Evidence-Based Reviews

Nausea and vomiting in pregnancy (NVP) is a misunderstood disorder associated with stress, anxiety, and depression. Prejudice toward women is thought to have guided the historical psychoanalytic concept of NVP as psychogenic, but this view is being replaced by newer biologic theories.

This article examines the evidence for psychological and organic causes of NVP to inform psychiatrists treating pregnant patients. We review guidelines for pharmacologic treatment of NVP and discuss potentially useful psychotherapies and alternative approaches.

Definitive cause unknown

“Morning sickness” affects 50% to 80% of pregnant women, occurring so commonly that NVP is often considered normal.^1,2 Approximately 0.5% to 2% of women experience the most severe NVP—hyperemesis gravidarum (HG)³—characterized by intractable vomiting, weight loss, and electrolyte imbalance that can lead to hospitalization.

Without modern supportive care, HG can be lethal; although Charlotte Brontë’s death certificate states she died of “phthisis” (tuberculosis), the author of Jane Eyre is popularly believed to have succumbed to HG.^4,5

The search for effective NVP treatments has been disappointing, partly because no cause has been identified. After other conditions that may lead to nausea and vomiting are ruled out (Table 1), NVP medical management is supportive. Correcting dehydration and encouraging dietary and lifestyle changes (Table 2)⁶ are important adjuncts to step-wise pharmacologic treatment recommended by the American College of Obstetrics and Gynecology (Algorithm).⁷

Algorithm Pharmacologic treatment of nausea and vomiting in pregnancy*

Source: Adapted and reprinted with permission from Canadian Family Physician. Levichek Z, Atanackovic G, Oepkes D, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002;48:267-77Table 1

Medical causes of nausea and vomiting in pregnancy

Table 2

Advice for patients: Strategies to manage NVP

Prejudice vs evidence

Psychological factors. Historically, psychological factors have been blamed for NVP, but support comes from a few poorly designed studies or case reports.^3,4

Psychoanalytically, pregnancy and childbirth are significant events in a woman’s life and a rich environment for conflict that could lead to physical expression of symptoms. Freud believed pregnancy and childbirth involve the unconscious substitution of the penis with the child.⁸ Later writers viewed motherhood as woman’s most powerful wish and the primary organizer of her sexual drive and personality.⁸

NVP has been considered a conversion or somatization disorder in which symptoms are a “hysterical” expression of unconscious conflict. A psychoanalytic view contends that women who experience NVP are ambivalent about the pregnancy and seek to reject it.^1,9 Vomiting, in this view, represents an oral abortion attempt.¹⁰ Others claim NVP is a rejection of femininity³ or that symptoms in women with overly attached maternal relationships mask unconscious aggressive feelings toward their mothers.¹¹

Robertson¹¹ proposed an association between NVP and a woman’s view of sexual experiences and her ability to achieve orgasm. He interviewed 100 women and found that 40 of 57 with NVP had “disturbed sexual functioning” or were “frigid” (defined as experiencing coitus as undesirable and unaccompanied by orgasm).

Higgins¹² in 1887 proposed that the cause of NVP “is sexual intercourse, the husband too eager for it and the wife too adverse.” Additionally, NVP and HG have been associated with infantile, childish, immature, and hysterical personalities.^12-14

Psychiatric comorbidities. Attempts have been made to associate NVP with other psychiatric disorders such as depression, bipolar disorder, schizophrenia, and anxiety disorders, including posttraumatic stress disorder (PTSD). No definitive association has been found between NVP and depressive illness, bipolar disorder, or schizophrenia¹⁵ or the use of antidepressants before or during early pregnancy.¹⁶ Studies reporting an association with depression have not established a cause-effect relationship.¹⁷

Seng¹⁸ reported increased NVP risk in women with PTSD. High levels of stress, anxiety, and depression found in women with NVP are thought to result from—rather than cause—NVP’s physical symptoms, however.^3,19,20

Psychosocial stressors have been implicated, with higher NVP rates reported in unmarried women, those with unwanted or unplanned pregnancies, immigrants, and those living in crowded situations.²¹ NVP also is more frequent among women who experience emotionally disturbing events or interpersonal, economic, or occupational difficulties during pregnancy.²² Physical symptoms may provide secondary gain in attention and sympathy and a time-out from stressful home events.¹⁴

These psychosocial theories are poorly supported by data, but some clinicians may still believe NVP has a psychogenic cause. Lennane and Lennane²³ proposed in 1973 that this perception may result from gender bias because:

• most conditions believed to have psychogenic causes affect women more than men
• the belief that NVP is psychogenic has been perpetuated primarily by male authors.

They argued that sexual prejudice may prevent women from receiving necessary symptomatic treatment and impede research into the cause of NVP.²³

Gender bias continues to be found in the diagnosis of women with physical complaints. In 2006, Chiaramonte and Friend²⁴ found strong, consistent gender bias among medical students and residents when evaluating women who reported coronary disease symptoms during stressful life events.

Organic theories

Organic theories view NVP as multifactorial, with contributions from evolution and multiple organ systems. Endocrine, vestibular, gastrointestinal, and CNS contributions have been described, but none have solved NVP’s etiologic mystery.

Evolutionary. NVP may provide an evolutionary advantage by protecting the embryo and mother. This theory states that potential toxins are present in many foods, especially if eaten in large quantities. NVP prevents the pregnant woman from eating very much and harming the embryo. Below-average miscarriage rates are seen in women with NVP.^1,2,25

And because a woman’s immune system is depressed during pregnancy, NVP may be advantageous for the mother by limiting her ingestion of potential toxins.²⁵

Endocrine. Human chorionic gonadotropin (hCG), estrogens, progesterone, and leptin, as well as adrenal cortex insufficiencies have been investigated for a role in NVP. Only hCG has shown clear evidence of an association, and some researchers believe it is the most likely cause of NVP.²⁰

NVP rates are higher in pregnancies with elevated hCG. Molar and multiple-gestation pregnancies—each associated with elevated hCG—are complicated more frequently with the severest form of NVP.^20,26 Conversely, NVP is less common in women who smoke, which is associated with lower hCG.²⁶

During pregnancy, actions of hCG stimulate the thyroid. Hyperstimulation, leading to transient hyperthyroidism, has been implicated in NVP development.^20,26 Symptom severity and the degree of thyroid stimulating hormone (TSH) suppression are closely correlated.²⁶

Elevated hCG levels, hypersensitive TSH receptors, and the presence of a hyperactive hCG isoform have been proposed.²⁰

Gastrointestinal disorders are believed to be involved in the pathogenesis of persistent NVP. Women with NVP usually lack structural or mucosal abnormalities and have normal endoscopic upper GI evaluations. They may, however, have disorders of the stomach’s neuromuscular function. Severe cases of gastric dysrhythmias and abnormalities of gastric tone may lead to gastroparesis.²⁷

Stomach motility in pregnancy is influenced by neurohormonal changes, specifically in estrogen and thyroid hormones. Gastric motility abnormalities—evaluated by electrogastrography (EGG)—have been associated with NVP symptoms and normal EGGs with the absence of symptoms. Some women who had NVP and abnormal EGGs were retested after delivery when symptom-free and found to have normal myoelectric EGG patterns.²⁷

Helicobacter pylori also may be involved in NVP, and at least 1 study found active H pylori infection and HG to be highly correlated. Pregnancy is not believed to predispose to H pylori infection, but active infection compounded by pregnancy’s hormonal changes may exacerbate NVP.²⁸

NVP and motion sickness share many features, suggesting that NVP treatment could be targeted if a vestibular disorder could be discovered.²⁹ Abnormal electroencephalography—particularly generalized slowing—that is not present in asymptomatic pregnant women has been reported in women with NVP.³⁰

CNS contributions. Persistent NVP may be a learned behavior,²⁴ a view based on findings of anticipatory nausea and vomiting in chemotherapy patients. Through conditioning, a pregnant woman may associate her physical symptoms with elements in her life that maintain the cycle of nausea and vomiting.³¹

Treating psychological symptoms

Brief psychotherapy to identify and correct sources of anxiety in pregnancy may alleviate a patient’s nausea and vomiting.³²

• Progressive muscle relaxation training, often combined with guided imagery, can decrease nausea and vomiting associated with chemotherapy and may prevent anticipatory symptoms by decreasing anxiety.
• Systematic desensitization is successful in most chemotherapy patients who try it. In this technique, relaxation is counter-conditioned as a response to stimuli known to elicit symptoms.³¹

Hypnosis allows patients to achieve a physiologic state incompatible with nausea and vomiting³¹ and can terminate vomiting after 1 to 3 sessions.³

Medication. Similar to ondansetron, the antidepressant mirtazapine exhibits an antiemetic effect by blocking the 5-HT3 receptor. In treatment-resistant cases, mirtazapine, 30 mg/d, has been reported to ameliorate NVP symptoms, usually within 24 hours. Patients were able to return to normal diets and discontinue treatment after 6 to 10 days. Mirtazapine appears to be safe during pregnancy, based on animal studies using 17 and 20 times the maximum recommended human dose.³³

For patients with anxiety symptoms, consider other medications—including selective serotonin reuptake inhibitors and benzodiazepines—only after counseling the patient about potential risks and benefits to her and the fetus.³⁴

Alternative treatments. In traditional Indian medicine, a mixture of powdered ginger and honey is given to women with NVP. At least 2 studies demonstrate ginger’s efficacy.³⁵

In traditional Chinese medicine, stimulating the Neiguan point (P6) on the wrist is believed to relieve nausea and vomiting. Although results are inconclusive, studies suggest that P6 stimulation can help control NVP.³⁶ The FDA has approved wristbands that stimulate the P6 site, either electrically or by acupressure (Figure).³⁶

Figure Wristband to manage nausea and vomiting in pregnancy

The FDA-cleared BioBand acupressure wristband may help control nausea and vomiting in pregnancy by stimulating the Neiguan point (P6) on the wrist.
Source: Reference 36Consider thiamine supplementation for women with severe symptoms, as Wernicke’s encephalopathy is a rare complication of prolonged NVP.^19,37

Related resources

• Motherisk Program at The Hospital for Sick Children, Toronto, Ontario, Canada. Website with information on vomiting during pregnancy: www.motherisk.org/women/morningSickness.jsp. Nausea and vomiting of pregnancy (NVP) forum. www.motherisk.org/women/forum.jsp.
• BioBand acupuncture wristband. www.BioBands.com.
• Koren G, Bishai R, eds. Nausea and vomiting of pregnancy: state of the art 2000. Toronto, Ontario, Canada: The Motherisk Program; 2000.

Drug brand names

• Dimenhydrinate • Dramamine
• Doxylamine • Unisom
• Methylprednisolone • Medrol
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Ondansetron • Zofran
• Promethazine • Phenergan
• Trimethobenzamide • Tigan

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Nausea and vomiting in pregnancy (NVP) is a misunderstood disorder associated with stress, anxiety, and depression. Prejudice toward women is thought to have guided the historical psychoanalytic concept of NVP as psychogenic, but this view is being replaced by newer biologic theories.

This article examines the evidence for psychological and organic causes of NVP to inform psychiatrists treating pregnant patients. We review guidelines for pharmacologic treatment of NVP and discuss potentially useful psychotherapies and alternative approaches.

Definitive cause unknown

“Morning sickness” affects 50% to 80% of pregnant women, occurring so commonly that NVP is often considered normal.^1,2 Approximately 0.5% to 2% of women experience the most severe NVP—hyperemesis gravidarum (HG)³—characterized by intractable vomiting, weight loss, and electrolyte imbalance that can lead to hospitalization.

Without modern supportive care, HG can be lethal; although Charlotte Brontë’s death certificate states she died of “phthisis” (tuberculosis), the author of Jane Eyre is popularly believed to have succumbed to HG.^4,5

The search for effective NVP treatments has been disappointing, partly because no cause has been identified. After other conditions that may lead to nausea and vomiting are ruled out (Table 1), NVP medical management is supportive. Correcting dehydration and encouraging dietary and lifestyle changes (Table 2)⁶ are important adjuncts to step-wise pharmacologic treatment recommended by the American College of Obstetrics and Gynecology (Algorithm).⁷

Algorithm Pharmacologic treatment of nausea and vomiting in pregnancy*

Source: Adapted and reprinted with permission from Canadian Family Physician. Levichek Z, Atanackovic G, Oepkes D, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002;48:267-77Table 1

Medical causes of nausea and vomiting in pregnancy

Table 2

Advice for patients: Strategies to manage NVP

Prejudice vs evidence

Psychological factors. Historically, psychological factors have been blamed for NVP, but support comes from a few poorly designed studies or case reports.^3,4

Psychoanalytically, pregnancy and childbirth are significant events in a woman’s life and a rich environment for conflict that could lead to physical expression of symptoms. Freud believed pregnancy and childbirth involve the unconscious substitution of the penis with the child.⁸ Later writers viewed motherhood as woman’s most powerful wish and the primary organizer of her sexual drive and personality.⁸

NVP has been considered a conversion or somatization disorder in which symptoms are a “hysterical” expression of unconscious conflict. A psychoanalytic view contends that women who experience NVP are ambivalent about the pregnancy and seek to reject it.^1,9 Vomiting, in this view, represents an oral abortion attempt.¹⁰ Others claim NVP is a rejection of femininity³ or that symptoms in women with overly attached maternal relationships mask unconscious aggressive feelings toward their mothers.¹¹

Robertson¹¹ proposed an association between NVP and a woman’s view of sexual experiences and her ability to achieve orgasm. He interviewed 100 women and found that 40 of 57 with NVP had “disturbed sexual functioning” or were “frigid” (defined as experiencing coitus as undesirable and unaccompanied by orgasm).

Higgins¹² in 1887 proposed that the cause of NVP “is sexual intercourse, the husband too eager for it and the wife too adverse.” Additionally, NVP and HG have been associated with infantile, childish, immature, and hysterical personalities.^12-14

Psychiatric comorbidities. Attempts have been made to associate NVP with other psychiatric disorders such as depression, bipolar disorder, schizophrenia, and anxiety disorders, including posttraumatic stress disorder (PTSD). No definitive association has been found between NVP and depressive illness, bipolar disorder, or schizophrenia¹⁵ or the use of antidepressants before or during early pregnancy.¹⁶ Studies reporting an association with depression have not established a cause-effect relationship.¹⁷

Seng¹⁸ reported increased NVP risk in women with PTSD. High levels of stress, anxiety, and depression found in women with NVP are thought to result from—rather than cause—NVP’s physical symptoms, however.^3,19,20

Psychosocial stressors have been implicated, with higher NVP rates reported in unmarried women, those with unwanted or unplanned pregnancies, immigrants, and those living in crowded situations.²¹ NVP also is more frequent among women who experience emotionally disturbing events or interpersonal, economic, or occupational difficulties during pregnancy.²² Physical symptoms may provide secondary gain in attention and sympathy and a time-out from stressful home events.¹⁴

These psychosocial theories are poorly supported by data, but some clinicians may still believe NVP has a psychogenic cause. Lennane and Lennane²³ proposed in 1973 that this perception may result from gender bias because:

• most conditions believed to have psychogenic causes affect women more than men
• the belief that NVP is psychogenic has been perpetuated primarily by male authors.

They argued that sexual prejudice may prevent women from receiving necessary symptomatic treatment and impede research into the cause of NVP.²³

Gender bias continues to be found in the diagnosis of women with physical complaints. In 2006, Chiaramonte and Friend²⁴ found strong, consistent gender bias among medical students and residents when evaluating women who reported coronary disease symptoms during stressful life events.

Organic theories

Organic theories view NVP as multifactorial, with contributions from evolution and multiple organ systems. Endocrine, vestibular, gastrointestinal, and CNS contributions have been described, but none have solved NVP’s etiologic mystery.

Evolutionary. NVP may provide an evolutionary advantage by protecting the embryo and mother. This theory states that potential toxins are present in many foods, especially if eaten in large quantities. NVP prevents the pregnant woman from eating very much and harming the embryo. Below-average miscarriage rates are seen in women with NVP.^1,2,25

And because a woman’s immune system is depressed during pregnancy, NVP may be advantageous for the mother by limiting her ingestion of potential toxins.²⁵

Endocrine. Human chorionic gonadotropin (hCG), estrogens, progesterone, and leptin, as well as adrenal cortex insufficiencies have been investigated for a role in NVP. Only hCG has shown clear evidence of an association, and some researchers believe it is the most likely cause of NVP.²⁰

NVP rates are higher in pregnancies with elevated hCG. Molar and multiple-gestation pregnancies—each associated with elevated hCG—are complicated more frequently with the severest form of NVP.^20,26 Conversely, NVP is less common in women who smoke, which is associated with lower hCG.²⁶

During pregnancy, actions of hCG stimulate the thyroid. Hyperstimulation, leading to transient hyperthyroidism, has been implicated in NVP development.^20,26 Symptom severity and the degree of thyroid stimulating hormone (TSH) suppression are closely correlated.²⁶

Elevated hCG levels, hypersensitive TSH receptors, and the presence of a hyperactive hCG isoform have been proposed.²⁰

Gastrointestinal disorders are believed to be involved in the pathogenesis of persistent NVP. Women with NVP usually lack structural or mucosal abnormalities and have normal endoscopic upper GI evaluations. They may, however, have disorders of the stomach’s neuromuscular function. Severe cases of gastric dysrhythmias and abnormalities of gastric tone may lead to gastroparesis.²⁷

Stomach motility in pregnancy is influenced by neurohormonal changes, specifically in estrogen and thyroid hormones. Gastric motility abnormalities—evaluated by electrogastrography (EGG)—have been associated with NVP symptoms and normal EGGs with the absence of symptoms. Some women who had NVP and abnormal EGGs were retested after delivery when symptom-free and found to have normal myoelectric EGG patterns.²⁷

Helicobacter pylori also may be involved in NVP, and at least 1 study found active H pylori infection and HG to be highly correlated. Pregnancy is not believed to predispose to H pylori infection, but active infection compounded by pregnancy’s hormonal changes may exacerbate NVP.²⁸

NVP and motion sickness share many features, suggesting that NVP treatment could be targeted if a vestibular disorder could be discovered.²⁹ Abnormal electroencephalography—particularly generalized slowing—that is not present in asymptomatic pregnant women has been reported in women with NVP.³⁰

CNS contributions. Persistent NVP may be a learned behavior,²⁴ a view based on findings of anticipatory nausea and vomiting in chemotherapy patients. Through conditioning, a pregnant woman may associate her physical symptoms with elements in her life that maintain the cycle of nausea and vomiting.³¹

Treating psychological symptoms

Brief psychotherapy to identify and correct sources of anxiety in pregnancy may alleviate a patient’s nausea and vomiting.³²

• Progressive muscle relaxation training, often combined with guided imagery, can decrease nausea and vomiting associated with chemotherapy and may prevent anticipatory symptoms by decreasing anxiety.
• Systematic desensitization is successful in most chemotherapy patients who try it. In this technique, relaxation is counter-conditioned as a response to stimuli known to elicit symptoms.³¹

Hypnosis allows patients to achieve a physiologic state incompatible with nausea and vomiting³¹ and can terminate vomiting after 1 to 3 sessions.³

Medication. Similar to ondansetron, the antidepressant mirtazapine exhibits an antiemetic effect by blocking the 5-HT3 receptor. In treatment-resistant cases, mirtazapine, 30 mg/d, has been reported to ameliorate NVP symptoms, usually within 24 hours. Patients were able to return to normal diets and discontinue treatment after 6 to 10 days. Mirtazapine appears to be safe during pregnancy, based on animal studies using 17 and 20 times the maximum recommended human dose.³³

For patients with anxiety symptoms, consider other medications—including selective serotonin reuptake inhibitors and benzodiazepines—only after counseling the patient about potential risks and benefits to her and the fetus.³⁴

Alternative treatments. In traditional Indian medicine, a mixture of powdered ginger and honey is given to women with NVP. At least 2 studies demonstrate ginger’s efficacy.³⁵

In traditional Chinese medicine, stimulating the Neiguan point (P6) on the wrist is believed to relieve nausea and vomiting. Although results are inconclusive, studies suggest that P6 stimulation can help control NVP.³⁶ The FDA has approved wristbands that stimulate the P6 site, either electrically or by acupressure (Figure).³⁶

Figure Wristband to manage nausea and vomiting in pregnancy

The FDA-cleared BioBand acupressure wristband may help control nausea and vomiting in pregnancy by stimulating the Neiguan point (P6) on the wrist.
Source: Reference 36Consider thiamine supplementation for women with severe symptoms, as Wernicke’s encephalopathy is a rare complication of prolonged NVP.^19,37

Related resources

• Motherisk Program at The Hospital for Sick Children, Toronto, Ontario, Canada. Website with information on vomiting during pregnancy: www.motherisk.org/women/morningSickness.jsp. Nausea and vomiting of pregnancy (NVP) forum. www.motherisk.org/women/forum.jsp.
• BioBand acupuncture wristband. www.BioBands.com.
• Koren G, Bishai R, eds. Nausea and vomiting of pregnancy: state of the art 2000. Toronto, Ontario, Canada: The Motherisk Program; 2000.

Drug brand names

• Dimenhydrinate • Dramamine
• Doxylamine • Unisom
• Methylprednisolone • Medrol
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Ondansetron • Zofran
• Promethazine • Phenergan
• Trimethobenzamide • Tigan

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Nausea and vomiting in pregnancy (NVP) is a misunderstood disorder associated with stress, anxiety, and depression. Prejudice toward women is thought to have guided the historical psychoanalytic concept of NVP as psychogenic, but this view is being replaced by newer biologic theories.

This article examines the evidence for psychological and organic causes of NVP to inform psychiatrists treating pregnant patients. We review guidelines for pharmacologic treatment of NVP and discuss potentially useful psychotherapies and alternative approaches.

Definitive cause unknown

“Morning sickness” affects 50% to 80% of pregnant women, occurring so commonly that NVP is often considered normal.^1,2 Approximately 0.5% to 2% of women experience the most severe NVP—hyperemesis gravidarum (HG)³—characterized by intractable vomiting, weight loss, and electrolyte imbalance that can lead to hospitalization.

Without modern supportive care, HG can be lethal; although Charlotte Brontë’s death certificate states she died of “phthisis” (tuberculosis), the author of Jane Eyre is popularly believed to have succumbed to HG.^4,5

The search for effective NVP treatments has been disappointing, partly because no cause has been identified. After other conditions that may lead to nausea and vomiting are ruled out (Table 1), NVP medical management is supportive. Correcting dehydration and encouraging dietary and lifestyle changes (Table 2)⁶ are important adjuncts to step-wise pharmacologic treatment recommended by the American College of Obstetrics and Gynecology (Algorithm).⁷

Algorithm Pharmacologic treatment of nausea and vomiting in pregnancy*

Source: Adapted and reprinted with permission from Canadian Family Physician. Levichek Z, Atanackovic G, Oepkes D, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002;48:267-77Table 1

Medical causes of nausea and vomiting in pregnancy

Table 2

Advice for patients: Strategies to manage NVP

Prejudice vs evidence

Psychological factors. Historically, psychological factors have been blamed for NVP, but support comes from a few poorly designed studies or case reports.^3,4

Psychoanalytically, pregnancy and childbirth are significant events in a woman’s life and a rich environment for conflict that could lead to physical expression of symptoms. Freud believed pregnancy and childbirth involve the unconscious substitution of the penis with the child.⁸ Later writers viewed motherhood as woman’s most powerful wish and the primary organizer of her sexual drive and personality.⁸

NVP has been considered a conversion or somatization disorder in which symptoms are a “hysterical” expression of unconscious conflict. A psychoanalytic view contends that women who experience NVP are ambivalent about the pregnancy and seek to reject it.^1,9 Vomiting, in this view, represents an oral abortion attempt.¹⁰ Others claim NVP is a rejection of femininity³ or that symptoms in women with overly attached maternal relationships mask unconscious aggressive feelings toward their mothers.¹¹

Robertson¹¹ proposed an association between NVP and a woman’s view of sexual experiences and her ability to achieve orgasm. He interviewed 100 women and found that 40 of 57 with NVP had “disturbed sexual functioning” or were “frigid” (defined as experiencing coitus as undesirable and unaccompanied by orgasm).

Higgins¹² in 1887 proposed that the cause of NVP “is sexual intercourse, the husband too eager for it and the wife too adverse.” Additionally, NVP and HG have been associated with infantile, childish, immature, and hysterical personalities.^12-14

Psychiatric comorbidities. Attempts have been made to associate NVP with other psychiatric disorders such as depression, bipolar disorder, schizophrenia, and anxiety disorders, including posttraumatic stress disorder (PTSD). No definitive association has been found between NVP and depressive illness, bipolar disorder, or schizophrenia¹⁵ or the use of antidepressants before or during early pregnancy.¹⁶ Studies reporting an association with depression have not established a cause-effect relationship.¹⁷

Seng¹⁸ reported increased NVP risk in women with PTSD. High levels of stress, anxiety, and depression found in women with NVP are thought to result from—rather than cause—NVP’s physical symptoms, however.^3,19,20

Psychosocial stressors have been implicated, with higher NVP rates reported in unmarried women, those with unwanted or unplanned pregnancies, immigrants, and those living in crowded situations.²¹ NVP also is more frequent among women who experience emotionally disturbing events or interpersonal, economic, or occupational difficulties during pregnancy.²² Physical symptoms may provide secondary gain in attention and sympathy and a time-out from stressful home events.¹⁴

These psychosocial theories are poorly supported by data, but some clinicians may still believe NVP has a psychogenic cause. Lennane and Lennane²³ proposed in 1973 that this perception may result from gender bias because:

• most conditions believed to have psychogenic causes affect women more than men
• the belief that NVP is psychogenic has been perpetuated primarily by male authors.

They argued that sexual prejudice may prevent women from receiving necessary symptomatic treatment and impede research into the cause of NVP.²³

Gender bias continues to be found in the diagnosis of women with physical complaints. In 2006, Chiaramonte and Friend²⁴ found strong, consistent gender bias among medical students and residents when evaluating women who reported coronary disease symptoms during stressful life events.

Organic theories

Organic theories view NVP as multifactorial, with contributions from evolution and multiple organ systems. Endocrine, vestibular, gastrointestinal, and CNS contributions have been described, but none have solved NVP’s etiologic mystery.

Evolutionary. NVP may provide an evolutionary advantage by protecting the embryo and mother. This theory states that potential toxins are present in many foods, especially if eaten in large quantities. NVP prevents the pregnant woman from eating very much and harming the embryo. Below-average miscarriage rates are seen in women with NVP.^1,2,25

And because a woman’s immune system is depressed during pregnancy, NVP may be advantageous for the mother by limiting her ingestion of potential toxins.²⁵

Endocrine. Human chorionic gonadotropin (hCG), estrogens, progesterone, and leptin, as well as adrenal cortex insufficiencies have been investigated for a role in NVP. Only hCG has shown clear evidence of an association, and some researchers believe it is the most likely cause of NVP.²⁰

NVP rates are higher in pregnancies with elevated hCG. Molar and multiple-gestation pregnancies—each associated with elevated hCG—are complicated more frequently with the severest form of NVP.^20,26 Conversely, NVP is less common in women who smoke, which is associated with lower hCG.²⁶

During pregnancy, actions of hCG stimulate the thyroid. Hyperstimulation, leading to transient hyperthyroidism, has been implicated in NVP development.^20,26 Symptom severity and the degree of thyroid stimulating hormone (TSH) suppression are closely correlated.²⁶

Elevated hCG levels, hypersensitive TSH receptors, and the presence of a hyperactive hCG isoform have been proposed.²⁰

Gastrointestinal disorders are believed to be involved in the pathogenesis of persistent NVP. Women with NVP usually lack structural or mucosal abnormalities and have normal endoscopic upper GI evaluations. They may, however, have disorders of the stomach’s neuromuscular function. Severe cases of gastric dysrhythmias and abnormalities of gastric tone may lead to gastroparesis.²⁷

Stomach motility in pregnancy is influenced by neurohormonal changes, specifically in estrogen and thyroid hormones. Gastric motility abnormalities—evaluated by electrogastrography (EGG)—have been associated with NVP symptoms and normal EGGs with the absence of symptoms. Some women who had NVP and abnormal EGGs were retested after delivery when symptom-free and found to have normal myoelectric EGG patterns.²⁷

Helicobacter pylori also may be involved in NVP, and at least 1 study found active H pylori infection and HG to be highly correlated. Pregnancy is not believed to predispose to H pylori infection, but active infection compounded by pregnancy’s hormonal changes may exacerbate NVP.²⁸

NVP and motion sickness share many features, suggesting that NVP treatment could be targeted if a vestibular disorder could be discovered.²⁹ Abnormal electroencephalography—particularly generalized slowing—that is not present in asymptomatic pregnant women has been reported in women with NVP.³⁰

CNS contributions. Persistent NVP may be a learned behavior,²⁴ a view based on findings of anticipatory nausea and vomiting in chemotherapy patients. Through conditioning, a pregnant woman may associate her physical symptoms with elements in her life that maintain the cycle of nausea and vomiting.³¹

Treating psychological symptoms

Brief psychotherapy to identify and correct sources of anxiety in pregnancy may alleviate a patient’s nausea and vomiting.³²

• Progressive muscle relaxation training, often combined with guided imagery, can decrease nausea and vomiting associated with chemotherapy and may prevent anticipatory symptoms by decreasing anxiety.
• Systematic desensitization is successful in most chemotherapy patients who try it. In this technique, relaxation is counter-conditioned as a response to stimuli known to elicit symptoms.³¹

Hypnosis allows patients to achieve a physiologic state incompatible with nausea and vomiting³¹ and can terminate vomiting after 1 to 3 sessions.³

Medication. Similar to ondansetron, the antidepressant mirtazapine exhibits an antiemetic effect by blocking the 5-HT3 receptor. In treatment-resistant cases, mirtazapine, 30 mg/d, has been reported to ameliorate NVP symptoms, usually within 24 hours. Patients were able to return to normal diets and discontinue treatment after 6 to 10 days. Mirtazapine appears to be safe during pregnancy, based on animal studies using 17 and 20 times the maximum recommended human dose.³³

For patients with anxiety symptoms, consider other medications—including selective serotonin reuptake inhibitors and benzodiazepines—only after counseling the patient about potential risks and benefits to her and the fetus.³⁴

Alternative treatments. In traditional Indian medicine, a mixture of powdered ginger and honey is given to women with NVP. At least 2 studies demonstrate ginger’s efficacy.³⁵

In traditional Chinese medicine, stimulating the Neiguan point (P6) on the wrist is believed to relieve nausea and vomiting. Although results are inconclusive, studies suggest that P6 stimulation can help control NVP.³⁶ The FDA has approved wristbands that stimulate the P6 site, either electrically or by acupressure (Figure).³⁶

Figure Wristband to manage nausea and vomiting in pregnancy

The FDA-cleared BioBand acupressure wristband may help control nausea and vomiting in pregnancy by stimulating the Neiguan point (P6) on the wrist.
Source: Reference 36Consider thiamine supplementation for women with severe symptoms, as Wernicke’s encephalopathy is a rare complication of prolonged NVP.^19,37

Related resources

• Motherisk Program at The Hospital for Sick Children, Toronto, Ontario, Canada. Website with information on vomiting during pregnancy: www.motherisk.org/women/morningSickness.jsp. Nausea and vomiting of pregnancy (NVP) forum. www.motherisk.org/women/forum.jsp.
• BioBand acupuncture wristband. www.BioBands.com.
• Koren G, Bishai R, eds. Nausea and vomiting of pregnancy: state of the art 2000. Toronto, Ontario, Canada: The Motherisk Program; 2000.

Drug brand names

• Dimenhydrinate • Dramamine
• Doxylamine • Unisom
• Methylprednisolone • Medrol
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Ondansetron • Zofran
• Promethazine • Phenergan
• Trimethobenzamide • Tigan

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.

General psychiatry practitioners such as myself traditionally have relied on writing case reports to describe our clinical experience. One obstacle to getting cases published is that many research journals require submitted articles to include large samples and rating scales as measures of change in the conditions of patients being studied.

I have published articles about my clinical experiences using patient data collected with the Clinical Global Impressions (CGI) scale and other standardized tests. Research instruments such as the CGI can gather empiric data and are easy to use in clinical practice.¹

This article describes how routine standardized testing provides useful data for research and improves diagnostic accuracy—and patient outcomes—even before I meet my patients for the first time.

Why use standardized tests?

Benefits. All my new patients undergo screening before their first face-to-face meeting with a psychiatrist. This registration visit takes about 2 hours, after which they are scheduled for an appointment based on clinical urgency. We charge no fee for the screening visit; the benefits of gathering a comprehensive database before the clinical evaluation outweigh the cost of the tests, software, and staff time.

Along with completing insurance and biographical paperwork, patients perform self-administered psychosocial and medical histories and a battery of standardized tests. This information allows me to focus on interpersonal issues—rather than fact-finding—during the first interview. It also ensures a comprehensive patient history.

Box 1

Limitations. One limitation to using rating scales to publish experiences in clinical practice is that clinical need, rather than a research protocol, determines the frequency of visits. Another is that we ask patients to rate symptoms they experience in the week before office visits. Thus, the data do not capture changes that occurred in other weeks.

Standardized tests we use

Except for the Quick Inventory of Depressive Symptomatology (QIDS), I selected the tests I use in the late 1980s because of:

• their ease of use and affordability
  
• my familiarity with them from my academic work
  
• their suitability for a mood disorder clinical practice such as mine.
  

Psychosocial history. Patients use an office computer to complete a questionnaire about family and developmental history, financial and employment history, education, health, alcohol and drug history, current stressors, and the presenting problem. Software from Multi-Health Systems (See Related Resources) allows me to add or remove questions as needed.

To ensure privacy when the next patient uses the computer, each patient’s report is deleted after it is printed. I receive the printed report, which details all responses and flags those that may require clarification.

Medical history. A standardized form asks patients about whether they have had most common medical conditions, their present symptoms, and family members’ health. An additional form inquires into psychiatric treatment, family history of psychiatric illnesses, and present medications.

Mini-SCID. The Mini-SCID has several advantages over the Structured Clinical Interview for DSM (SCID):

• Patients self-administer the test on a computer at the office.
  
• For research purposes, Mini-SCID results are protected from clinician biases because patients are interviewed using uniform questions and circumstances.
  

Box 2

Symptom Checklist-90 (SCL-90). This tool adds another layer of support for bipolar illness diagnosis (Box 1). It also is useful in conjunction with rating scales specific to other diagnostic categories, such as depression and anxiety.

The SCL-90³ consists of 90 statements that measure the severity of 9 dimensions of psychopathology: somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Using a scale of 0 (not at all) to 4 (a great deal), patients rate how much they are bothered by the feelings expressed in each statement.

In its standard scoring, the SCL-90 returns a score for 9 scales. Hunter et al⁴ developed an alternate set of 8 scales that uses SCL-90 questions to screen for depression, mania, schizophrenia, antisocial personality disorder, somatization disorder, obsessive-compulsive disorder, panic disorder, and agoraphobia. These SCL-90 diagnostic scales showed good reliability as an aid to the Mini-SCID in identifying diagnoses among 1,457 adult psychiatric outpatients.

Clinical Global Impressions scale. The CGI uses a 7-point Likert scale to describe the clinician’s impression of change in a patient’s condition. This scale:

• transcends symptom checklists by incorporating knowledge of the patient’s history, symptoms, and behaviors
  
• lends itself easily to repeated measures of change and severity of the condition being rated.¹
  

Every office visit

At the screening visit and before every office visit, my patients complete 2 depression rating tests to document changes between visits and over time: a visual analog scale (VAS) and the QIDS.

The VAS’ 10-cm line with the left side marked “worst ever” and the right side marked “best ever” is a simple tool. It captures patients’ subjective impressions of their mood states in answer to the question, “How do you feel today?” I used the VAS as an outcome measure in a study of modafinil augmentation of antidepressant therapy.⁷

The QIDS is a 16-item screen that measures 9 depressive symptoms.⁸ It has been validated against the Hamilton Depression Rating Scale (HAM-D)⁹ and was used as the outcome measure in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.¹⁰ The QIDS-16 is available online for free use in many languages (see Related Resources).¹¹

Until recently, our office performed routine depression screening with the 52-item Carroll Depression Rating Scale (CDRS),¹³ a self-administered inventory designed to mirror results from the HAM-D. I published articles using the CDRS as the primary outcome measure in a chart review of long-term effectiveness of antidepressant monotherapy (Box 3)^13,14 and in a study of modafinil’s effectiveness as adjunctive therapy in patients with unipolar depression.⁷

Box 3

Logistical concerns

Patient feedback. Although some patients complain about having to complete depression rating scales at every visit, most accept this as equivalent to having routine blood pressure measurements. Many become interested in tracking their improvement by test scores in addition to subjective feelings.

Related resources

• Multi-Health Systems. Publishers of mental health assessment tools. www.mhs.com.
  
• Inventory of Depressive Symptomatology (IDS) and Quick Inventory of Depressive Symptomatology (QIDS). www.ids-qids.org.
  

• Modafinil • Provigil
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Dr. Nasr is a speaker for Takeda Pharmaceutical Company, Pfizer Inc, Eli Lilly and Company, Bristol-Myers Squibb, Forest Pharmaceuticals, and GlaxoSmithKline.

Acknowledgment

Dr. Nasr acknowledges the contribution of research assistant Burdette J. Wendt, who collects and analyzes the data referenced above and helped prepare this manuscript.

HIPAA. The Health Insurance Portability and Accountability Act (HIPAA) allows publication of large-scale studies that do not identify patients individually. We also obtained permission from the local Institutional Review Board to disseminate non-identifying cumulative data.

General psychiatry practitioners such as myself traditionally have relied on writing case reports to describe our clinical experience. One obstacle to getting cases published is that many research journals require submitted articles to include large samples and rating scales as measures of change in the conditions of patients being studied.

I have published articles about my clinical experiences using patient data collected with the Clinical Global Impressions (CGI) scale and other standardized tests. Research instruments such as the CGI can gather empiric data and are easy to use in clinical practice.¹

This article describes how routine standardized testing provides useful data for research and improves diagnostic accuracy—and patient outcomes—even before I meet my patients for the first time.

Why use standardized tests?

Benefits. All my new patients undergo screening before their first face-to-face meeting with a psychiatrist. This registration visit takes about 2 hours, after which they are scheduled for an appointment based on clinical urgency. We charge no fee for the screening visit; the benefits of gathering a comprehensive database before the clinical evaluation outweigh the cost of the tests, software, and staff time.

Along with completing insurance and biographical paperwork, patients perform self-administered psychosocial and medical histories and a battery of standardized tests. This information allows me to focus on interpersonal issues—rather than fact-finding—during the first interview. It also ensures a comprehensive patient history.

Box 1

Limitations. One limitation to using rating scales to publish experiences in clinical practice is that clinical need, rather than a research protocol, determines the frequency of visits. Another is that we ask patients to rate symptoms they experience in the week before office visits. Thus, the data do not capture changes that occurred in other weeks.

Standardized tests we use

Except for the Quick Inventory of Depressive Symptomatology (QIDS), I selected the tests I use in the late 1980s because of:

• their ease of use and affordability
  
• my familiarity with them from my academic work
  
• their suitability for a mood disorder clinical practice such as mine.
  

Psychosocial history. Patients use an office computer to complete a questionnaire about family and developmental history, financial and employment history, education, health, alcohol and drug history, current stressors, and the presenting problem. Software from Multi-Health Systems (See Related Resources) allows me to add or remove questions as needed.

To ensure privacy when the next patient uses the computer, each patient’s report is deleted after it is printed. I receive the printed report, which details all responses and flags those that may require clarification.

Medical history. A standardized form asks patients about whether they have had most common medical conditions, their present symptoms, and family members’ health. An additional form inquires into psychiatric treatment, family history of psychiatric illnesses, and present medications.

Mini-SCID. The Mini-SCID has several advantages over the Structured Clinical Interview for DSM (SCID):

• Patients self-administer the test on a computer at the office.
  
• For research purposes, Mini-SCID results are protected from clinician biases because patients are interviewed using uniform questions and circumstances.
  

Box 2

Symptom Checklist-90 (SCL-90). This tool adds another layer of support for bipolar illness diagnosis (Box 1). It also is useful in conjunction with rating scales specific to other diagnostic categories, such as depression and anxiety.

The SCL-90³ consists of 90 statements that measure the severity of 9 dimensions of psychopathology: somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Using a scale of 0 (not at all) to 4 (a great deal), patients rate how much they are bothered by the feelings expressed in each statement.

In its standard scoring, the SCL-90 returns a score for 9 scales. Hunter et al⁴ developed an alternate set of 8 scales that uses SCL-90 questions to screen for depression, mania, schizophrenia, antisocial personality disorder, somatization disorder, obsessive-compulsive disorder, panic disorder, and agoraphobia. These SCL-90 diagnostic scales showed good reliability as an aid to the Mini-SCID in identifying diagnoses among 1,457 adult psychiatric outpatients.

Clinical Global Impressions scale. The CGI uses a 7-point Likert scale to describe the clinician’s impression of change in a patient’s condition. This scale:

• transcends symptom checklists by incorporating knowledge of the patient’s history, symptoms, and behaviors
  
• lends itself easily to repeated measures of change and severity of the condition being rated.¹
  

Every office visit

At the screening visit and before every office visit, my patients complete 2 depression rating tests to document changes between visits and over time: a visual analog scale (VAS) and the QIDS.

The VAS’ 10-cm line with the left side marked “worst ever” and the right side marked “best ever” is a simple tool. It captures patients’ subjective impressions of their mood states in answer to the question, “How do you feel today?” I used the VAS as an outcome measure in a study of modafinil augmentation of antidepressant therapy.⁷

The QIDS is a 16-item screen that measures 9 depressive symptoms.⁸ It has been validated against the Hamilton Depression Rating Scale (HAM-D)⁹ and was used as the outcome measure in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.¹⁰ The QIDS-16 is available online for free use in many languages (see Related Resources).¹¹

Until recently, our office performed routine depression screening with the 52-item Carroll Depression Rating Scale (CDRS),¹³ a self-administered inventory designed to mirror results from the HAM-D. I published articles using the CDRS as the primary outcome measure in a chart review of long-term effectiveness of antidepressant monotherapy (Box 3)^13,14 and in a study of modafinil’s effectiveness as adjunctive therapy in patients with unipolar depression.⁷

Box 3

Logistical concerns

Patient feedback. Although some patients complain about having to complete depression rating scales at every visit, most accept this as equivalent to having routine blood pressure measurements. Many become interested in tracking their improvement by test scores in addition to subjective feelings.

Related resources

• Multi-Health Systems. Publishers of mental health assessment tools. www.mhs.com.
  
• Inventory of Depressive Symptomatology (IDS) and Quick Inventory of Depressive Symptomatology (QIDS). www.ids-qids.org.
  

• Modafinil • Provigil
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Dr. Nasr is a speaker for Takeda Pharmaceutical Company, Pfizer Inc, Eli Lilly and Company, Bristol-Myers Squibb, Forest Pharmaceuticals, and GlaxoSmithKline.

Acknowledgment

Dr. Nasr acknowledges the contribution of research assistant Burdette J. Wendt, who collects and analyzes the data referenced above and helped prepare this manuscript.

HIPAA. The Health Insurance Portability and Accountability Act (HIPAA) allows publication of large-scale studies that do not identify patients individually. We also obtained permission from the local Institutional Review Board to disseminate non-identifying cumulative data.

General psychiatry practitioners such as myself traditionally have relied on writing case reports to describe our clinical experience. One obstacle to getting cases published is that many research journals require submitted articles to include large samples and rating scales as measures of change in the conditions of patients being studied.

I have published articles about my clinical experiences using patient data collected with the Clinical Global Impressions (CGI) scale and other standardized tests. Research instruments such as the CGI can gather empiric data and are easy to use in clinical practice.¹

This article describes how routine standardized testing provides useful data for research and improves diagnostic accuracy—and patient outcomes—even before I meet my patients for the first time.

Why use standardized tests?

Benefits. All my new patients undergo screening before their first face-to-face meeting with a psychiatrist. This registration visit takes about 2 hours, after which they are scheduled for an appointment based on clinical urgency. We charge no fee for the screening visit; the benefits of gathering a comprehensive database before the clinical evaluation outweigh the cost of the tests, software, and staff time.

Along with completing insurance and biographical paperwork, patients perform self-administered psychosocial and medical histories and a battery of standardized tests. This information allows me to focus on interpersonal issues—rather than fact-finding—during the first interview. It also ensures a comprehensive patient history.

Box 1

Limitations. One limitation to using rating scales to publish experiences in clinical practice is that clinical need, rather than a research protocol, determines the frequency of visits. Another is that we ask patients to rate symptoms they experience in the week before office visits. Thus, the data do not capture changes that occurred in other weeks.

Standardized tests we use

Except for the Quick Inventory of Depressive Symptomatology (QIDS), I selected the tests I use in the late 1980s because of:

• their ease of use and affordability
  
• my familiarity with them from my academic work
  
• their suitability for a mood disorder clinical practice such as mine.
  

Psychosocial history. Patients use an office computer to complete a questionnaire about family and developmental history, financial and employment history, education, health, alcohol and drug history, current stressors, and the presenting problem. Software from Multi-Health Systems (See Related Resources) allows me to add or remove questions as needed.

To ensure privacy when the next patient uses the computer, each patient’s report is deleted after it is printed. I receive the printed report, which details all responses and flags those that may require clarification.

Medical history. A standardized form asks patients about whether they have had most common medical conditions, their present symptoms, and family members’ health. An additional form inquires into psychiatric treatment, family history of psychiatric illnesses, and present medications.

Mini-SCID. The Mini-SCID has several advantages over the Structured Clinical Interview for DSM (SCID):

• Patients self-administer the test on a computer at the office.
  
• For research purposes, Mini-SCID results are protected from clinician biases because patients are interviewed using uniform questions and circumstances.
  

Box 2

Symptom Checklist-90 (SCL-90). This tool adds another layer of support for bipolar illness diagnosis (Box 1). It also is useful in conjunction with rating scales specific to other diagnostic categories, such as depression and anxiety.

The SCL-90³ consists of 90 statements that measure the severity of 9 dimensions of psychopathology: somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Using a scale of 0 (not at all) to 4 (a great deal), patients rate how much they are bothered by the feelings expressed in each statement.

In its standard scoring, the SCL-90 returns a score for 9 scales. Hunter et al⁴ developed an alternate set of 8 scales that uses SCL-90 questions to screen for depression, mania, schizophrenia, antisocial personality disorder, somatization disorder, obsessive-compulsive disorder, panic disorder, and agoraphobia. These SCL-90 diagnostic scales showed good reliability as an aid to the Mini-SCID in identifying diagnoses among 1,457 adult psychiatric outpatients.

Clinical Global Impressions scale. The CGI uses a 7-point Likert scale to describe the clinician’s impression of change in a patient’s condition. This scale:

• transcends symptom checklists by incorporating knowledge of the patient’s history, symptoms, and behaviors
  
• lends itself easily to repeated measures of change and severity of the condition being rated.¹
  

Every office visit

At the screening visit and before every office visit, my patients complete 2 depression rating tests to document changes between visits and over time: a visual analog scale (VAS) and the QIDS.

The VAS’ 10-cm line with the left side marked “worst ever” and the right side marked “best ever” is a simple tool. It captures patients’ subjective impressions of their mood states in answer to the question, “How do you feel today?” I used the VAS as an outcome measure in a study of modafinil augmentation of antidepressant therapy.⁷

The QIDS is a 16-item screen that measures 9 depressive symptoms.⁸ It has been validated against the Hamilton Depression Rating Scale (HAM-D)⁹ and was used as the outcome measure in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.¹⁰ The QIDS-16 is available online for free use in many languages (see Related Resources).¹¹

Until recently, our office performed routine depression screening with the 52-item Carroll Depression Rating Scale (CDRS),¹³ a self-administered inventory designed to mirror results from the HAM-D. I published articles using the CDRS as the primary outcome measure in a chart review of long-term effectiveness of antidepressant monotherapy (Box 3)^13,14 and in a study of modafinil’s effectiveness as adjunctive therapy in patients with unipolar depression.⁷

Box 3

Logistical concerns

Patient feedback. Although some patients complain about having to complete depression rating scales at every visit, most accept this as equivalent to having routine blood pressure measurements. Many become interested in tracking their improvement by test scores in addition to subjective feelings.

Related resources

• Multi-Health Systems. Publishers of mental health assessment tools. www.mhs.com.
  
• Inventory of Depressive Symptomatology (IDS) and Quick Inventory of Depressive Symptomatology (QIDS). www.ids-qids.org.
  

• Modafinil • Provigil
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Dr. Nasr is a speaker for Takeda Pharmaceutical Company, Pfizer Inc, Eli Lilly and Company, Bristol-Myers Squibb, Forest Pharmaceuticals, and GlaxoSmithKline.

Acknowledgment

Dr. Nasr acknowledges the contribution of research assistant Burdette J. Wendt, who collects and analyzes the data referenced above and helped prepare this manuscript.

HIPAA. The Health Insurance Portability and Accountability Act (HIPAA) allows publication of large-scale studies that do not identify patients individually. We also obtained permission from the local Institutional Review Board to disseminate non-identifying cumulative data.

Sexual disorders such as premature ejaculation, erectile dysfunction (ED), and low libido reduce quality of life in patients with depression, anxiety, and other psychiatric illnesses. In addition, sexual dysfunction is a side effect of many drugs used to treat psychiatric disorders.¹

Psychiatry—with its biopsychosocial model—can easily assume the evaluation and treatment of sexual disorders. To inform your practice, this article provides an update on pharmacotherapy for the 3 most common sexual disorders. Its emphasis on biologic treatment is not intended to minimize the importance of psychological interventions.

Premature ejaculation

Premature ejaculation is one of the most common male sexual complaints. In some surveys, approximately 30% of men express concern about ejaculating too rapidly.² Behavioral therapy often is effective (Box 1), but in my experience most male patients prefer a pharmacologic approach to sexual problems.

Anesthetic creams. Locally applied anesthetic creams—such as prilocaine, lidocaine mixtures, and creams consisting of natural herbs—can increase ejaculatory latency by approximately 7 to 10 minutes. The major side effect of these preparations is penile hypoanesthesia. The man also must use a condom or wash off the cream before vaginal penetration to minimize vaginal absorption.³

Box 1

Among the SSRIs, paroxetine appears to have the greatest effect on ejaculatory latency (Table 1).⁵ Most trials have found that the dose needed to delay ejaculation is similar to the dose necessary to treat depressive disorders.

Some case reports suggest that phosphodiesterase type 5 inhibitors (PDE-5 inhibitors) may help to delay ejaculation, but this effect has not been borne out in double-blind studies.⁶

Table 1

Drug treatment options for premature ejaculation

Erectile dysfunction

Men with major depressive disorder, anxiety disorders, and psychotic disorders have higher rates of ED, compared with the general male population. ED also can be a side effect of—and adversely affect adherence to—antidepressant and antipsychotic therapy.⁷ Restored erectile function can positively affect patients’ self-esteem and sense of personal efficacy and may facilitate recovery from depression.⁸

PDE-5 inhibitors. Nitric oxide release triggers the production of cyclic guanosine monophosphate, which leads to decreased intracellular calcium, smooth muscle relaxation, and penile erection. All available PDE-5 inhibitors work by inhibiting the degradation of cyclic guanosine monophosphate. They are highly specific, vary somewhat in selectivity for other phosphodiesterase enzyme types, and differ in duration of action (Table 2).

Common side effects include dyspepsia, stuffy nose, and headache. The use of PDE-5 inhibitors with nitrates is contraindicated because of the risk of severe hypotension. Use PDE-5 inhibitors cautiously:

• with alpha blockers because of the risk of hypotension
  
• in men with aortic stenosis, recent myocardial infarction, unstable angina, heart failure, arrhythmias, degenerative retinal disease, or poorly controlled hypertension.⁹
  

Table 2

Duration of action of PDE-5 inhibitors

Other options. Other accepted options for treating ED include intracavernosal injection of vasoactive substances such as phentolamine or prostaglandin E1, or intraurethral insertion of prostaglandins.¹² Since the advent of PDE-5 inhibitors, these approaches are rarely used.

Cabergoline. Off-label use of dopaminergic agents such as cabergoline may be moderately effective in treating ED in men who do not respond adequately to PDE-5 inhibitors. Cabergoline is a dopamine D2 receptor agonist used to treat hyperprolactinemia and Parkinson’s disease.

In a randomized, double-blind, placebo- controlled study, 402 men who did not respond to sildenafil received cabergoline, 0.5 to 1 mg weekly for 6 months. Among the 370 men (92%) who completed the trial, mean weekly intercourse episodes increased from 1.4 to 2.2, compared with 1.2 to 1.4 in men who received placebo.¹³

Cabergoline also improved erectile function and sexual satisfaction in a randomized, double-blind, placebo-controlled trial of 50 men with psychogenic erectile dysfunction.¹⁴

Treatment outcomes. Most studies report positive psychological responses to ED reversal in men using PDE-5 inhibitors. Successful therapy has been associated with increased self-esteem, satisfaction, and sexual satisfaction.⁸ Some studies have found increased sexual satisfaction in the partner as well.¹⁵

Approximately 50% of PDE-5 inhibitor prescriptions are not refilled, however, and some case reports suggest that restored erectile function can result in:

• divorce and marital discord
  
• no change in partner-related activity.¹⁶
  

Hypoactive sexual desire

PDE-5 inhibitors. The success of PDE-5 inhibitors in treating ED led to investigations into whether these agents also could treat female sexual disorders. Large multisite trials using sildenafil failed to find evidence of efficacy in treating female hypoactive sexual desire or arousal disorders, however.¹⁸ Similarly, trials of topical prostaglandin E1 and alpha blockers were unsuccessful in women.

Some small studies suggested that PDE-5 inhibitors might be useful in:

• women with normal libido but decreased arousal¹⁹
  
• young women with normal libido and inability to reach orgasm.²⁰
  

More recently, Shifren et al²² showed in a randomized, placebo-controlled trial that transdermal testosterone, 150 or 300 micrograms/day for 12 weeks, improved sexual function and psychological wellbeing in women age 31 to 56 after surgical menopause. Since then, numerous large, multisite, double-blind studies have demonstrated the efficacy of transdermal testosterone in treating low sexual desire in surgically menopausal women.²³ Transdermal testosterone has been approved for this indication in the European Union but not in the United States.

Testosterone also has been reported to increase sexual desire in women who experienced natural menopause and in normal premenopausal women.²⁴ The study of the relationship of testosterone to libido in women is complicated by numerous factors, however (Box 2).^23,24

Other agents. Recent research has focused on centrally active compounds’ effect on libido. One agent in development is flibanserin, a serotonergic 5HT2 antagonist and a 5HT1a agonist. Data from large, multisite studies indicates that this compound increases libido in women with low sexual desire.

Box 2

The investigational compound bremelanotide—a synthetic version of melanocytes stimulating hormone—is administered intranasally and appears to acutely influence libido in women.²⁶ Trials have been delayed because of this agent’s effects on blood pressure.

Herbal compounds. Some herbal compounds are being sold for low-desire complaints. Web sites for 2 herbal compounds, Ziti and Alibi, cite unpublished double-blind studies attesting to their efficacy. Because these studies are unpublished, one cannot evaluate their methodologies.

One double-blind study of the herbal compound ArginMax—which contains ginseng, ginkgo, damiana, L-arginine, and multivitamins—suggests efficacy in a small group of women with poorly specified sexual problems.²⁷ Zestra, a topical herbal compound, has been evaluated in large multisite studies and found to be effective in increasing female sexual responsiveness.²⁸

Other approaches. Some clinicians advocate using the testosterone precursor dehydroepiandrosterone (DHEA) for low sexual desire, although evidence does not support its efficacy.²⁹

A battery-operated device is FDA -approved for treating sexual dysfunction in women. The clitoral vacuum increases vaginal engorgement and various indices of sexual responsiveness. This device’s target population is not clearly defined.³⁰

When medication side effects are causing hypoactive sexual desire, consider substituting another drug or using antidotes such as buspirone or bupropion. Unfortunately, however, most sexual desire problems are idiopathic.

Testosterone therapy has been shown to improve libido, although it is not FDA-approved for this indication. Considerable off-label use occurs, but long-term safety is unknown.

Related resource

• Medline Plus. Sexual problems overview. www.nlm.nih.gov/medlineplus/ency/article/001951.htm.
  

• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Cabergoline • Dostinex
  
• Clomipramine • Anafranil
  
• Fluoxetine • Prozac
  
• Lorazepam • Ativan
  
• Paroxetine • Paxil
  
• Phentolamine • Regitine
  
• Prostaglandin E1 • Liprostin
  
• Sertraline • Zoloft
  
• Sildenafil • Viagr
  
• Tadalafil • Cialis
  
• Vardenafil • Levitra
  

Dr. Segraves receives grant/research support from Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Novartis and is a consultant to Eli Lilly and Company, GlaxoSmithKline, Boehringer Ingelheim, and Bristol-Myers Squibb.

Sexual disorders such as premature ejaculation, erectile dysfunction (ED), and low libido reduce quality of life in patients with depression, anxiety, and other psychiatric illnesses. In addition, sexual dysfunction is a side effect of many drugs used to treat psychiatric disorders.¹

Psychiatry—with its biopsychosocial model—can easily assume the evaluation and treatment of sexual disorders. To inform your practice, this article provides an update on pharmacotherapy for the 3 most common sexual disorders. Its emphasis on biologic treatment is not intended to minimize the importance of psychological interventions.

Premature ejaculation

Premature ejaculation is one of the most common male sexual complaints. In some surveys, approximately 30% of men express concern about ejaculating too rapidly.² Behavioral therapy often is effective (Box 1), but in my experience most male patients prefer a pharmacologic approach to sexual problems.

Anesthetic creams. Locally applied anesthetic creams—such as prilocaine, lidocaine mixtures, and creams consisting of natural herbs—can increase ejaculatory latency by approximately 7 to 10 minutes. The major side effect of these preparations is penile hypoanesthesia. The man also must use a condom or wash off the cream before vaginal penetration to minimize vaginal absorption.³

Box 1

Among the SSRIs, paroxetine appears to have the greatest effect on ejaculatory latency (Table 1).⁵ Most trials have found that the dose needed to delay ejaculation is similar to the dose necessary to treat depressive disorders.

Some case reports suggest that phosphodiesterase type 5 inhibitors (PDE-5 inhibitors) may help to delay ejaculation, but this effect has not been borne out in double-blind studies.⁶

Table 1

Drug treatment options for premature ejaculation

Erectile dysfunction

Men with major depressive disorder, anxiety disorders, and psychotic disorders have higher rates of ED, compared with the general male population. ED also can be a side effect of—and adversely affect adherence to—antidepressant and antipsychotic therapy.⁷ Restored erectile function can positively affect patients’ self-esteem and sense of personal efficacy and may facilitate recovery from depression.⁸

PDE-5 inhibitors. Nitric oxide release triggers the production of cyclic guanosine monophosphate, which leads to decreased intracellular calcium, smooth muscle relaxation, and penile erection. All available PDE-5 inhibitors work by inhibiting the degradation of cyclic guanosine monophosphate. They are highly specific, vary somewhat in selectivity for other phosphodiesterase enzyme types, and differ in duration of action (Table 2).

Common side effects include dyspepsia, stuffy nose, and headache. The use of PDE-5 inhibitors with nitrates is contraindicated because of the risk of severe hypotension. Use PDE-5 inhibitors cautiously:

• with alpha blockers because of the risk of hypotension
  
• in men with aortic stenosis, recent myocardial infarction, unstable angina, heart failure, arrhythmias, degenerative retinal disease, or poorly controlled hypertension.⁹
  

Table 2

Duration of action of PDE-5 inhibitors

Other options. Other accepted options for treating ED include intracavernosal injection of vasoactive substances such as phentolamine or prostaglandin E1, or intraurethral insertion of prostaglandins.¹² Since the advent of PDE-5 inhibitors, these approaches are rarely used.

Cabergoline. Off-label use of dopaminergic agents such as cabergoline may be moderately effective in treating ED in men who do not respond adequately to PDE-5 inhibitors. Cabergoline is a dopamine D2 receptor agonist used to treat hyperprolactinemia and Parkinson’s disease.

In a randomized, double-blind, placebo- controlled study, 402 men who did not respond to sildenafil received cabergoline, 0.5 to 1 mg weekly for 6 months. Among the 370 men (92%) who completed the trial, mean weekly intercourse episodes increased from 1.4 to 2.2, compared with 1.2 to 1.4 in men who received placebo.¹³

Cabergoline also improved erectile function and sexual satisfaction in a randomized, double-blind, placebo-controlled trial of 50 men with psychogenic erectile dysfunction.¹⁴

Treatment outcomes. Most studies report positive psychological responses to ED reversal in men using PDE-5 inhibitors. Successful therapy has been associated with increased self-esteem, satisfaction, and sexual satisfaction.⁸ Some studies have found increased sexual satisfaction in the partner as well.¹⁵

Approximately 50% of PDE-5 inhibitor prescriptions are not refilled, however, and some case reports suggest that restored erectile function can result in:

• divorce and marital discord
  
• no change in partner-related activity.¹⁶
  

Hypoactive sexual desire

PDE-5 inhibitors. The success of PDE-5 inhibitors in treating ED led to investigations into whether these agents also could treat female sexual disorders. Large multisite trials using sildenafil failed to find evidence of efficacy in treating female hypoactive sexual desire or arousal disorders, however.¹⁸ Similarly, trials of topical prostaglandin E1 and alpha blockers were unsuccessful in women.

Some small studies suggested that PDE-5 inhibitors might be useful in:

• women with normal libido but decreased arousal¹⁹
  
• young women with normal libido and inability to reach orgasm.²⁰
  

More recently, Shifren et al²² showed in a randomized, placebo-controlled trial that transdermal testosterone, 150 or 300 micrograms/day for 12 weeks, improved sexual function and psychological wellbeing in women age 31 to 56 after surgical menopause. Since then, numerous large, multisite, double-blind studies have demonstrated the efficacy of transdermal testosterone in treating low sexual desire in surgically menopausal women.²³ Transdermal testosterone has been approved for this indication in the European Union but not in the United States.

Testosterone also has been reported to increase sexual desire in women who experienced natural menopause and in normal premenopausal women.²⁴ The study of the relationship of testosterone to libido in women is complicated by numerous factors, however (Box 2).^23,24

Other agents. Recent research has focused on centrally active compounds’ effect on libido. One agent in development is flibanserin, a serotonergic 5HT2 antagonist and a 5HT1a agonist. Data from large, multisite studies indicates that this compound increases libido in women with low sexual desire.

Box 2

The investigational compound bremelanotide—a synthetic version of melanocytes stimulating hormone—is administered intranasally and appears to acutely influence libido in women.²⁶ Trials have been delayed because of this agent’s effects on blood pressure.

Herbal compounds. Some herbal compounds are being sold for low-desire complaints. Web sites for 2 herbal compounds, Ziti and Alibi, cite unpublished double-blind studies attesting to their efficacy. Because these studies are unpublished, one cannot evaluate their methodologies.

One double-blind study of the herbal compound ArginMax—which contains ginseng, ginkgo, damiana, L-arginine, and multivitamins—suggests efficacy in a small group of women with poorly specified sexual problems.²⁷ Zestra, a topical herbal compound, has been evaluated in large multisite studies and found to be effective in increasing female sexual responsiveness.²⁸

Other approaches. Some clinicians advocate using the testosterone precursor dehydroepiandrosterone (DHEA) for low sexual desire, although evidence does not support its efficacy.²⁹

A battery-operated device is FDA -approved for treating sexual dysfunction in women. The clitoral vacuum increases vaginal engorgement and various indices of sexual responsiveness. This device’s target population is not clearly defined.³⁰

When medication side effects are causing hypoactive sexual desire, consider substituting another drug or using antidotes such as buspirone or bupropion. Unfortunately, however, most sexual desire problems are idiopathic.

Testosterone therapy has been shown to improve libido, although it is not FDA-approved for this indication. Considerable off-label use occurs, but long-term safety is unknown.

Related resource

• Medline Plus. Sexual problems overview. www.nlm.nih.gov/medlineplus/ency/article/001951.htm.
  

• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Cabergoline • Dostinex
  
• Clomipramine • Anafranil
  
• Fluoxetine • Prozac
  
• Lorazepam • Ativan
  
• Paroxetine • Paxil
  
• Phentolamine • Regitine
  
• Prostaglandin E1 • Liprostin
  
• Sertraline • Zoloft
  
• Sildenafil • Viagr
  
• Tadalafil • Cialis
  
• Vardenafil • Levitra
  

Dr. Segraves receives grant/research support from Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Novartis and is a consultant to Eli Lilly and Company, GlaxoSmithKline, Boehringer Ingelheim, and Bristol-Myers Squibb.

Sexual disorders such as premature ejaculation, erectile dysfunction (ED), and low libido reduce quality of life in patients with depression, anxiety, and other psychiatric illnesses. In addition, sexual dysfunction is a side effect of many drugs used to treat psychiatric disorders.¹

Psychiatry—with its biopsychosocial model—can easily assume the evaluation and treatment of sexual disorders. To inform your practice, this article provides an update on pharmacotherapy for the 3 most common sexual disorders. Its emphasis on biologic treatment is not intended to minimize the importance of psychological interventions.

Premature ejaculation

Premature ejaculation is one of the most common male sexual complaints. In some surveys, approximately 30% of men express concern about ejaculating too rapidly.² Behavioral therapy often is effective (Box 1), but in my experience most male patients prefer a pharmacologic approach to sexual problems.

Anesthetic creams. Locally applied anesthetic creams—such as prilocaine, lidocaine mixtures, and creams consisting of natural herbs—can increase ejaculatory latency by approximately 7 to 10 minutes. The major side effect of these preparations is penile hypoanesthesia. The man also must use a condom or wash off the cream before vaginal penetration to minimize vaginal absorption.³

Box 1

Among the SSRIs, paroxetine appears to have the greatest effect on ejaculatory latency (Table 1).⁵ Most trials have found that the dose needed to delay ejaculation is similar to the dose necessary to treat depressive disorders.

Some case reports suggest that phosphodiesterase type 5 inhibitors (PDE-5 inhibitors) may help to delay ejaculation, but this effect has not been borne out in double-blind studies.⁶

Table 1

Drug treatment options for premature ejaculation

Erectile dysfunction

Men with major depressive disorder, anxiety disorders, and psychotic disorders have higher rates of ED, compared with the general male population. ED also can be a side effect of—and adversely affect adherence to—antidepressant and antipsychotic therapy.⁷ Restored erectile function can positively affect patients’ self-esteem and sense of personal efficacy and may facilitate recovery from depression.⁸

PDE-5 inhibitors. Nitric oxide release triggers the production of cyclic guanosine monophosphate, which leads to decreased intracellular calcium, smooth muscle relaxation, and penile erection. All available PDE-5 inhibitors work by inhibiting the degradation of cyclic guanosine monophosphate. They are highly specific, vary somewhat in selectivity for other phosphodiesterase enzyme types, and differ in duration of action (Table 2).

Common side effects include dyspepsia, stuffy nose, and headache. The use of PDE-5 inhibitors with nitrates is contraindicated because of the risk of severe hypotension. Use PDE-5 inhibitors cautiously:

• with alpha blockers because of the risk of hypotension
  
• in men with aortic stenosis, recent myocardial infarction, unstable angina, heart failure, arrhythmias, degenerative retinal disease, or poorly controlled hypertension.⁹
  

Table 2

Duration of action of PDE-5 inhibitors

Other options. Other accepted options for treating ED include intracavernosal injection of vasoactive substances such as phentolamine or prostaglandin E1, or intraurethral insertion of prostaglandins.¹² Since the advent of PDE-5 inhibitors, these approaches are rarely used.

Cabergoline. Off-label use of dopaminergic agents such as cabergoline may be moderately effective in treating ED in men who do not respond adequately to PDE-5 inhibitors. Cabergoline is a dopamine D2 receptor agonist used to treat hyperprolactinemia and Parkinson’s disease.

In a randomized, double-blind, placebo- controlled study, 402 men who did not respond to sildenafil received cabergoline, 0.5 to 1 mg weekly for 6 months. Among the 370 men (92%) who completed the trial, mean weekly intercourse episodes increased from 1.4 to 2.2, compared with 1.2 to 1.4 in men who received placebo.¹³

Cabergoline also improved erectile function and sexual satisfaction in a randomized, double-blind, placebo-controlled trial of 50 men with psychogenic erectile dysfunction.¹⁴

Treatment outcomes. Most studies report positive psychological responses to ED reversal in men using PDE-5 inhibitors. Successful therapy has been associated with increased self-esteem, satisfaction, and sexual satisfaction.⁸ Some studies have found increased sexual satisfaction in the partner as well.¹⁵

Approximately 50% of PDE-5 inhibitor prescriptions are not refilled, however, and some case reports suggest that restored erectile function can result in:

• divorce and marital discord
  
• no change in partner-related activity.¹⁶
  

Hypoactive sexual desire

PDE-5 inhibitors. The success of PDE-5 inhibitors in treating ED led to investigations into whether these agents also could treat female sexual disorders. Large multisite trials using sildenafil failed to find evidence of efficacy in treating female hypoactive sexual desire or arousal disorders, however.¹⁸ Similarly, trials of topical prostaglandin E1 and alpha blockers were unsuccessful in women.

Some small studies suggested that PDE-5 inhibitors might be useful in:

• women with normal libido but decreased arousal¹⁹
  
• young women with normal libido and inability to reach orgasm.²⁰
  

More recently, Shifren et al²² showed in a randomized, placebo-controlled trial that transdermal testosterone, 150 or 300 micrograms/day for 12 weeks, improved sexual function and psychological wellbeing in women age 31 to 56 after surgical menopause. Since then, numerous large, multisite, double-blind studies have demonstrated the efficacy of transdermal testosterone in treating low sexual desire in surgically menopausal women.²³ Transdermal testosterone has been approved for this indication in the European Union but not in the United States.

Testosterone also has been reported to increase sexual desire in women who experienced natural menopause and in normal premenopausal women.²⁴ The study of the relationship of testosterone to libido in women is complicated by numerous factors, however (Box 2).^23,24

Other agents. Recent research has focused on centrally active compounds’ effect on libido. One agent in development is flibanserin, a serotonergic 5HT2 antagonist and a 5HT1a agonist. Data from large, multisite studies indicates that this compound increases libido in women with low sexual desire.

Box 2

The investigational compound bremelanotide—a synthetic version of melanocytes stimulating hormone—is administered intranasally and appears to acutely influence libido in women.²⁶ Trials have been delayed because of this agent’s effects on blood pressure.

Herbal compounds. Some herbal compounds are being sold for low-desire complaints. Web sites for 2 herbal compounds, Ziti and Alibi, cite unpublished double-blind studies attesting to their efficacy. Because these studies are unpublished, one cannot evaluate their methodologies.

One double-blind study of the herbal compound ArginMax—which contains ginseng, ginkgo, damiana, L-arginine, and multivitamins—suggests efficacy in a small group of women with poorly specified sexual problems.²⁷ Zestra, a topical herbal compound, has been evaluated in large multisite studies and found to be effective in increasing female sexual responsiveness.²⁸

Other approaches. Some clinicians advocate using the testosterone precursor dehydroepiandrosterone (DHEA) for low sexual desire, although evidence does not support its efficacy.²⁹

A battery-operated device is FDA -approved for treating sexual dysfunction in women. The clitoral vacuum increases vaginal engorgement and various indices of sexual responsiveness. This device’s target population is not clearly defined.³⁰

When medication side effects are causing hypoactive sexual desire, consider substituting another drug or using antidotes such as buspirone or bupropion. Unfortunately, however, most sexual desire problems are idiopathic.

Testosterone therapy has been shown to improve libido, although it is not FDA-approved for this indication. Considerable off-label use occurs, but long-term safety is unknown.

Related resource

• Medline Plus. Sexual problems overview. www.nlm.nih.gov/medlineplus/ency/article/001951.htm.
  

• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Cabergoline • Dostinex
  
• Clomipramine • Anafranil
  
• Fluoxetine • Prozac
  
• Lorazepam • Ativan
  
• Paroxetine • Paxil
  
• Phentolamine • Regitine
  
• Prostaglandin E1 • Liprostin
  
• Sertraline • Zoloft
  
• Sildenafil • Viagr
  
• Tadalafil • Cialis
  
• Vardenafil • Levitra
  

Dr. Segraves receives grant/research support from Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Novartis and is a consultant to Eli Lilly and Company, GlaxoSmithKline, Boehringer Ingelheim, and Bristol-Myers Squibb.

From alcohol to opioids, most addictive substances can induce sleep disturbances that persist despite abstinence and may increase the risk for relapse. Nearly all FDA-approved hypnotics are Schedule IV controlled substances that—although safe and effective for most populations—are prone to abuse by patients with substance use disorders.

You’re not alone if you hesitate to prescribe hypnotics to these patients; a study of 311 addiction medicine physicians found that they prescribed sleep-promoting medication to only 30% of their alcohol-dependent patients with insomnia.¹

This article presents evidence on how alcohol and other substances disturb sleep in patients with addictions. We discuss the usefulness of hypnotics, off-label sedatives, and cognitive-behavioral therapy (CBT). Our goal is to help you reduce your patients’ risk of relapse by addressing their sleep complaints.

Workup: 3 principles

Insomnia is multifactorial. Don’t assume that substance abuse is the only cause of prominent insomnia complaints. Insomnia in patients with substance use disorders may be a manifestation of protracted withdrawal or a primary sleep disorder. Evaluate your patient’s:

• other illnesses (psychiatric, medical, and other sleep disorders)
  
• sleep-impairing medications (such as activating antidepressants and theophylline)
  
• inadequate sleep hygiene
  
• dysfunctional beliefs about sleep.