental Stuttering. Presented at the American College of Neuropsychopharmacology, Waikoloa, Hawaii Dec. 10, 2001.
21. Orton ST. Studies in stuttering. Arch Neurology Psychiatry 1927;18:671-2.
22. Travis LE. Speech Pathology. New York: Appleton-Century-Crofts, 1931.
23. Sadock BJ, Sadock VA. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 7th ed. Baltimore, Md: Lippincott Williams & Wilkins, 2000.
24. Manning WH. Clinical Decision Making in Fluency Disorders. 2nd ed. San Diego, Calif: Singular Publishing, 2001;311-14.
25. Riley G, Ingham J. Acoustic duration changes associated with two types of treatment for children who stutter. J Speech Language Hearing 2000;43:965-78.
1. American Psychiatric Association. DSM-IV-R. Washington, DC: American Psychiatric Association, 2000.
2. Maguire GA, Riley GD, Franklin DL, Wu JC, et al. The dopamine hypothesis of stuttering and its treatment implications. Intern J Neuropsychopharmacology 2000;3(1):
3. Ludlow CL, Dooman AG. Genetic aspects of idiopathic speech and language disorders. Otolaryngol Clin N Am 1992;25(5):979-94.
4. Manning WH. Clinical decision making in fluency disorders. 2nd ed. San Diego, Calif: Singular, 2001;107-8.
5. Riley G, Ingham J. Acoustic duration changes associated with two types of treatment for children who stutter. J Speech Language Hearing 2000;43:965-78.
6. Wu JC, Maguire GA, et al. A positron emission tomography [18F] deoxyglucose study of developmental stuttering. Neuroreport 1995;6:501-5.
7. Felsenfeld S, Kirk KM, Zhu G, et al. A study of the genetic and environmental etiology of stuttering in a selected twin sample. Behav Gen 2000;30(5):359-66.
8. Howie PM. Concordance for stuttering in monozygotic and dizygotic twin pairs. J Speech Hearing Research 1981;24(3):317-21.
9. Riley GD, Wu JC, Maguire GA. Pet scan evidence of parallel cerebral systems related to treatment effects. In Hulstijn W, Peters HFM, Van Lieshout PHHM (eds.), Speech Production: Motor Control, Brain Research and Fluency Disorders. Amsterdam: Excerpta Medica, 1997.
10. Burd, Kerbeshian J. Stuttering and stimulants [letter]. J Clin Psychopharmacology 1991;11(1):72-3.
11. Wu JC, Maguire G, Riley G, et al. Increased dopamine activity associated with stuttering. Neuroreport 1997;8(3):767-70.
12. Maguire GA. The Dopamine Hypothesis of Stuttering and its Treatment Implications. Presented at Collegium Internationale Neuro-Psychopharmacologicum. Brussels, Belgium, July 2000.
13. Riley G. Stuttering Severity Instrument. 3rd ed. Austin, Tex: ProEd, 1994.
14. Brady JP, McAllister TW, Price TR. Verapamil in stuttering [letter]. Biol Psychiatry 1990;27(6):680-1.
15. Maguire G, Riley G, Hahn R, Plon L. Nimodipine in the treatment of stuttering. ASHA Journal 1994;36:51.-
16. Stager S, Calis K, Grothe D, et al. A double-blind trial of pimozide and paroxetine for stuttering. In: Hulstijn W, Peters HRM, van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam: Excerpta Medica, 1997;379-82.
17. Maguire GA, Riley GD, Franklin DL, Gottshalk LA. Risperidone for the Treatment of Stuttering. J Clin Psychopharmacology 2000-20:479-82.
18. Margolese HC, Annabel L, Dion Y. Depression and dysphoria in adult and adolescent patients with Tourette syndrome treated with risperidone. Presented at the American College of Neuropsychopharmacology, Waikoloa, Hawaii Dec. 10, 2001.
19. Lavid N, Franklin DL, Maguire GA. Management of Child and Adolescent Stuttering with Olanzapine: Three Case Reports. Ann Clin Psychiatry 1999;11(4):233-36.
20. Maguire GA, et al. Olanzapine in the Treatment of Adult Developmental Stuttering. Presented at the American College of Neuropsychopharmacology, Waikoloa, Hawaii Dec. 10, 2001.
21. Orton ST. Studies in stuttering. Arch Neurology Psychiatry 1927;18:671-2.
22. Travis LE. Speech Pathology. New York: Appleton-Century-Crofts, 1931.
23. Sadock BJ, Sadock VA. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 7th ed. Baltimore, Md: Lippincott Williams & Wilkins, 2000.
24. Manning WH. Clinical Decision Making in Fluency Disorders. 2nd ed. San Diego, Calif: Singular Publishing, 2001;311-14.
25. Riley G, Ingham J. Acoustic duration changes associated with two types of treatment for children who stutter. J Speech Language Hearing 2000;43:965-78.