Current Psychiatry

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Hyperprolactinemia—increased levels of prolactin (PRL) in the blood that may be caused by hypothyroidism, pituitary disorders, atypical antipsychotics, or other conditions and medications—has numerous physiologic manifestations, including amenorrhea, infertility, abnormal bone resorption, increased risk of breast cancer, and compromised immunity. Evaluation of hyperprolactinemia in patients taking psychotropics—particularly children and adolescents, in whom hyperprolactinemia’s adverse effects may be more pronounced—should include an examination for signs and symptoms of hyperprolactinemia and assessment to rule out other potential causes. This article reviews hyperprolactinemia’s causes, symptoms, evaluation, and treatment, with an emphasis on younger patients.

Causes of hyperprolactinemia

PRL is a circulating autocrine or paracrine factor (Box 1).^1,2 Its primary biologic activities can be broadly divided into 4 areas: reproductive, metabolic, osmoregulatory, and immunoregulatory (Box 2).^1,3-8

Hyperprolactinemia has numerous physiologic and iatrogenic causes (Table 1).⁹ Substantially increased serum PRL levels may be seen with:

• prolactinomas, which usually present as incidental findings on a brain CT or MRI or with symptoms of tumor mass
• a craniopharyngioma or other tumor that compresses the pituitary stalk or hypothalamus and interrupts the hypothalamic-dopa minergic inhibition of PRL release.¹⁰

Primary thyroid failure (hypothyroidism) can produce a compensatory increase in the discharge of central hypothalamic thyrotropin-releasing hormone, resulting in increased stimulation of PRL secretion.¹⁰

Medications can increase serum PRL (Table 2)⁹ and cause clinical symptoms similar to those of physiologically induced hyperprolactinemia.

Conventional antipsychotics. The anti-psychotic potency of phenothiazines, thioxanthenes, butyrophenones, and dibenzoxazepines generally parallels their potency in increasing PRL levels.⁹ Although a dose-response relationship between PRL concentrations and conventional antipsychotics is likely, immediate and pronounced increases in PRL can occur even with low doses.

Prospective studies have shown that 3 to 9 weeks of treatment with an antipsychotic such as chlorpromazine increased mean baseline PRL levels up to 10-fold, even at therapeutic doses.¹¹ Conventional antipsychotics can cause marked increases in PRL, probably by blocking dopamine receptors in the tuberoinfundibular tract.¹² The blockage of D2 receptors removes the main inhibitory influence on PRL secretion and is associated with increased PRL release.¹²

Atypical antipsychotics cause less elevation in PRL levels than conventional anti-psychotics. This may be because of their:

• highly selective mesolimbic and meso-cortical dopamine receptor antagonism, which spares dopamine blockade within the tuberoinfundibular tract
• relatively lower D2 receptor affinity.¹¹

Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) have a high affinity for D2 receptors and thus have potent D2 antagonistic effects.^12,13 At dosages of 8 mg/d to 11.8 mg/d, risperidone and paliperidone are associated with the greatest increase in PRL levels among atypical antipsychotics.¹⁴

The rate of risperidone metabolism depends on the patient’s cytochrome P (CYP) 2D6 liver enzyme genotype. “Extensive” CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas “poor” CYP2D6 metabolizers convert it much more slowly. Six percent to 8% of white individuals and a very low percentage of Asians have little or no CYP2D6 activity and are “poor metabolizers.” CYP2D6 also is inhibited by various substrates and nonsubstrates, notably quinidine. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active moiety after single and multiple doses are similar in extensive and poor metabolizers.¹⁵

Clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole are associated with a much lower risk of PRL elevation than risperidone. In an 8-week open-label trial, aripiprazole (mean dose 9.4±4.2 mg/d), did not increase serum PRL in 15 children and adolescents.²

Ziprasidone may cause only transient PRL elevation.¹⁶ PRL abnormalities may be least likely with clozapine and quetiapine, possibly because of their relatively lower D2 receptor affinity. Amenorrhea, galactorrhea, or inhibition of ejaculation have not been reported with the use of these 2 antipsychotics.¹⁶ Patients who developed hyperprolactinemia on conventional anti-psychotics have been treated subsequently with clozapine without hyperprolactinemia recurrence.¹⁶ Iloperidone has been associated with decreased PRL levels.¹⁷

Antidepressants that work by blocking catecholamine reuptake also cause hyperprolactinemia. This increase may be related to the antidopaminergic, stimulatory effects of estrogen. Numerous cases of galactorrhea and amenorrhea have been reported with the use of selective serotonin reuptake inhibitors (SSRIs).¹⁶ Galactorrhea has been reported in women who took venlafaxine.¹² Less is known about the effects of nefazodone or bupropion on serum PRL. Mirtazapine can decrease serum PRL in men, probably through indirect 5-HT1 agonist and 5-HT2 and 5-HT3 antagonist activity.¹⁶

PRL elevation is greater in children and adolescents than adults because of increased density of D2 receptors in the developing striatum and differential D2 receptor sensitivity in the tuberoinfundibular tract.¹⁶ Unfortunately, few studies have examined the consequences of elevated PRL in children and adolescents.

Box 1

Box 2

Table 1

Causes of hyperprolactinemia

Table 2

Relative risk of hyperprolactinemia with common psychotropics

Clinical features

Adenomas. Primary hyperprolactinemia related to excessive secretion from the pituitary and other tissues causes multiple clinical effects, including:

• amenorrhea, oligomenorrhea, anovulatory cycles, galactorrhea, breast pain, breast enlargement, infertility, hirsutism, and loss of libido in females
• impotence, loss of libido, decrease in seminal fluid volume, galactorrhea, and gynecomastia in males.¹²

Preclinical studies of risperidone suggested an association with pituitary adenomas in female mice.¹⁸ To determine if there was a similar association in humans, Szarfman et al¹⁸ retrospectively evaluated data on 7 antipsychotics—aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol—and found 77 pituitary tumors associated with use of these medications. Risperidone was associated with 54 of the pituitary tumors—including 3 in adolescents age 14 to 16. No pituitary tumors were reported with aripiprazole. Approximately one-half of the pituitary tumors were benign. Symptoms included visual field defects, headaches, pituitary hemorrhage, convulsions, and coma.

Other adverse effects reported in the study were hyperprolactinemia, galactorrhea, amenorrhea, and gynecomastia. The incidence of adverse effects with risperidone was >10-fold higher than with haloperidol or olanzapine and >25-fold higher than with clozapine, ziprasidone, quetiapine, and aripiprazole.

Hyperprolactinemia secondary to macroadenoma or microadenoma in children and adolescents is rare and difficult to diagnose because typically it is suspected only when symptoms of tumor expansion occur. The usual initial symptoms of microadenomas are menstrual disturbances and galactorrhea in girls and galactorrhea and gynecomastia in boys.¹⁹

Decreased bone mass. Long-term hyperprolactinemia may lead to delayed puberty, primary amenorrhea, short stature, infertility, and osteopenia and/or osteoporosis due to decreased bone mass density (BMD).¹⁶ The risk of osteoporosis and/or osteopenia is directly related to the duration of hyperprolactinemia. A serum PRL level twice the upper limit of normal can result in osteopenia.

Breast cancer risk may be increased in hyperprolactinemia because of the effects of PRL on breast tissue and mammary gland development. A study of premenopausal (n=235) and postmenopausal women (n=851) reported a positive correlation between elevated PRL levels and breast cancer risk.³ “Crosstalk” between PRL and estradiol in activating AP-1 activity may promote carcinogenesis. Furthermore, tamoxifen, a common treatment for breast cancer, lowers PRL concentrations.³

Not all patients with hyperprolactinemia develop problems. Whether hyperprolactinemia secondary to antipsychotic treatment adversely affects bone density or sexual maturation is unknown. Furthermore, sexual side effects—such as a decrease or loss of libido, erectile dysfunction, impotence, and ejaculatory or orgasmic difficulties—do not show a strong correlation with PRL levels.¹¹

Effects of hyperprolactinemia may be more pronounced in adolescents because PRL synthesis and release are stimulated by estrogen. In adolescent females elevated estrogen levels can be related to:

• increased estrogen levels in menstruating females
• increased estrogen levels in females taking oral contraceptives.¹⁶

Therefore, adolescent females taking antipsychotics are at high risk for increased PRL levels and resultant effects. For example, the BMD of adolescent girls with 6 months of hypothalamic-pituitary-gonadal (HPG) axis dysfunction caused by hyperprolactinemia was reduced by 2 standard deviations (SDs) below the population mean.¹⁶ A BMD 1 SD below the mean age-population value may double the risk for fractures.¹⁶ Unfortunately, there are no studies that measure estrogen levels or BMDs of children taking psychotropics¹⁶ or that assess PRL in pubertal girls taking atypical antipsychotics or SSRIs.

Evaluation of hyperprolactinemia

Blood samples to measure PRL levels must be collected under standardized conditions. A morning fasting serum PRL level should be obtained between 8 am and 10 am (3 hours after waking up). It is best to avoid emotional stress or strenuous exercise for at least 30 minutes before the blood draw because these conditions can raise PRL. Avoid nipple stimulation for 24 hours before testing because this also can raise PRL levels. A woman having abnormal nipple discharge should not do anything to cause more discharge before the test. Serum PRL levels should be monitored every 6 months in pubertal girls taking psychotropics until they experience sexual maturity or regular menstrual cycles so that abnormalities can be identified early and irreversible BMD loss is minimized.¹⁶

Absolute PRL level is not useful in guiding treatment because it is not consistently correlated with adverse effects. However, the degree of change of serum PRL levels over time or the change of PRL levels from baseline may be important in diagnosing asymptomatic hyperprolactinemia.¹⁶ Suspect pathologic hyperprolactinemia in patients (except newborns and pregnant women) with plasma PRL levels consistently >15 to 25 ng/mL.¹² This finding occurs in <1% of the population, but the rate is higher among individuals with specific symptoms attributable to hyperprolactinemia. For example, 9% of women with amenorrhea, 25% of women with galactorrhea, and 70% of women with both amenorrhea and galactorrhea have hyperprolactinemia. The prevalence is approximately 5% among men with impotence or infertility.¹⁰

If hyperprolactinemia is detected, the degree of PRL elevation can help determine etiology. In the absence of pregnancy and breastfeeding, a serum PRL level of >600 ng/mL is highly suggestive of a macroprolactinoma.¹² PRL concentrations >250 ng/mL suggest a microprolactinoma or a nonfunctioning adenoma.¹² Antipsychotics usually produce moderate PRL elevation (up to 6 times the upper limit of the reference range of 100 ng/mL).¹² In 1 study, the median time to onset of galactorrhea was 20 days after initiating antipsychotics in female patients.¹² Hyperprolactinemia-induced HPG axis dysfunction causes delayed pubertal development or loss of bone mineral deposit.¹⁶ Measuring BMD in children and adolescents with hyperprolactinemia is important during this critical time of skeletal development.¹⁶

Managing hyperprolactinemia

Before starting any antipsychotic, inform patients and families of possible side effects, including hyperprolactinemia. Educate them about recognizing the signs and symptoms of hyperprolactinemia (Table 3).¹² Although PRL blood levels typically are not routinely measured in pubertal girls who take PRL-modulating agents, consider monitoring serum PRL levels every 6 months until patients achieve sexual maturity and menstrual cycle regularity.¹⁶

If laboratory testing detects elevated PRL levels in a child or adolescent, determine if the patient had sexual intercourse, nipple stimulation, stress (including venipuncture), sleep disturbances, seizures, head injury, or surgery before the blood sample was obtained. This information will help to determine if the PRL elevation is caused by one of these factors.

To treat hyperprolactinemia, address the underlying medical cause(s). If patients using antipsychotics have signs and symptoms of hyperprolactinemia, consider discontinuing the drug or reducing the dosage.¹¹ If dose change fails to reduce hyperprolactinemia, consider a switch to a low-potency D2 agent or aripiprazole. Shim et al²⁰ studied the effects of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in schizophrenia patients maintained on haloperidol. In this study, aripiprazole reversed hyperprolactinemia in both sexes but plasma levels of haloperidol were not significantly altered. The authors hypothesized that decreased PRL levels may have been the result of pharmacodynamic interaction at dopamine receptors rather than pharmacokinetic interaction between aripiprazole and haloperidol. Additional studies are needed to confirm these findings.

If a medication switch is contraindicated, pharmacologic treatment for hyperprolactinemia may be required.¹¹ Bromocriptine, cabergoline, and amantadine have been used to treat hyperprolactinemia.¹¹ Bromocriptine lowers PRL levels and restores normal gonadal function for men and women with hyperprolactinemia regardless of etiology, but may worsen psychiatric symptoms and can cause nausea, headaches, dizziness, and orthostatic hypotension.¹¹ In a pilot study, amantadine, 300 mg/d, used to treat neuroleptic-induced extrapyramidal effects also decreased PRL levels and reduced galactorrhea.¹¹

Osteoporosis can be minimized by exercising, taking adequate calcium and vitamin D, and avoiding caffeinated drinks.⁹ Simmons et al²¹ found bisphosphonate treatment in children and adolescents improved bone density and fragility within 2 to 4 years. Unfortunately, information about optimal duration and long-term effects of bisphosphonate therapy is limited.²²

Surgical treatment may be necessary to remove a pituitary tumor that causes hyperprolactinemia. For some patients, referral to pediatric endocrinologist for further treatment may be needed.

Table 3

Presenting symptoms of hyperprolactinemia

Related Resources

• Ali J, Khemka M. Hyperprolactinemia: Monitoring children on long-term risperidone. Current Psychiatry. 2008;7(11):64-72.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bendroflumethiazide • Naturetin
• Bromocriptine • Parlodel
• Bupropion • Wellbutrin
• Cabergoline • Dostinex
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clozapine • Clozaril
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Indinavir • Crixivan
• Methyldopa • Aldomet
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Paliperidone • Invega
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Quinidine • Quinidex
• Ranitidine • Zantac
• Reserpine • Serpasil
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Triptorelin • Trelstar
• Venlafaxine • Effexor
• Verapamil • Calan, Isoptin
• Zidovudine • Retrovir
• Ziprasidone • Geodon

Disclosure

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

Acknowledgment

The authors wish to thank Yunyoung C. Chang, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Hyperprolactinemia—increased levels of prolactin (PRL) in the blood that may be caused by hypothyroidism, pituitary disorders, atypical antipsychotics, or other conditions and medications—has numerous physiologic manifestations, including amenorrhea, infertility, abnormal bone resorption, increased risk of breast cancer, and compromised immunity. Evaluation of hyperprolactinemia in patients taking psychotropics—particularly children and adolescents, in whom hyperprolactinemia’s adverse effects may be more pronounced—should include an examination for signs and symptoms of hyperprolactinemia and assessment to rule out other potential causes. This article reviews hyperprolactinemia’s causes, symptoms, evaluation, and treatment, with an emphasis on younger patients.

Causes of hyperprolactinemia

PRL is a circulating autocrine or paracrine factor (Box 1).^1,2 Its primary biologic activities can be broadly divided into 4 areas: reproductive, metabolic, osmoregulatory, and immunoregulatory (Box 2).^1,3-8

Hyperprolactinemia has numerous physiologic and iatrogenic causes (Table 1).⁹ Substantially increased serum PRL levels may be seen with:

• prolactinomas, which usually present as incidental findings on a brain CT or MRI or with symptoms of tumor mass
• a craniopharyngioma or other tumor that compresses the pituitary stalk or hypothalamus and interrupts the hypothalamic-dopa minergic inhibition of PRL release.¹⁰

Primary thyroid failure (hypothyroidism) can produce a compensatory increase in the discharge of central hypothalamic thyrotropin-releasing hormone, resulting in increased stimulation of PRL secretion.¹⁰

Medications can increase serum PRL (Table 2)⁹ and cause clinical symptoms similar to those of physiologically induced hyperprolactinemia.

Conventional antipsychotics. The anti-psychotic potency of phenothiazines, thioxanthenes, butyrophenones, and dibenzoxazepines generally parallels their potency in increasing PRL levels.⁹ Although a dose-response relationship between PRL concentrations and conventional antipsychotics is likely, immediate and pronounced increases in PRL can occur even with low doses.

Prospective studies have shown that 3 to 9 weeks of treatment with an antipsychotic such as chlorpromazine increased mean baseline PRL levels up to 10-fold, even at therapeutic doses.¹¹ Conventional antipsychotics can cause marked increases in PRL, probably by blocking dopamine receptors in the tuberoinfundibular tract.¹² The blockage of D2 receptors removes the main inhibitory influence on PRL secretion and is associated with increased PRL release.¹²

Atypical antipsychotics cause less elevation in PRL levels than conventional anti-psychotics. This may be because of their:

• highly selective mesolimbic and meso-cortical dopamine receptor antagonism, which spares dopamine blockade within the tuberoinfundibular tract
• relatively lower D2 receptor affinity.¹¹

Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) have a high affinity for D2 receptors and thus have potent D2 antagonistic effects.^12,13 At dosages of 8 mg/d to 11.8 mg/d, risperidone and paliperidone are associated with the greatest increase in PRL levels among atypical antipsychotics.¹⁴

The rate of risperidone metabolism depends on the patient’s cytochrome P (CYP) 2D6 liver enzyme genotype. “Extensive” CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas “poor” CYP2D6 metabolizers convert it much more slowly. Six percent to 8% of white individuals and a very low percentage of Asians have little or no CYP2D6 activity and are “poor metabolizers.” CYP2D6 also is inhibited by various substrates and nonsubstrates, notably quinidine. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active moiety after single and multiple doses are similar in extensive and poor metabolizers.¹⁵

Clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole are associated with a much lower risk of PRL elevation than risperidone. In an 8-week open-label trial, aripiprazole (mean dose 9.4±4.2 mg/d), did not increase serum PRL in 15 children and adolescents.²

Ziprasidone may cause only transient PRL elevation.¹⁶ PRL abnormalities may be least likely with clozapine and quetiapine, possibly because of their relatively lower D2 receptor affinity. Amenorrhea, galactorrhea, or inhibition of ejaculation have not been reported with the use of these 2 antipsychotics.¹⁶ Patients who developed hyperprolactinemia on conventional anti-psychotics have been treated subsequently with clozapine without hyperprolactinemia recurrence.¹⁶ Iloperidone has been associated with decreased PRL levels.¹⁷

Antidepressants that work by blocking catecholamine reuptake also cause hyperprolactinemia. This increase may be related to the antidopaminergic, stimulatory effects of estrogen. Numerous cases of galactorrhea and amenorrhea have been reported with the use of selective serotonin reuptake inhibitors (SSRIs).¹⁶ Galactorrhea has been reported in women who took venlafaxine.¹² Less is known about the effects of nefazodone or bupropion on serum PRL. Mirtazapine can decrease serum PRL in men, probably through indirect 5-HT1 agonist and 5-HT2 and 5-HT3 antagonist activity.¹⁶

PRL elevation is greater in children and adolescents than adults because of increased density of D2 receptors in the developing striatum and differential D2 receptor sensitivity in the tuberoinfundibular tract.¹⁶ Unfortunately, few studies have examined the consequences of elevated PRL in children and adolescents.

Box 1

Box 2

Table 1

Causes of hyperprolactinemia

Table 2

Relative risk of hyperprolactinemia with common psychotropics

Clinical features

Adenomas. Primary hyperprolactinemia related to excessive secretion from the pituitary and other tissues causes multiple clinical effects, including:

• amenorrhea, oligomenorrhea, anovulatory cycles, galactorrhea, breast pain, breast enlargement, infertility, hirsutism, and loss of libido in females
• impotence, loss of libido, decrease in seminal fluid volume, galactorrhea, and gynecomastia in males.¹²

Preclinical studies of risperidone suggested an association with pituitary adenomas in female mice.¹⁸ To determine if there was a similar association in humans, Szarfman et al¹⁸ retrospectively evaluated data on 7 antipsychotics—aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol—and found 77 pituitary tumors associated with use of these medications. Risperidone was associated with 54 of the pituitary tumors—including 3 in adolescents age 14 to 16. No pituitary tumors were reported with aripiprazole. Approximately one-half of the pituitary tumors were benign. Symptoms included visual field defects, headaches, pituitary hemorrhage, convulsions, and coma.

Other adverse effects reported in the study were hyperprolactinemia, galactorrhea, amenorrhea, and gynecomastia. The incidence of adverse effects with risperidone was >10-fold higher than with haloperidol or olanzapine and >25-fold higher than with clozapine, ziprasidone, quetiapine, and aripiprazole.

Hyperprolactinemia secondary to macroadenoma or microadenoma in children and adolescents is rare and difficult to diagnose because typically it is suspected only when symptoms of tumor expansion occur. The usual initial symptoms of microadenomas are menstrual disturbances and galactorrhea in girls and galactorrhea and gynecomastia in boys.¹⁹

Decreased bone mass. Long-term hyperprolactinemia may lead to delayed puberty, primary amenorrhea, short stature, infertility, and osteopenia and/or osteoporosis due to decreased bone mass density (BMD).¹⁶ The risk of osteoporosis and/or osteopenia is directly related to the duration of hyperprolactinemia. A serum PRL level twice the upper limit of normal can result in osteopenia.

Breast cancer risk may be increased in hyperprolactinemia because of the effects of PRL on breast tissue and mammary gland development. A study of premenopausal (n=235) and postmenopausal women (n=851) reported a positive correlation between elevated PRL levels and breast cancer risk.³ “Crosstalk” between PRL and estradiol in activating AP-1 activity may promote carcinogenesis. Furthermore, tamoxifen, a common treatment for breast cancer, lowers PRL concentrations.³

Not all patients with hyperprolactinemia develop problems. Whether hyperprolactinemia secondary to antipsychotic treatment adversely affects bone density or sexual maturation is unknown. Furthermore, sexual side effects—such as a decrease or loss of libido, erectile dysfunction, impotence, and ejaculatory or orgasmic difficulties—do not show a strong correlation with PRL levels.¹¹

Effects of hyperprolactinemia may be more pronounced in adolescents because PRL synthesis and release are stimulated by estrogen. In adolescent females elevated estrogen levels can be related to:

• increased estrogen levels in menstruating females
• increased estrogen levels in females taking oral contraceptives.¹⁶

Therefore, adolescent females taking antipsychotics are at high risk for increased PRL levels and resultant effects. For example, the BMD of adolescent girls with 6 months of hypothalamic-pituitary-gonadal (HPG) axis dysfunction caused by hyperprolactinemia was reduced by 2 standard deviations (SDs) below the population mean.¹⁶ A BMD 1 SD below the mean age-population value may double the risk for fractures.¹⁶ Unfortunately, there are no studies that measure estrogen levels or BMDs of children taking psychotropics¹⁶ or that assess PRL in pubertal girls taking atypical antipsychotics or SSRIs.

Evaluation of hyperprolactinemia

Blood samples to measure PRL levels must be collected under standardized conditions. A morning fasting serum PRL level should be obtained between 8 am and 10 am (3 hours after waking up). It is best to avoid emotional stress or strenuous exercise for at least 30 minutes before the blood draw because these conditions can raise PRL. Avoid nipple stimulation for 24 hours before testing because this also can raise PRL levels. A woman having abnormal nipple discharge should not do anything to cause more discharge before the test. Serum PRL levels should be monitored every 6 months in pubertal girls taking psychotropics until they experience sexual maturity or regular menstrual cycles so that abnormalities can be identified early and irreversible BMD loss is minimized.¹⁶

Absolute PRL level is not useful in guiding treatment because it is not consistently correlated with adverse effects. However, the degree of change of serum PRL levels over time or the change of PRL levels from baseline may be important in diagnosing asymptomatic hyperprolactinemia.¹⁶ Suspect pathologic hyperprolactinemia in patients (except newborns and pregnant women) with plasma PRL levels consistently >15 to 25 ng/mL.¹² This finding occurs in <1% of the population, but the rate is higher among individuals with specific symptoms attributable to hyperprolactinemia. For example, 9% of women with amenorrhea, 25% of women with galactorrhea, and 70% of women with both amenorrhea and galactorrhea have hyperprolactinemia. The prevalence is approximately 5% among men with impotence or infertility.¹⁰

If hyperprolactinemia is detected, the degree of PRL elevation can help determine etiology. In the absence of pregnancy and breastfeeding, a serum PRL level of >600 ng/mL is highly suggestive of a macroprolactinoma.¹² PRL concentrations >250 ng/mL suggest a microprolactinoma or a nonfunctioning adenoma.¹² Antipsychotics usually produce moderate PRL elevation (up to 6 times the upper limit of the reference range of 100 ng/mL).¹² In 1 study, the median time to onset of galactorrhea was 20 days after initiating antipsychotics in female patients.¹² Hyperprolactinemia-induced HPG axis dysfunction causes delayed pubertal development or loss of bone mineral deposit.¹⁶ Measuring BMD in children and adolescents with hyperprolactinemia is important during this critical time of skeletal development.¹⁶

Managing hyperprolactinemia

Before starting any antipsychotic, inform patients and families of possible side effects, including hyperprolactinemia. Educate them about recognizing the signs and symptoms of hyperprolactinemia (Table 3).¹² Although PRL blood levels typically are not routinely measured in pubertal girls who take PRL-modulating agents, consider monitoring serum PRL levels every 6 months until patients achieve sexual maturity and menstrual cycle regularity.¹⁶

If laboratory testing detects elevated PRL levels in a child or adolescent, determine if the patient had sexual intercourse, nipple stimulation, stress (including venipuncture), sleep disturbances, seizures, head injury, or surgery before the blood sample was obtained. This information will help to determine if the PRL elevation is caused by one of these factors.

To treat hyperprolactinemia, address the underlying medical cause(s). If patients using antipsychotics have signs and symptoms of hyperprolactinemia, consider discontinuing the drug or reducing the dosage.¹¹ If dose change fails to reduce hyperprolactinemia, consider a switch to a low-potency D2 agent or aripiprazole. Shim et al²⁰ studied the effects of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in schizophrenia patients maintained on haloperidol. In this study, aripiprazole reversed hyperprolactinemia in both sexes but plasma levels of haloperidol were not significantly altered. The authors hypothesized that decreased PRL levels may have been the result of pharmacodynamic interaction at dopamine receptors rather than pharmacokinetic interaction between aripiprazole and haloperidol. Additional studies are needed to confirm these findings.

If a medication switch is contraindicated, pharmacologic treatment for hyperprolactinemia may be required.¹¹ Bromocriptine, cabergoline, and amantadine have been used to treat hyperprolactinemia.¹¹ Bromocriptine lowers PRL levels and restores normal gonadal function for men and women with hyperprolactinemia regardless of etiology, but may worsen psychiatric symptoms and can cause nausea, headaches, dizziness, and orthostatic hypotension.¹¹ In a pilot study, amantadine, 300 mg/d, used to treat neuroleptic-induced extrapyramidal effects also decreased PRL levels and reduced galactorrhea.¹¹

Osteoporosis can be minimized by exercising, taking adequate calcium and vitamin D, and avoiding caffeinated drinks.⁹ Simmons et al²¹ found bisphosphonate treatment in children and adolescents improved bone density and fragility within 2 to 4 years. Unfortunately, information about optimal duration and long-term effects of bisphosphonate therapy is limited.²²

Surgical treatment may be necessary to remove a pituitary tumor that causes hyperprolactinemia. For some patients, referral to pediatric endocrinologist for further treatment may be needed.

Table 3

Presenting symptoms of hyperprolactinemia

Related Resources

• Ali J, Khemka M. Hyperprolactinemia: Monitoring children on long-term risperidone. Current Psychiatry. 2008;7(11):64-72.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bendroflumethiazide • Naturetin
• Bromocriptine • Parlodel
• Bupropion • Wellbutrin
• Cabergoline • Dostinex
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clozapine • Clozaril
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Indinavir • Crixivan
• Methyldopa • Aldomet
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Paliperidone • Invega
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Quinidine • Quinidex
• Ranitidine • Zantac
• Reserpine • Serpasil
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Triptorelin • Trelstar
• Venlafaxine • Effexor
• Verapamil • Calan, Isoptin
• Zidovudine • Retrovir
• Ziprasidone • Geodon

Disclosure

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

Acknowledgment

The authors wish to thank Yunyoung C. Chang, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Hyperprolactinemia—increased levels of prolactin (PRL) in the blood that may be caused by hypothyroidism, pituitary disorders, atypical antipsychotics, or other conditions and medications—has numerous physiologic manifestations, including amenorrhea, infertility, abnormal bone resorption, increased risk of breast cancer, and compromised immunity. Evaluation of hyperprolactinemia in patients taking psychotropics—particularly children and adolescents, in whom hyperprolactinemia’s adverse effects may be more pronounced—should include an examination for signs and symptoms of hyperprolactinemia and assessment to rule out other potential causes. This article reviews hyperprolactinemia’s causes, symptoms, evaluation, and treatment, with an emphasis on younger patients.

Causes of hyperprolactinemia

PRL is a circulating autocrine or paracrine factor (Box 1).^1,2 Its primary biologic activities can be broadly divided into 4 areas: reproductive, metabolic, osmoregulatory, and immunoregulatory (Box 2).^1,3-8

Hyperprolactinemia has numerous physiologic and iatrogenic causes (Table 1).⁹ Substantially increased serum PRL levels may be seen with:

• prolactinomas, which usually present as incidental findings on a brain CT or MRI or with symptoms of tumor mass
• a craniopharyngioma or other tumor that compresses the pituitary stalk or hypothalamus and interrupts the hypothalamic-dopa minergic inhibition of PRL release.¹⁰

Primary thyroid failure (hypothyroidism) can produce a compensatory increase in the discharge of central hypothalamic thyrotropin-releasing hormone, resulting in increased stimulation of PRL secretion.¹⁰

Medications can increase serum PRL (Table 2)⁹ and cause clinical symptoms similar to those of physiologically induced hyperprolactinemia.

Conventional antipsychotics. The anti-psychotic potency of phenothiazines, thioxanthenes, butyrophenones, and dibenzoxazepines generally parallels their potency in increasing PRL levels.⁹ Although a dose-response relationship between PRL concentrations and conventional antipsychotics is likely, immediate and pronounced increases in PRL can occur even with low doses.

Prospective studies have shown that 3 to 9 weeks of treatment with an antipsychotic such as chlorpromazine increased mean baseline PRL levels up to 10-fold, even at therapeutic doses.¹¹ Conventional antipsychotics can cause marked increases in PRL, probably by blocking dopamine receptors in the tuberoinfundibular tract.¹² The blockage of D2 receptors removes the main inhibitory influence on PRL secretion and is associated with increased PRL release.¹²

Atypical antipsychotics cause less elevation in PRL levels than conventional anti-psychotics. This may be because of their:

• highly selective mesolimbic and meso-cortical dopamine receptor antagonism, which spares dopamine blockade within the tuberoinfundibular tract
• relatively lower D2 receptor affinity.¹¹

Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) have a high affinity for D2 receptors and thus have potent D2 antagonistic effects.^12,13 At dosages of 8 mg/d to 11.8 mg/d, risperidone and paliperidone are associated with the greatest increase in PRL levels among atypical antipsychotics.¹⁴

The rate of risperidone metabolism depends on the patient’s cytochrome P (CYP) 2D6 liver enzyme genotype. “Extensive” CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas “poor” CYP2D6 metabolizers convert it much more slowly. Six percent to 8% of white individuals and a very low percentage of Asians have little or no CYP2D6 activity and are “poor metabolizers.” CYP2D6 also is inhibited by various substrates and nonsubstrates, notably quinidine. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active moiety after single and multiple doses are similar in extensive and poor metabolizers.¹⁵

Clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole are associated with a much lower risk of PRL elevation than risperidone. In an 8-week open-label trial, aripiprazole (mean dose 9.4±4.2 mg/d), did not increase serum PRL in 15 children and adolescents.²

Ziprasidone may cause only transient PRL elevation.¹⁶ PRL abnormalities may be least likely with clozapine and quetiapine, possibly because of their relatively lower D2 receptor affinity. Amenorrhea, galactorrhea, or inhibition of ejaculation have not been reported with the use of these 2 antipsychotics.¹⁶ Patients who developed hyperprolactinemia on conventional anti-psychotics have been treated subsequently with clozapine without hyperprolactinemia recurrence.¹⁶ Iloperidone has been associated with decreased PRL levels.¹⁷

Antidepressants that work by blocking catecholamine reuptake also cause hyperprolactinemia. This increase may be related to the antidopaminergic, stimulatory effects of estrogen. Numerous cases of galactorrhea and amenorrhea have been reported with the use of selective serotonin reuptake inhibitors (SSRIs).¹⁶ Galactorrhea has been reported in women who took venlafaxine.¹² Less is known about the effects of nefazodone or bupropion on serum PRL. Mirtazapine can decrease serum PRL in men, probably through indirect 5-HT1 agonist and 5-HT2 and 5-HT3 antagonist activity.¹⁶

PRL elevation is greater in children and adolescents than adults because of increased density of D2 receptors in the developing striatum and differential D2 receptor sensitivity in the tuberoinfundibular tract.¹⁶ Unfortunately, few studies have examined the consequences of elevated PRL in children and adolescents.

Box 1

Box 2

Table 1

Causes of hyperprolactinemia

Table 2

Relative risk of hyperprolactinemia with common psychotropics

Clinical features

Adenomas. Primary hyperprolactinemia related to excessive secretion from the pituitary and other tissues causes multiple clinical effects, including:

• amenorrhea, oligomenorrhea, anovulatory cycles, galactorrhea, breast pain, breast enlargement, infertility, hirsutism, and loss of libido in females
• impotence, loss of libido, decrease in seminal fluid volume, galactorrhea, and gynecomastia in males.¹²

Preclinical studies of risperidone suggested an association with pituitary adenomas in female mice.¹⁸ To determine if there was a similar association in humans, Szarfman et al¹⁸ retrospectively evaluated data on 7 antipsychotics—aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol—and found 77 pituitary tumors associated with use of these medications. Risperidone was associated with 54 of the pituitary tumors—including 3 in adolescents age 14 to 16. No pituitary tumors were reported with aripiprazole. Approximately one-half of the pituitary tumors were benign. Symptoms included visual field defects, headaches, pituitary hemorrhage, convulsions, and coma.

Other adverse effects reported in the study were hyperprolactinemia, galactorrhea, amenorrhea, and gynecomastia. The incidence of adverse effects with risperidone was >10-fold higher than with haloperidol or olanzapine and >25-fold higher than with clozapine, ziprasidone, quetiapine, and aripiprazole.

Hyperprolactinemia secondary to macroadenoma or microadenoma in children and adolescents is rare and difficult to diagnose because typically it is suspected only when symptoms of tumor expansion occur. The usual initial symptoms of microadenomas are menstrual disturbances and galactorrhea in girls and galactorrhea and gynecomastia in boys.¹⁹

Decreased bone mass. Long-term hyperprolactinemia may lead to delayed puberty, primary amenorrhea, short stature, infertility, and osteopenia and/or osteoporosis due to decreased bone mass density (BMD).¹⁶ The risk of osteoporosis and/or osteopenia is directly related to the duration of hyperprolactinemia. A serum PRL level twice the upper limit of normal can result in osteopenia.

Breast cancer risk may be increased in hyperprolactinemia because of the effects of PRL on breast tissue and mammary gland development. A study of premenopausal (n=235) and postmenopausal women (n=851) reported a positive correlation between elevated PRL levels and breast cancer risk.³ “Crosstalk” between PRL and estradiol in activating AP-1 activity may promote carcinogenesis. Furthermore, tamoxifen, a common treatment for breast cancer, lowers PRL concentrations.³

Not all patients with hyperprolactinemia develop problems. Whether hyperprolactinemia secondary to antipsychotic treatment adversely affects bone density or sexual maturation is unknown. Furthermore, sexual side effects—such as a decrease or loss of libido, erectile dysfunction, impotence, and ejaculatory or orgasmic difficulties—do not show a strong correlation with PRL levels.¹¹

Effects of hyperprolactinemia may be more pronounced in adolescents because PRL synthesis and release are stimulated by estrogen. In adolescent females elevated estrogen levels can be related to:

• increased estrogen levels in menstruating females
• increased estrogen levels in females taking oral contraceptives.¹⁶

Therefore, adolescent females taking antipsychotics are at high risk for increased PRL levels and resultant effects. For example, the BMD of adolescent girls with 6 months of hypothalamic-pituitary-gonadal (HPG) axis dysfunction caused by hyperprolactinemia was reduced by 2 standard deviations (SDs) below the population mean.¹⁶ A BMD 1 SD below the mean age-population value may double the risk for fractures.¹⁶ Unfortunately, there are no studies that measure estrogen levels or BMDs of children taking psychotropics¹⁶ or that assess PRL in pubertal girls taking atypical antipsychotics or SSRIs.

Evaluation of hyperprolactinemia

Blood samples to measure PRL levels must be collected under standardized conditions. A morning fasting serum PRL level should be obtained between 8 am and 10 am (3 hours after waking up). It is best to avoid emotional stress or strenuous exercise for at least 30 minutes before the blood draw because these conditions can raise PRL. Avoid nipple stimulation for 24 hours before testing because this also can raise PRL levels. A woman having abnormal nipple discharge should not do anything to cause more discharge before the test. Serum PRL levels should be monitored every 6 months in pubertal girls taking psychotropics until they experience sexual maturity or regular menstrual cycles so that abnormalities can be identified early and irreversible BMD loss is minimized.¹⁶

Absolute PRL level is not useful in guiding treatment because it is not consistently correlated with adverse effects. However, the degree of change of serum PRL levels over time or the change of PRL levels from baseline may be important in diagnosing asymptomatic hyperprolactinemia.¹⁶ Suspect pathologic hyperprolactinemia in patients (except newborns and pregnant women) with plasma PRL levels consistently >15 to 25 ng/mL.¹² This finding occurs in <1% of the population, but the rate is higher among individuals with specific symptoms attributable to hyperprolactinemia. For example, 9% of women with amenorrhea, 25% of women with galactorrhea, and 70% of women with both amenorrhea and galactorrhea have hyperprolactinemia. The prevalence is approximately 5% among men with impotence or infertility.¹⁰

If hyperprolactinemia is detected, the degree of PRL elevation can help determine etiology. In the absence of pregnancy and breastfeeding, a serum PRL level of >600 ng/mL is highly suggestive of a macroprolactinoma.¹² PRL concentrations >250 ng/mL suggest a microprolactinoma or a nonfunctioning adenoma.¹² Antipsychotics usually produce moderate PRL elevation (up to 6 times the upper limit of the reference range of 100 ng/mL).¹² In 1 study, the median time to onset of galactorrhea was 20 days after initiating antipsychotics in female patients.¹² Hyperprolactinemia-induced HPG axis dysfunction causes delayed pubertal development or loss of bone mineral deposit.¹⁶ Measuring BMD in children and adolescents with hyperprolactinemia is important during this critical time of skeletal development.¹⁶

Managing hyperprolactinemia

Before starting any antipsychotic, inform patients and families of possible side effects, including hyperprolactinemia. Educate them about recognizing the signs and symptoms of hyperprolactinemia (Table 3).¹² Although PRL blood levels typically are not routinely measured in pubertal girls who take PRL-modulating agents, consider monitoring serum PRL levels every 6 months until patients achieve sexual maturity and menstrual cycle regularity.¹⁶

If laboratory testing detects elevated PRL levels in a child or adolescent, determine if the patient had sexual intercourse, nipple stimulation, stress (including venipuncture), sleep disturbances, seizures, head injury, or surgery before the blood sample was obtained. This information will help to determine if the PRL elevation is caused by one of these factors.

To treat hyperprolactinemia, address the underlying medical cause(s). If patients using antipsychotics have signs and symptoms of hyperprolactinemia, consider discontinuing the drug or reducing the dosage.¹¹ If dose change fails to reduce hyperprolactinemia, consider a switch to a low-potency D2 agent or aripiprazole. Shim et al²⁰ studied the effects of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in schizophrenia patients maintained on haloperidol. In this study, aripiprazole reversed hyperprolactinemia in both sexes but plasma levels of haloperidol were not significantly altered. The authors hypothesized that decreased PRL levels may have been the result of pharmacodynamic interaction at dopamine receptors rather than pharmacokinetic interaction between aripiprazole and haloperidol. Additional studies are needed to confirm these findings.

If a medication switch is contraindicated, pharmacologic treatment for hyperprolactinemia may be required.¹¹ Bromocriptine, cabergoline, and amantadine have been used to treat hyperprolactinemia.¹¹ Bromocriptine lowers PRL levels and restores normal gonadal function for men and women with hyperprolactinemia regardless of etiology, but may worsen psychiatric symptoms and can cause nausea, headaches, dizziness, and orthostatic hypotension.¹¹ In a pilot study, amantadine, 300 mg/d, used to treat neuroleptic-induced extrapyramidal effects also decreased PRL levels and reduced galactorrhea.¹¹

Osteoporosis can be minimized by exercising, taking adequate calcium and vitamin D, and avoiding caffeinated drinks.⁹ Simmons et al²¹ found bisphosphonate treatment in children and adolescents improved bone density and fragility within 2 to 4 years. Unfortunately, information about optimal duration and long-term effects of bisphosphonate therapy is limited.²²

Surgical treatment may be necessary to remove a pituitary tumor that causes hyperprolactinemia. For some patients, referral to pediatric endocrinologist for further treatment may be needed.

Table 3

Presenting symptoms of hyperprolactinemia

Related Resources

• Ali J, Khemka M. Hyperprolactinemia: Monitoring children on long-term risperidone. Current Psychiatry. 2008;7(11):64-72.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bendroflumethiazide • Naturetin
• Bromocriptine • Parlodel
• Bupropion • Wellbutrin
• Cabergoline • Dostinex
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clozapine • Clozaril
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Indinavir • Crixivan
• Methyldopa • Aldomet
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Paliperidone • Invega
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Quinidine • Quinidex
• Ranitidine • Zantac
• Reserpine • Serpasil
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Triptorelin • Trelstar
• Venlafaxine • Effexor
• Verapamil • Calan, Isoptin
• Zidovudine • Retrovir
• Ziprasidone • Geodon

Disclosure

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

Acknowledgment

The authors wish to thank Yunyoung C. Chang, BS, for her assistance with this article.

Although benzodiazepines and stimulants have well-documented efficacy for numerous psychiatric disorders, psychiatrists hesitate to prescribe these medications to patients with substance use disorders (SUDs)—even to those with a comorbid condition that likely would respond to a benzodiazepine or stimulant—because of risk of abuse or dependence. Conventional practice typically has focused on treating active substance use first rather than using simultaneous treatments. Prejudice, fear, and misinformation can influence this decision.

We believe these cases lie on a continuum. At one extreme, ignoring a past or present SUD may lead a remitted patient toward relapse, or further delay recovery for an active user. At the other end, psychiatrists who overreact to a remote history of substance use may deprive patients of legitimate pharmacologic symptom relief. Most cases lie somewhere in the middle.

A literature review does not support the assertion that the use of these medications leads to future substance use or worsens active use, especially for stimulants. In fact, stepwise—as opposed to concurrent—treatment for both conditions actually may delay recovery and increase patients’ risk for morbidity.

We outline issues involved in these complex clinical situations, point out controversies, review relevant research data, and offer guidelines for treatment.

CASE 1 Panic disorder in sobriety

Since he was a teen, Mr. A, age 51, drank heavily, which cost him jobs and relationships. After being convicted for driving under the influence, he was court-ordered to attend a rehabilitation facility, where, as he describes it, he “finally turned [his] life around.” He followed up residential treatment with regular attendance at Alcoholics Anonymous meetings.

After 1 year of sobriety, Mr. A develops increasingly frequent episodes of intense anxiety with sweating, nausea, chest pain, and hyperventilation and is diagnosed with panic disorder. His internist prescribes alprazolam, 0.5 mg 3 times a day, which provides some symptom relief, and refers him for follow-up psychiatric care. At his first visit, Mr. A confides to his psychiatrist that he is taking much more than the prescribed dosage of alprazolam, even when he is not experiencing anxiety, and is contemplating “buying it on the street” if his dosage is not raised to “at least 3 mg 3 times a day.”

CASE 2 Anxiety in controlled psychosis

Ms. B, age 40, had her first psychotic break at age 18 and was diagnosed with schizophrenia. Since then, she has had multiple psychiatric hospitalizations, usually presenting with auditory hallucinations and a recurring delusion that the person who calls herself Ms. B’s mother is really an actress “playing” her mother. At times this delusion has led Ms. B to attack her “imposter” mother. Over several years Ms. B began to drink heavily, but recently achieved a few months of sobriety by attending dual-diagnosis groups at her local community mental health center and individual psychotherapy sessions with her case manager. Fortunately, Ms. B’s psychosis has been stabilized with risperidone long-acting injection, 25 mg every 2 weeks, which she tolerates well.

When her beloved calico cat passes away, Ms. B experiences intense anxiety. Ms. B’s friend tells her she “needs some Valium,” but her psychiatrist, case manager, and the other patients in her dual-diagnosis group are not sure this is a good idea.

Benzodiazepines

Pros. There are multiple legitimate uses of benzodiazepines in general medicine and psychiatric practice, based upon their considerable sedative/hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties (Table 1).¹

Recommendations regarding benzodiazepine use for anxious patients with a history of SUD are not clear-cut. First, it often is difficult to determine whether the patient truly has an anxiety disorder or is suffering anxiety symptoms secondary to substance use and/or withdrawal. In addition, even if a diagnosis of a separate anxiety disorder is established, psychiatrists debate how to treat such patients. Some clinicians maintain that benzodiazepines should be used only for acute detoxification, and that ongoing benzodiazepine use will lead to relapse or benzodiazepine dependence. However, in a prospective study of 545 alcohol use disorder (AUD) patients receiving benzodiazepines for anxiety disorders, Mueller et al² found no association—at 12 months or at 12 years—between benzodiazepine use and AUD recurrence. Furthermore, there was no difference in benzodiazepine usage when comparing patients with and without an AUD.³

Table 1

Clinical uses of benzodiazepines

Cons. Although widely prescribed—and despite their efficacy in numerous conditions— both acute or long-term benzodiazepine use frequently causes adverse effects.⁴ Patients may develop tolerance, which can lead to escalating dosages and/or to withdrawal symptoms when patients attempt to cut back. Benzodiazepines eventually become ineffective for sleep, and continued use can cause rebound insomnia. Also, with many patients taking benzodiazepines long-term, clinicians struggle to differentiate between “real” anxiety symptoms and subtle states of withdrawal from fluctuating benzodiazepine blood levels.⁵

Geriatric patients who take benzodiazepines are at risk for falls and hip fractures.⁴ Although older dementia patients are at particular risk for cognitive problems— including frank delirium—secondary to benzodiazepine use, patients of all ages are susceptible to these medications’ deleterious neurocognitive effects.

Benzodiazepines can lead to excessive sedation, thereby impairing performance at work or school, and have been implicated as a cause of motor vehicle accidents.⁶ Finally, a serious drawback to benzodiazepine use is possible lethality in overdose, especially when combined with alcohol.

Benzodiazepine prescribing should not be taken lightly. Always analyze the difference between benzodiazepines’ well-documented efficacy and their adverse effect profile. This risk-benefit analysis becomes much more complex for patients with SUDs.

Special considerations. Patients at higher risk for benzodiazepine abuse include those with:

• severe alcohol dependence (ie, long-term use, drinking since a young age [“Type II”])
• intravenous drug use
• comorbid alcoholism and antisocial personality disorder.^7,8

Exercise special caution when considering benzodiazepines for patients with severe psychiatric illness such as schizophrenia-spectrum disorders, bipolar disorder, or severe depression. Patients with schizophrenia have high rates of alcohol, cocaine, cannabis, and benzodiazepine abuse.^9,10 Bipolar disorder patients show similar vulnerability—up to 56% of patients screen positive for substance abuse or dependence.¹¹ Vulnerability to addiction in severely ill psychiatric patients is thought to be related to several factors, including:

• use of drugs as self-medication
• genetic predisposition
• environment/lifestyle that supports substance abuse
• neurobiologic deficits that lead to lack of inhibition of reward-seeking behaviors.¹¹

Bipolar disorder patients in particular score high on measures of sensation seeking, which leaves them vulnerable to abusing all classes of substances.¹²

In a 6-year study of 203 patients with severe psychiatric illnesses and SUDs, Brunette et al¹³ found that these patients were 2.5 times more likely than patients with severe psychiatric illness alone to abuse prescribed benzodiazepines. In an analysis of Medicaid records, Clark et al¹⁴ found similar vulnerability in patients with major depressive disorder (MDD) and SUD. Not only did these patients show a higher rate of benzodiazepine use than patients with MDD without SUD, but the dual-diagnosis group also gravitated toward more addictive high-potency/fast-acting benzodiazepines, such as alprazolam, estazolam, or triazolam.

Case discussion/suggestions. Initially, Mr. A may seem to be an appropriate candidate for closely monitored benzodiazepine use. However, he shows a pattern of misuse, likely related to his history of severe alcohol dependence and alprazolam use. This benzodiazepine is fast-acting and has a short half-life, and thus is highly reinforcing.

Similarly, Ms. B might benefit from benzodiazepine treatment. However, her history of schizophrenia and alcohol abuse makes her a risky candidate, and alternative treatments for anxiety symptoms should be considered. If prescribed at all, a benzodiazepine should be used only short-term (eg, 1 to 2 weeks).

In general, avoid prescribing benzodiazepines to most patients who have an ongoing or past SUD.¹⁵ Consider making an exception for SUD patients with comorbid anxiety disorders, with close monitoring of their benzodiazepine use. Clonazepam, chlordiazepoxide, clorazepate, and oxazepam may be less reinforcing for SUD patients than diazepam, lorazepam, alprazolam, estazolam, or triazolam.^7,16 The drawbacks of benzodiazepines, especially in the situations described above, point to the need to find alternative treatments (Table 2).¹⁷ Keep in mind nonpharmacologic options, which completely avoid the risks of medication misuse and diversion. Cognitive-behavioral therapy (CBT), for instance, has well-documented efficacy in treating insomnia and anxiety disorders.^18,19

Table 2

Alternatives to benzodiazepines for anxiety and/or insomnia

CASE 3 Adult ADHD and marijuana use

Mr. C, age 30, presents to a psychiatrist with ongoing complaints of inattention, fatigue, and difficulty staying organized. A self-report screen yields symptoms consistent with adult attention-deficit/hyperactivity disorder (ADHD). Mr. C’s school and job history and collateral history from his wife appear to corroborate his assertion that his symptoms have been lifelong. He later admits to regular marijuana use. After further discussion and full evaluation of his substance use, Mr. C is started on bupropion, titrated to 300 mg/d. After 2 months, despite faithful attendance at appointments and openness about his continued marijuana use, Mr. C’s symptoms remain unchanged. He asks about atomoxetine.

Stimulants

Pros. Despite many clinicians’ hesitance to prescribe controlled substances to patients with SUDs, psychostimulants should be considered in a variety of scenarios. Although nonstimulant options are available, stimulants consistently have demonstrated superior efficacy over other treatments and remain first-line agents for adult ADHD.²⁰ Methylphenidate, mixed amphetamine salts, lisdexamfetamine, and atomoxetine are FDA-approved for adult ADHD. Both stimulant classes (methylphenidate and amphetamine-based products) are equally effective for ADHD. In addition, stimulants are used to treat narcolepsy, cognitive disorders such as traumatic brain injury, and as augmentation to antidepressants for MDD.

ADHD affects 5% to 12% of children, and >60% of patients remain symptomatic into adulthood and require continued treatment.²¹ In particular, problematic inattention may persist throughout adulthood. ADHD does not appear to be an independent risk factor for SUDs in children and adolescents.²² However, substance use increases sharply as ADHD patients enter late adolescence and adulthood, and eventually becomes a problem for 20% of adolescents and adults with ADHD. Conversely, 17% to 50% of patients with alcohol, cocaine, or opioid dependence have co-occurring ADHD.²³

Withholding ADHD treatment based on concerns about future or increased current substance abuse is unfounded. A meta-analysis of 6 studies that included 674 medicated and 360 unmedicated patients with ADHD who were followed at least 4 years demonstrated that childhood treatment of ADHD with stimulants reduces the risk of developing alcohol and other drug disorders in adulthood.²⁴ Regarding the effect stimulants have on active substance use, a 12-week, double-blind, randomized controlled trial of 48 cocaine-dependent adults with ADHD showed methylphenidate did not change cocaine abuse or craving, but did improve ADHD symptoms.²⁵

Clinicians also must assess whether untreated ADHD symptoms impair patients’ work or other activities. Driving is a particular concern because ADHD is associated with risky driving habits, motor vehicle accidents, traffic violations, and driving license suspensions.²⁶ In a study that administered cognitive tests to 27 adults with ADHD, methylphenidate treatment improved cognitive performance related to driving (eg, better visual-motor coordination under high-stress conditions, improved visual orientation, and sustained visual attention).²⁷ It is likely this effect could be generalized to other activities where safety is important. Finally, appropriate stimulant treatment may improve participation in rehabilitative programs.

Cons. Despite their positive effects, stimulants can have adverse effects and consequences.²⁸ In routinely prescribed dosages, methylphenidate and amphetamines can cause symptoms related to sympathetic activation, including anxiety, tics, anorexia/ weight loss, and sleep disturbance. A 5-year study of 79 school-age children prescribed methylphenidate, dextroamphetamine, or pemoline, which is no longer available in the United States, showed a significant association between adherence to stimulants and persistence of physiological (eg, headaches, insomnia, anorexia) and mood-related (eg, irritability, dysphoria) side effects.²⁹ Stimulants’ sympathomimetic properties also can lead to dangerous drug-drug interactions with monoamine oxidase inhibitors. For both methylphenidate and amphetamines, overdose can lead to seizures, cardiac toxicity, dysrhythmias, and hyperthermia. All stimulants carry an FDA “black-box” warning that lists increased risk of cardiac complications, sudden death, and psychiatric complications such as psychosis or mania.³⁰

Special considerations. All stimulants have potential for diversion or abuse. Pay close attention to these issues, especially in vulnerable populations and situations where rates of abuse and diversion are elevated. Among college students, white patients, fraternity/sorority members, and individuals with lower grade point averages may be at higher risk for nonmedical stimulant use.³¹ Adults who misuse or divert stimulants commonly have a history of substance abuse and conduct disorder.³² Short-acting stimulants are abused 4 times more often than extended-release preparations.³³

If your ADHD patient has active substance use, be clear that continued substance use is likely to limit stimulants’ effectiveness. In patients who are actively using substances, it will be difficult to disentangle apparent nonresponse to stimulants from the negative cognitive effects of substance use.

Case discussion/suggestions. As Mr. C’s case illustrates, there are alternatives to stimulants for ADHD. For example, atomoxetine, a selective norepinephrine reuptake inhibitor, may be considered a first-line agent in patients with mostly inattentive ADHD symptoms and comorbid stimulant abuse, or for those in whom stimulants cause adverse effects such as mood lability or tics.³⁴ Other alternatives to stimulants are listed in Table 3.³⁵

Because Mr. C did not respond to bupropion, which presumably was tried first because of his ongoing substance use, he asked about atomoxetine. This agent is not addictive and there is no evidence that it leads to or exacerbates substance use. Depending on Mr. C’s symptom profile, atomoxetine might be a good choice. Continued monitoring of his marijuana use and frequent assessment of his motivation to quit are necessary. Psychoeducation about the cognitive effects of marijuana, including inattention and poor concentration, is important.

If Mr. C does not respond to atomoxetine, his psychiatrist will face a difficult decision. Setting Mr. C’s marijuana use aside, symptoms that do not respond to atomoxetine or a second-line agent are likely to respond to a stimulant. However, several issues must be addressed. If Mr. C’s motivation to stop using marijuana is low, how motivated is he to improve his ADHD symptoms? Next, would marijuana’s depressive/blunting effects counteract the anticipated benefit of a stimulant? Also, what is the risk that Mr. C might sell or exchange his stimulants to obtain marijuana? Assessing these complicated questions is key. Another important factor in Mr. C’s case is his wife’s involvement. Does she monitor his marijuana use? Would she be willing to supervise Mr. C’s stimulant use, and would he allow it?

Past or present SUDs are not an absolute contraindication to stimulant use. You should affirm the diagnosis and identify target symptoms. Consider nonstimulant alternatives if appropriate.

Table 3

Alternatives to stimulants for ADHD

Legal liabilities

Being aware of the medicolegal issues of benzodiazepine and/or stimulant prescribing is crucial because a court may find a psychiatrist liable for negative outcomes (eg, suicide) when controlled substances are prescribed to a patient with a history of addiction.³⁶ The most prudent course is to weigh the pros and cons for each patient individually, taking into consideration the factors described above.⁸ This is consistent with guidelines from the American Psychiatric Association and the British Association for Psychopharmacology,³⁷ both of which call for extreme caution in these cases.

Educate patients and caregivers about the risks of taking a controlled substance, including misuse, diversion, and theft. Provide and document explicit instructions that the patient will receive stimulants from only a single provider. Remind patients that state and federal authorities closely track controlled medications. Finally, a “stimulant contract” or “benzodiazepine contract,” similar to a pain or narcotic contact, may be useful to formally document discussions about appropriate medication use.

Related Resources

• National Institute on Drug Abuse. Prescription drugs: abuse and addiction. Research Report Series, 2005. http://drugabuse.gov/ResearchReports/Prescription/Prescription.html.
• Galanter M, Kleber HD. The American Psychiatric Publishing textbook of substance abuse treatment. 4th ed. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, others
• Chlordiazepoxide • Librium
• Clonazepam • Klonopin
• Clonidine • Catapres
• Clorazepate • Tranxene
• Dextroamphetamine • Dexedrine
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Doxepin • Silenor
• Estazolam • ProSom
• Gabapentin • Neurontin
• Guanfacine • Tenex, Intuniv
• Lisdexamfetamine • Vyvanse
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta, others
• Mirtazapine • Remeron
• Mixed amphetamine salts • Adderall
• Modafinil • Provigil
• Oxazepam • Serax
• Pemoline • Cylert
• Propranolol • Inderal
• Trazodone • Desyrel, Oleptro
• Triazolam • Halcion

Disclosures

Dr. Casher is a speaker for AstraZeneca and Pfizer Inc.

Drs. Gih and Bess report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although benzodiazepines and stimulants have well-documented efficacy for numerous psychiatric disorders, psychiatrists hesitate to prescribe these medications to patients with substance use disorders (SUDs)—even to those with a comorbid condition that likely would respond to a benzodiazepine or stimulant—because of risk of abuse or dependence. Conventional practice typically has focused on treating active substance use first rather than using simultaneous treatments. Prejudice, fear, and misinformation can influence this decision.

We believe these cases lie on a continuum. At one extreme, ignoring a past or present SUD may lead a remitted patient toward relapse, or further delay recovery for an active user. At the other end, psychiatrists who overreact to a remote history of substance use may deprive patients of legitimate pharmacologic symptom relief. Most cases lie somewhere in the middle.

A literature review does not support the assertion that the use of these medications leads to future substance use or worsens active use, especially for stimulants. In fact, stepwise—as opposed to concurrent—treatment for both conditions actually may delay recovery and increase patients’ risk for morbidity.

We outline issues involved in these complex clinical situations, point out controversies, review relevant research data, and offer guidelines for treatment.

CASE 1 Panic disorder in sobriety

Since he was a teen, Mr. A, age 51, drank heavily, which cost him jobs and relationships. After being convicted for driving under the influence, he was court-ordered to attend a rehabilitation facility, where, as he describes it, he “finally turned [his] life around.” He followed up residential treatment with regular attendance at Alcoholics Anonymous meetings.

After 1 year of sobriety, Mr. A develops increasingly frequent episodes of intense anxiety with sweating, nausea, chest pain, and hyperventilation and is diagnosed with panic disorder. His internist prescribes alprazolam, 0.5 mg 3 times a day, which provides some symptom relief, and refers him for follow-up psychiatric care. At his first visit, Mr. A confides to his psychiatrist that he is taking much more than the prescribed dosage of alprazolam, even when he is not experiencing anxiety, and is contemplating “buying it on the street” if his dosage is not raised to “at least 3 mg 3 times a day.”

CASE 2 Anxiety in controlled psychosis

Ms. B, age 40, had her first psychotic break at age 18 and was diagnosed with schizophrenia. Since then, she has had multiple psychiatric hospitalizations, usually presenting with auditory hallucinations and a recurring delusion that the person who calls herself Ms. B’s mother is really an actress “playing” her mother. At times this delusion has led Ms. B to attack her “imposter” mother. Over several years Ms. B began to drink heavily, but recently achieved a few months of sobriety by attending dual-diagnosis groups at her local community mental health center and individual psychotherapy sessions with her case manager. Fortunately, Ms. B’s psychosis has been stabilized with risperidone long-acting injection, 25 mg every 2 weeks, which she tolerates well.

When her beloved calico cat passes away, Ms. B experiences intense anxiety. Ms. B’s friend tells her she “needs some Valium,” but her psychiatrist, case manager, and the other patients in her dual-diagnosis group are not sure this is a good idea.

Benzodiazepines

Pros. There are multiple legitimate uses of benzodiazepines in general medicine and psychiatric practice, based upon their considerable sedative/hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties (Table 1).¹

Recommendations regarding benzodiazepine use for anxious patients with a history of SUD are not clear-cut. First, it often is difficult to determine whether the patient truly has an anxiety disorder or is suffering anxiety symptoms secondary to substance use and/or withdrawal. In addition, even if a diagnosis of a separate anxiety disorder is established, psychiatrists debate how to treat such patients. Some clinicians maintain that benzodiazepines should be used only for acute detoxification, and that ongoing benzodiazepine use will lead to relapse or benzodiazepine dependence. However, in a prospective study of 545 alcohol use disorder (AUD) patients receiving benzodiazepines for anxiety disorders, Mueller et al² found no association—at 12 months or at 12 years—between benzodiazepine use and AUD recurrence. Furthermore, there was no difference in benzodiazepine usage when comparing patients with and without an AUD.³

Table 1

Clinical uses of benzodiazepines

Cons. Although widely prescribed—and despite their efficacy in numerous conditions— both acute or long-term benzodiazepine use frequently causes adverse effects.⁴ Patients may develop tolerance, which can lead to escalating dosages and/or to withdrawal symptoms when patients attempt to cut back. Benzodiazepines eventually become ineffective for sleep, and continued use can cause rebound insomnia. Also, with many patients taking benzodiazepines long-term, clinicians struggle to differentiate between “real” anxiety symptoms and subtle states of withdrawal from fluctuating benzodiazepine blood levels.⁵

Geriatric patients who take benzodiazepines are at risk for falls and hip fractures.⁴ Although older dementia patients are at particular risk for cognitive problems— including frank delirium—secondary to benzodiazepine use, patients of all ages are susceptible to these medications’ deleterious neurocognitive effects.

Benzodiazepines can lead to excessive sedation, thereby impairing performance at work or school, and have been implicated as a cause of motor vehicle accidents.⁶ Finally, a serious drawback to benzodiazepine use is possible lethality in overdose, especially when combined with alcohol.

Benzodiazepine prescribing should not be taken lightly. Always analyze the difference between benzodiazepines’ well-documented efficacy and their adverse effect profile. This risk-benefit analysis becomes much more complex for patients with SUDs.

Special considerations. Patients at higher risk for benzodiazepine abuse include those with:

• severe alcohol dependence (ie, long-term use, drinking since a young age [“Type II”])
• intravenous drug use
• comorbid alcoholism and antisocial personality disorder.^7,8

Exercise special caution when considering benzodiazepines for patients with severe psychiatric illness such as schizophrenia-spectrum disorders, bipolar disorder, or severe depression. Patients with schizophrenia have high rates of alcohol, cocaine, cannabis, and benzodiazepine abuse.^9,10 Bipolar disorder patients show similar vulnerability—up to 56% of patients screen positive for substance abuse or dependence.¹¹ Vulnerability to addiction in severely ill psychiatric patients is thought to be related to several factors, including:

• use of drugs as self-medication
• genetic predisposition
• environment/lifestyle that supports substance abuse
• neurobiologic deficits that lead to lack of inhibition of reward-seeking behaviors.¹¹

Bipolar disorder patients in particular score high on measures of sensation seeking, which leaves them vulnerable to abusing all classes of substances.¹²

In a 6-year study of 203 patients with severe psychiatric illnesses and SUDs, Brunette et al¹³ found that these patients were 2.5 times more likely than patients with severe psychiatric illness alone to abuse prescribed benzodiazepines. In an analysis of Medicaid records, Clark et al¹⁴ found similar vulnerability in patients with major depressive disorder (MDD) and SUD. Not only did these patients show a higher rate of benzodiazepine use than patients with MDD without SUD, but the dual-diagnosis group also gravitated toward more addictive high-potency/fast-acting benzodiazepines, such as alprazolam, estazolam, or triazolam.

Case discussion/suggestions. Initially, Mr. A may seem to be an appropriate candidate for closely monitored benzodiazepine use. However, he shows a pattern of misuse, likely related to his history of severe alcohol dependence and alprazolam use. This benzodiazepine is fast-acting and has a short half-life, and thus is highly reinforcing.

Similarly, Ms. B might benefit from benzodiazepine treatment. However, her history of schizophrenia and alcohol abuse makes her a risky candidate, and alternative treatments for anxiety symptoms should be considered. If prescribed at all, a benzodiazepine should be used only short-term (eg, 1 to 2 weeks).

In general, avoid prescribing benzodiazepines to most patients who have an ongoing or past SUD.¹⁵ Consider making an exception for SUD patients with comorbid anxiety disorders, with close monitoring of their benzodiazepine use. Clonazepam, chlordiazepoxide, clorazepate, and oxazepam may be less reinforcing for SUD patients than diazepam, lorazepam, alprazolam, estazolam, or triazolam.^7,16 The drawbacks of benzodiazepines, especially in the situations described above, point to the need to find alternative treatments (Table 2).¹⁷ Keep in mind nonpharmacologic options, which completely avoid the risks of medication misuse and diversion. Cognitive-behavioral therapy (CBT), for instance, has well-documented efficacy in treating insomnia and anxiety disorders.^18,19

Table 2

Alternatives to benzodiazepines for anxiety and/or insomnia

CASE 3 Adult ADHD and marijuana use

Mr. C, age 30, presents to a psychiatrist with ongoing complaints of inattention, fatigue, and difficulty staying organized. A self-report screen yields symptoms consistent with adult attention-deficit/hyperactivity disorder (ADHD). Mr. C’s school and job history and collateral history from his wife appear to corroborate his assertion that his symptoms have been lifelong. He later admits to regular marijuana use. After further discussion and full evaluation of his substance use, Mr. C is started on bupropion, titrated to 300 mg/d. After 2 months, despite faithful attendance at appointments and openness about his continued marijuana use, Mr. C’s symptoms remain unchanged. He asks about atomoxetine.

Stimulants

Pros. Despite many clinicians’ hesitance to prescribe controlled substances to patients with SUDs, psychostimulants should be considered in a variety of scenarios. Although nonstimulant options are available, stimulants consistently have demonstrated superior efficacy over other treatments and remain first-line agents for adult ADHD.²⁰ Methylphenidate, mixed amphetamine salts, lisdexamfetamine, and atomoxetine are FDA-approved for adult ADHD. Both stimulant classes (methylphenidate and amphetamine-based products) are equally effective for ADHD. In addition, stimulants are used to treat narcolepsy, cognitive disorders such as traumatic brain injury, and as augmentation to antidepressants for MDD.

ADHD affects 5% to 12% of children, and >60% of patients remain symptomatic into adulthood and require continued treatment.²¹ In particular, problematic inattention may persist throughout adulthood. ADHD does not appear to be an independent risk factor for SUDs in children and adolescents.²² However, substance use increases sharply as ADHD patients enter late adolescence and adulthood, and eventually becomes a problem for 20% of adolescents and adults with ADHD. Conversely, 17% to 50% of patients with alcohol, cocaine, or opioid dependence have co-occurring ADHD.²³

Withholding ADHD treatment based on concerns about future or increased current substance abuse is unfounded. A meta-analysis of 6 studies that included 674 medicated and 360 unmedicated patients with ADHD who were followed at least 4 years demonstrated that childhood treatment of ADHD with stimulants reduces the risk of developing alcohol and other drug disorders in adulthood.²⁴ Regarding the effect stimulants have on active substance use, a 12-week, double-blind, randomized controlled trial of 48 cocaine-dependent adults with ADHD showed methylphenidate did not change cocaine abuse or craving, but did improve ADHD symptoms.²⁵

Clinicians also must assess whether untreated ADHD symptoms impair patients’ work or other activities. Driving is a particular concern because ADHD is associated with risky driving habits, motor vehicle accidents, traffic violations, and driving license suspensions.²⁶ In a study that administered cognitive tests to 27 adults with ADHD, methylphenidate treatment improved cognitive performance related to driving (eg, better visual-motor coordination under high-stress conditions, improved visual orientation, and sustained visual attention).²⁷ It is likely this effect could be generalized to other activities where safety is important. Finally, appropriate stimulant treatment may improve participation in rehabilitative programs.

Cons. Despite their positive effects, stimulants can have adverse effects and consequences.²⁸ In routinely prescribed dosages, methylphenidate and amphetamines can cause symptoms related to sympathetic activation, including anxiety, tics, anorexia/ weight loss, and sleep disturbance. A 5-year study of 79 school-age children prescribed methylphenidate, dextroamphetamine, or pemoline, which is no longer available in the United States, showed a significant association between adherence to stimulants and persistence of physiological (eg, headaches, insomnia, anorexia) and mood-related (eg, irritability, dysphoria) side effects.²⁹ Stimulants’ sympathomimetic properties also can lead to dangerous drug-drug interactions with monoamine oxidase inhibitors. For both methylphenidate and amphetamines, overdose can lead to seizures, cardiac toxicity, dysrhythmias, and hyperthermia. All stimulants carry an FDA “black-box” warning that lists increased risk of cardiac complications, sudden death, and psychiatric complications such as psychosis or mania.³⁰

Special considerations. All stimulants have potential for diversion or abuse. Pay close attention to these issues, especially in vulnerable populations and situations where rates of abuse and diversion are elevated. Among college students, white patients, fraternity/sorority members, and individuals with lower grade point averages may be at higher risk for nonmedical stimulant use.³¹ Adults who misuse or divert stimulants commonly have a history of substance abuse and conduct disorder.³² Short-acting stimulants are abused 4 times more often than extended-release preparations.³³

If your ADHD patient has active substance use, be clear that continued substance use is likely to limit stimulants’ effectiveness. In patients who are actively using substances, it will be difficult to disentangle apparent nonresponse to stimulants from the negative cognitive effects of substance use.

Case discussion/suggestions. As Mr. C’s case illustrates, there are alternatives to stimulants for ADHD. For example, atomoxetine, a selective norepinephrine reuptake inhibitor, may be considered a first-line agent in patients with mostly inattentive ADHD symptoms and comorbid stimulant abuse, or for those in whom stimulants cause adverse effects such as mood lability or tics.³⁴ Other alternatives to stimulants are listed in Table 3.³⁵

Because Mr. C did not respond to bupropion, which presumably was tried first because of his ongoing substance use, he asked about atomoxetine. This agent is not addictive and there is no evidence that it leads to or exacerbates substance use. Depending on Mr. C’s symptom profile, atomoxetine might be a good choice. Continued monitoring of his marijuana use and frequent assessment of his motivation to quit are necessary. Psychoeducation about the cognitive effects of marijuana, including inattention and poor concentration, is important.

If Mr. C does not respond to atomoxetine, his psychiatrist will face a difficult decision. Setting Mr. C’s marijuana use aside, symptoms that do not respond to atomoxetine or a second-line agent are likely to respond to a stimulant. However, several issues must be addressed. If Mr. C’s motivation to stop using marijuana is low, how motivated is he to improve his ADHD symptoms? Next, would marijuana’s depressive/blunting effects counteract the anticipated benefit of a stimulant? Also, what is the risk that Mr. C might sell or exchange his stimulants to obtain marijuana? Assessing these complicated questions is key. Another important factor in Mr. C’s case is his wife’s involvement. Does she monitor his marijuana use? Would she be willing to supervise Mr. C’s stimulant use, and would he allow it?

Past or present SUDs are not an absolute contraindication to stimulant use. You should affirm the diagnosis and identify target symptoms. Consider nonstimulant alternatives if appropriate.

Table 3

Alternatives to stimulants for ADHD

Legal liabilities

Being aware of the medicolegal issues of benzodiazepine and/or stimulant prescribing is crucial because a court may find a psychiatrist liable for negative outcomes (eg, suicide) when controlled substances are prescribed to a patient with a history of addiction.³⁶ The most prudent course is to weigh the pros and cons for each patient individually, taking into consideration the factors described above.⁸ This is consistent with guidelines from the American Psychiatric Association and the British Association for Psychopharmacology,³⁷ both of which call for extreme caution in these cases.

Educate patients and caregivers about the risks of taking a controlled substance, including misuse, diversion, and theft. Provide and document explicit instructions that the patient will receive stimulants from only a single provider. Remind patients that state and federal authorities closely track controlled medications. Finally, a “stimulant contract” or “benzodiazepine contract,” similar to a pain or narcotic contact, may be useful to formally document discussions about appropriate medication use.

Related Resources

• National Institute on Drug Abuse. Prescription drugs: abuse and addiction. Research Report Series, 2005. http://drugabuse.gov/ResearchReports/Prescription/Prescription.html.
• Galanter M, Kleber HD. The American Psychiatric Publishing textbook of substance abuse treatment. 4th ed. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, others
• Chlordiazepoxide • Librium
• Clonazepam • Klonopin
• Clonidine • Catapres
• Clorazepate • Tranxene
• Dextroamphetamine • Dexedrine
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Doxepin • Silenor
• Estazolam • ProSom
• Gabapentin • Neurontin
• Guanfacine • Tenex, Intuniv
• Lisdexamfetamine • Vyvanse
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta, others
• Mirtazapine • Remeron
• Mixed amphetamine salts • Adderall
• Modafinil • Provigil
• Oxazepam • Serax
• Pemoline • Cylert
• Propranolol • Inderal
• Trazodone • Desyrel, Oleptro
• Triazolam • Halcion

Disclosures

Dr. Casher is a speaker for AstraZeneca and Pfizer Inc.

Drs. Gih and Bess report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although benzodiazepines and stimulants have well-documented efficacy for numerous psychiatric disorders, psychiatrists hesitate to prescribe these medications to patients with substance use disorders (SUDs)—even to those with a comorbid condition that likely would respond to a benzodiazepine or stimulant—because of risk of abuse or dependence. Conventional practice typically has focused on treating active substance use first rather than using simultaneous treatments. Prejudice, fear, and misinformation can influence this decision.

We believe these cases lie on a continuum. At one extreme, ignoring a past or present SUD may lead a remitted patient toward relapse, or further delay recovery for an active user. At the other end, psychiatrists who overreact to a remote history of substance use may deprive patients of legitimate pharmacologic symptom relief. Most cases lie somewhere in the middle.

A literature review does not support the assertion that the use of these medications leads to future substance use or worsens active use, especially for stimulants. In fact, stepwise—as opposed to concurrent—treatment for both conditions actually may delay recovery and increase patients’ risk for morbidity.

We outline issues involved in these complex clinical situations, point out controversies, review relevant research data, and offer guidelines for treatment.

CASE 1 Panic disorder in sobriety

Since he was a teen, Mr. A, age 51, drank heavily, which cost him jobs and relationships. After being convicted for driving under the influence, he was court-ordered to attend a rehabilitation facility, where, as he describes it, he “finally turned [his] life around.” He followed up residential treatment with regular attendance at Alcoholics Anonymous meetings.

After 1 year of sobriety, Mr. A develops increasingly frequent episodes of intense anxiety with sweating, nausea, chest pain, and hyperventilation and is diagnosed with panic disorder. His internist prescribes alprazolam, 0.5 mg 3 times a day, which provides some symptom relief, and refers him for follow-up psychiatric care. At his first visit, Mr. A confides to his psychiatrist that he is taking much more than the prescribed dosage of alprazolam, even when he is not experiencing anxiety, and is contemplating “buying it on the street” if his dosage is not raised to “at least 3 mg 3 times a day.”

CASE 2 Anxiety in controlled psychosis

Ms. B, age 40, had her first psychotic break at age 18 and was diagnosed with schizophrenia. Since then, she has had multiple psychiatric hospitalizations, usually presenting with auditory hallucinations and a recurring delusion that the person who calls herself Ms. B’s mother is really an actress “playing” her mother. At times this delusion has led Ms. B to attack her “imposter” mother. Over several years Ms. B began to drink heavily, but recently achieved a few months of sobriety by attending dual-diagnosis groups at her local community mental health center and individual psychotherapy sessions with her case manager. Fortunately, Ms. B’s psychosis has been stabilized with risperidone long-acting injection, 25 mg every 2 weeks, which she tolerates well.

When her beloved calico cat passes away, Ms. B experiences intense anxiety. Ms. B’s friend tells her she “needs some Valium,” but her psychiatrist, case manager, and the other patients in her dual-diagnosis group are not sure this is a good idea.

Benzodiazepines

Pros. There are multiple legitimate uses of benzodiazepines in general medicine and psychiatric practice, based upon their considerable sedative/hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties (Table 1).¹

Recommendations regarding benzodiazepine use for anxious patients with a history of SUD are not clear-cut. First, it often is difficult to determine whether the patient truly has an anxiety disorder or is suffering anxiety symptoms secondary to substance use and/or withdrawal. In addition, even if a diagnosis of a separate anxiety disorder is established, psychiatrists debate how to treat such patients. Some clinicians maintain that benzodiazepines should be used only for acute detoxification, and that ongoing benzodiazepine use will lead to relapse or benzodiazepine dependence. However, in a prospective study of 545 alcohol use disorder (AUD) patients receiving benzodiazepines for anxiety disorders, Mueller et al² found no association—at 12 months or at 12 years—between benzodiazepine use and AUD recurrence. Furthermore, there was no difference in benzodiazepine usage when comparing patients with and without an AUD.³

Table 1

Clinical uses of benzodiazepines

Cons. Although widely prescribed—and despite their efficacy in numerous conditions— both acute or long-term benzodiazepine use frequently causes adverse effects.⁴ Patients may develop tolerance, which can lead to escalating dosages and/or to withdrawal symptoms when patients attempt to cut back. Benzodiazepines eventually become ineffective for sleep, and continued use can cause rebound insomnia. Also, with many patients taking benzodiazepines long-term, clinicians struggle to differentiate between “real” anxiety symptoms and subtle states of withdrawal from fluctuating benzodiazepine blood levels.⁵

Geriatric patients who take benzodiazepines are at risk for falls and hip fractures.⁴ Although older dementia patients are at particular risk for cognitive problems— including frank delirium—secondary to benzodiazepine use, patients of all ages are susceptible to these medications’ deleterious neurocognitive effects.

Benzodiazepines can lead to excessive sedation, thereby impairing performance at work or school, and have been implicated as a cause of motor vehicle accidents.⁶ Finally, a serious drawback to benzodiazepine use is possible lethality in overdose, especially when combined with alcohol.

Benzodiazepine prescribing should not be taken lightly. Always analyze the difference between benzodiazepines’ well-documented efficacy and their adverse effect profile. This risk-benefit analysis becomes much more complex for patients with SUDs.

Special considerations. Patients at higher risk for benzodiazepine abuse include those with:

• severe alcohol dependence (ie, long-term use, drinking since a young age [“Type II”])
• intravenous drug use
• comorbid alcoholism and antisocial personality disorder.^7,8

Exercise special caution when considering benzodiazepines for patients with severe psychiatric illness such as schizophrenia-spectrum disorders, bipolar disorder, or severe depression. Patients with schizophrenia have high rates of alcohol, cocaine, cannabis, and benzodiazepine abuse.^9,10 Bipolar disorder patients show similar vulnerability—up to 56% of patients screen positive for substance abuse or dependence.¹¹ Vulnerability to addiction in severely ill psychiatric patients is thought to be related to several factors, including:

• use of drugs as self-medication
• genetic predisposition
• environment/lifestyle that supports substance abuse
• neurobiologic deficits that lead to lack of inhibition of reward-seeking behaviors.¹¹

Bipolar disorder patients in particular score high on measures of sensation seeking, which leaves them vulnerable to abusing all classes of substances.¹²

In a 6-year study of 203 patients with severe psychiatric illnesses and SUDs, Brunette et al¹³ found that these patients were 2.5 times more likely than patients with severe psychiatric illness alone to abuse prescribed benzodiazepines. In an analysis of Medicaid records, Clark et al¹⁴ found similar vulnerability in patients with major depressive disorder (MDD) and SUD. Not only did these patients show a higher rate of benzodiazepine use than patients with MDD without SUD, but the dual-diagnosis group also gravitated toward more addictive high-potency/fast-acting benzodiazepines, such as alprazolam, estazolam, or triazolam.

Case discussion/suggestions. Initially, Mr. A may seem to be an appropriate candidate for closely monitored benzodiazepine use. However, he shows a pattern of misuse, likely related to his history of severe alcohol dependence and alprazolam use. This benzodiazepine is fast-acting and has a short half-life, and thus is highly reinforcing.

Similarly, Ms. B might benefit from benzodiazepine treatment. However, her history of schizophrenia and alcohol abuse makes her a risky candidate, and alternative treatments for anxiety symptoms should be considered. If prescribed at all, a benzodiazepine should be used only short-term (eg, 1 to 2 weeks).

In general, avoid prescribing benzodiazepines to most patients who have an ongoing or past SUD.¹⁵ Consider making an exception for SUD patients with comorbid anxiety disorders, with close monitoring of their benzodiazepine use. Clonazepam, chlordiazepoxide, clorazepate, and oxazepam may be less reinforcing for SUD patients than diazepam, lorazepam, alprazolam, estazolam, or triazolam.^7,16 The drawbacks of benzodiazepines, especially in the situations described above, point to the need to find alternative treatments (Table 2).¹⁷ Keep in mind nonpharmacologic options, which completely avoid the risks of medication misuse and diversion. Cognitive-behavioral therapy (CBT), for instance, has well-documented efficacy in treating insomnia and anxiety disorders.^18,19

Table 2

Alternatives to benzodiazepines for anxiety and/or insomnia

CASE 3 Adult ADHD and marijuana use

Mr. C, age 30, presents to a psychiatrist with ongoing complaints of inattention, fatigue, and difficulty staying organized. A self-report screen yields symptoms consistent with adult attention-deficit/hyperactivity disorder (ADHD). Mr. C’s school and job history and collateral history from his wife appear to corroborate his assertion that his symptoms have been lifelong. He later admits to regular marijuana use. After further discussion and full evaluation of his substance use, Mr. C is started on bupropion, titrated to 300 mg/d. After 2 months, despite faithful attendance at appointments and openness about his continued marijuana use, Mr. C’s symptoms remain unchanged. He asks about atomoxetine.

Stimulants

Pros. Despite many clinicians’ hesitance to prescribe controlled substances to patients with SUDs, psychostimulants should be considered in a variety of scenarios. Although nonstimulant options are available, stimulants consistently have demonstrated superior efficacy over other treatments and remain first-line agents for adult ADHD.²⁰ Methylphenidate, mixed amphetamine salts, lisdexamfetamine, and atomoxetine are FDA-approved for adult ADHD. Both stimulant classes (methylphenidate and amphetamine-based products) are equally effective for ADHD. In addition, stimulants are used to treat narcolepsy, cognitive disorders such as traumatic brain injury, and as augmentation to antidepressants for MDD.

ADHD affects 5% to 12% of children, and >60% of patients remain symptomatic into adulthood and require continued treatment.²¹ In particular, problematic inattention may persist throughout adulthood. ADHD does not appear to be an independent risk factor for SUDs in children and adolescents.²² However, substance use increases sharply as ADHD patients enter late adolescence and adulthood, and eventually becomes a problem for 20% of adolescents and adults with ADHD. Conversely, 17% to 50% of patients with alcohol, cocaine, or opioid dependence have co-occurring ADHD.²³

Withholding ADHD treatment based on concerns about future or increased current substance abuse is unfounded. A meta-analysis of 6 studies that included 674 medicated and 360 unmedicated patients with ADHD who were followed at least 4 years demonstrated that childhood treatment of ADHD with stimulants reduces the risk of developing alcohol and other drug disorders in adulthood.²⁴ Regarding the effect stimulants have on active substance use, a 12-week, double-blind, randomized controlled trial of 48 cocaine-dependent adults with ADHD showed methylphenidate did not change cocaine abuse or craving, but did improve ADHD symptoms.²⁵

Clinicians also must assess whether untreated ADHD symptoms impair patients’ work or other activities. Driving is a particular concern because ADHD is associated with risky driving habits, motor vehicle accidents, traffic violations, and driving license suspensions.²⁶ In a study that administered cognitive tests to 27 adults with ADHD, methylphenidate treatment improved cognitive performance related to driving (eg, better visual-motor coordination under high-stress conditions, improved visual orientation, and sustained visual attention).²⁷ It is likely this effect could be generalized to other activities where safety is important. Finally, appropriate stimulant treatment may improve participation in rehabilitative programs.

Cons. Despite their positive effects, stimulants can have adverse effects and consequences.²⁸ In routinely prescribed dosages, methylphenidate and amphetamines can cause symptoms related to sympathetic activation, including anxiety, tics, anorexia/ weight loss, and sleep disturbance. A 5-year study of 79 school-age children prescribed methylphenidate, dextroamphetamine, or pemoline, which is no longer available in the United States, showed a significant association between adherence to stimulants and persistence of physiological (eg, headaches, insomnia, anorexia) and mood-related (eg, irritability, dysphoria) side effects.²⁹ Stimulants’ sympathomimetic properties also can lead to dangerous drug-drug interactions with monoamine oxidase inhibitors. For both methylphenidate and amphetamines, overdose can lead to seizures, cardiac toxicity, dysrhythmias, and hyperthermia. All stimulants carry an FDA “black-box” warning that lists increased risk of cardiac complications, sudden death, and psychiatric complications such as psychosis or mania.³⁰

Special considerations. All stimulants have potential for diversion or abuse. Pay close attention to these issues, especially in vulnerable populations and situations where rates of abuse and diversion are elevated. Among college students, white patients, fraternity/sorority members, and individuals with lower grade point averages may be at higher risk for nonmedical stimulant use.³¹ Adults who misuse or divert stimulants commonly have a history of substance abuse and conduct disorder.³² Short-acting stimulants are abused 4 times more often than extended-release preparations.³³

If your ADHD patient has active substance use, be clear that continued substance use is likely to limit stimulants’ effectiveness. In patients who are actively using substances, it will be difficult to disentangle apparent nonresponse to stimulants from the negative cognitive effects of substance use.

Case discussion/suggestions. As Mr. C’s case illustrates, there are alternatives to stimulants for ADHD. For example, atomoxetine, a selective norepinephrine reuptake inhibitor, may be considered a first-line agent in patients with mostly inattentive ADHD symptoms and comorbid stimulant abuse, or for those in whom stimulants cause adverse effects such as mood lability or tics.³⁴ Other alternatives to stimulants are listed in Table 3.³⁵

Because Mr. C did not respond to bupropion, which presumably was tried first because of his ongoing substance use, he asked about atomoxetine. This agent is not addictive and there is no evidence that it leads to or exacerbates substance use. Depending on Mr. C’s symptom profile, atomoxetine might be a good choice. Continued monitoring of his marijuana use and frequent assessment of his motivation to quit are necessary. Psychoeducation about the cognitive effects of marijuana, including inattention and poor concentration, is important.

If Mr. C does not respond to atomoxetine, his psychiatrist will face a difficult decision. Setting Mr. C’s marijuana use aside, symptoms that do not respond to atomoxetine or a second-line agent are likely to respond to a stimulant. However, several issues must be addressed. If Mr. C’s motivation to stop using marijuana is low, how motivated is he to improve his ADHD symptoms? Next, would marijuana’s depressive/blunting effects counteract the anticipated benefit of a stimulant? Also, what is the risk that Mr. C might sell or exchange his stimulants to obtain marijuana? Assessing these complicated questions is key. Another important factor in Mr. C’s case is his wife’s involvement. Does she monitor his marijuana use? Would she be willing to supervise Mr. C’s stimulant use, and would he allow it?

Past or present SUDs are not an absolute contraindication to stimulant use. You should affirm the diagnosis and identify target symptoms. Consider nonstimulant alternatives if appropriate.

Table 3

Alternatives to stimulants for ADHD

Legal liabilities

Being aware of the medicolegal issues of benzodiazepine and/or stimulant prescribing is crucial because a court may find a psychiatrist liable for negative outcomes (eg, suicide) when controlled substances are prescribed to a patient with a history of addiction.³⁶ The most prudent course is to weigh the pros and cons for each patient individually, taking into consideration the factors described above.⁸ This is consistent with guidelines from the American Psychiatric Association and the British Association for Psychopharmacology,³⁷ both of which call for extreme caution in these cases.

Educate patients and caregivers about the risks of taking a controlled substance, including misuse, diversion, and theft. Provide and document explicit instructions that the patient will receive stimulants from only a single provider. Remind patients that state and federal authorities closely track controlled medications. Finally, a “stimulant contract” or “benzodiazepine contract,” similar to a pain or narcotic contact, may be useful to formally document discussions about appropriate medication use.

Related Resources

• National Institute on Drug Abuse. Prescription drugs: abuse and addiction. Research Report Series, 2005. http://drugabuse.gov/ResearchReports/Prescription/Prescription.html.
• Galanter M, Kleber HD. The American Psychiatric Publishing textbook of substance abuse treatment. 4th ed. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, others
• Chlordiazepoxide • Librium
• Clonazepam • Klonopin
• Clonidine • Catapres
• Clorazepate • Tranxene
• Dextroamphetamine • Dexedrine
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Doxepin • Silenor
• Estazolam • ProSom
• Gabapentin • Neurontin
• Guanfacine • Tenex, Intuniv
• Lisdexamfetamine • Vyvanse
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta, others
• Mirtazapine • Remeron
• Mixed amphetamine salts • Adderall
• Modafinil • Provigil
• Oxazepam • Serax
• Pemoline • Cylert
• Propranolol • Inderal
• Trazodone • Desyrel, Oleptro
• Triazolam • Halcion

Disclosures

Dr. Casher is a speaker for AstraZeneca and Pfizer Inc.

Drs. Gih and Bess report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Worsening depression

Mr. N, age 64, is a disabled factory worker with a complicated medical history. He has poorly controlled type II diabetes mellitus; obesity (body mass index 40 kg/m²); complicated cryptogenic cirrhosis with prior esophageal varices, portal gastropathy, splenomegaly, and no encephalopathy; surgically treated colon adenocarcinoma; and bilateral thalamic and right occipital infarcts with residual left homonymous hemianopsia and vertical gaze paresis. Mr. N sustained a perioperative stroke 18 months ago while undergoing a colectomy procedure for colon adenocarcinoma; an MRI done at that time showed the bilateral thalamic and right occipital infarcts. While in the internal medicine consultation clinic, Mr. N expresses suicidal and homicidal thoughts, which prompted the internal medicine team to refer him to the emergency department (ED). The team deems Mr. N’s medical problems stable except for diabetic dyscontrol.

In the ED, Mr. N says he feels sad, worthless, and “tired” of his complex family issues and multiple medical conditions. He says he’s had these feeling for at least a year, but his depression has worsened in the last few days. Mr. N is tearful while explaining his discouragement with following a diet for diabetes; earlier that day he ate an entire chocolate cake. He says all 3 of his children have ongoing substance abuse and relationship problems, but he is particularly focused on his youngest daughter, who is involved with a man who is addicted to drugs and physically abuses her and her children. Mr. N describes a detailed plan to shoot him and then commit suicide. This disclosure prompts the ED physician to admit Mr. N to ensure his safety and stabilize his mood.

Mr. N’s temperature is 36. 4°C (97. 5°F), blood pressure is 123/60 mm Hg, pulse is 81 beats per minute, respiratory rate is 24 breaths per minute, and oxygen saturation is 96% on ambient air. His physical exam is notable only for dysphoria and mild gynecomastia. He shows no evidence of acute cardiopulmonary, gastrointestinal, or other neurologic changes. His serum glucose is 650 mg/dL, and his recent hemoglobin A_1c (HbA_1c) is 10. 9%. His other laboratory tests include a hemoglobin of 11. 7 g/dL; white cell count, 3500/mm³; platelet count, 41, 000/mm³; sodium, 129 mEq/L; potassium, 5. 0 mEq/L; alkaline phosphatase, 90 U/L; aspartate aminotransferase, 23 U/L; alanine aminotransferase, 21 U/L; total bilirubin, 1. 8 mg/dL; creatinine, 1. 2 mg/dL; prothrombin time, 10. 4 sec; and arterial ammonia, <50 ?g/dL. Arterial blood gases are normal.

A year ago, his primary care physician prescribed fluoxetine, 20 mg/d, for fatigue and chronic back pain and neuropathic pain related to diabetes. We continue Mr. N’s outpatient prescription of fluoxetine, 20 mg/d, and low-dose acetaminophen as needed for pain. Furosemide, 40 mg/d, spironolactone, 100 mg/d, and propranolol sustained release, 60 mg/d, are maintained for complications of cirrhosis. Insulin aspart, 22 units with breakfast, 24 units with lunch, and 24 units with supper, also are administered routinely.

We consult with the internal medicine, ophthalmology, neurology, endocrinology, and diabetes services to assist in evaluating and managing Mr. N’s multiple medical conditions.

The authors’ observations

Depression and other forms of psychopathology may be underrecognized in geriatric patients because older adults may not report psychiatric symptoms that are secondary to physical conditions. Cognitive impairment in some older adults also may lead to underreporting of symptoms. Mr. N denies a history of depression, which we confirmed with his wife, daughter, and primary care physician. The late onset of his initial presentation prompted close investigation for a potential medical etiology (Table 1).^1,2

We considered post-stroke depression because shortly after Mr. N’s stroke, his neurologist described emotional lability and frustration related to his poor vision. Depression occurs in one-third of chronic stroke survivors and is prevalent among patients referred for neurologic rehabilitation.¹ Premorbid neuroticism³ and a history of mental illness are predictors of post-stroke depression. Stroke laterality is not related to risk of post-stroke depressive symptoms,³ but women have a higher risk of developing post-stroke depression.³

Table 1

When to consider medical causes of depressive symptoms

Diabetes and depression

Up to 30% of patients with type 2 diabetes mellitus report a lifetime history of major depression.² Depression increases the risk of hyperglycemia and accompanying long-term metabolic complications.^4,5 Few studies have explored the effects of poor glycemic control on depressive symptoms among diabetic patients.^6-9 A literature review revealed no large-scale study investigating worsened depressive symptoms in patients with poor glycemic control.^10,11

The cross-sectional difference between a single episode of major depression and adjustment disorder can be subtle. DSM-IV-TR describes the latter as a maladaptive reaction to an identifiable psychosocial stressor, or stressors, that occurs within 3 months of onset of that stressor (Table 2).¹² Because we did not deem Mr. N’s depressive symptoms, which were evident only when he was hyperglycemic, to be grossly disproportionate to his stressors, we diagnose him with major depression rather than adjustment disorder.

Table 2

DSM-IV-TR diagnostic criteria for adjustment disorder

EVALUATION: No psychiatric history

On admission, Mr. N is overwhelmed, tearful, and dysphoric when describing his situation. He displays no evidence of psychosis, but his judgment and insight are impaired. He shows no change in consciousness or ability to stay awake. Mr. N acknowledges hypersomnolence, anhedonia, anergia, and decreased concentration and continues to express suicidal and homicidal thoughts. He repeatedly denies any personal or family psychiatric history or personal substance abuse, including alcohol and nicotine.

TREATMENT: Glycemic control

Mr. N receives 1 L of saline in the ED and is encouraged to drink more water during hospitalization. With appropriate insulin dosing, Mr. N’s serum glucose levels improve from 650 to 426 mg/dL by the next morning. On his third hospital day, Mr. N’s glucose level is 155 mg/dL in the morning. With tighter glycemic control, his dysphoria improves. He is future-oriented, markedly less dysphoric, and denies homicidal or suicidal ideation. Mr. N is interested in participating in group therapy, and his insight and judgment regarding his homicidal and suicidal thoughts improve. He still doesn’t fully understand the importance of diabetic control, and he struggles with his diet.

On the fourth hospital day, Mr. N’s glucose level rises to 325 mg/dL in the early evening. Subsequently, his mood deteriorates; he becomes increasingly withdrawn and somnolent. With appropriate attention to his dietary intake and supplemental insulin, his serum glucose improves to the 100 to 200 mg/dL range overnight, and his mood improves. When the glucose is controlled, he attends group therapy, tends to his hygiene, denies feeling hopeless, and offers several ideas about how to manage his family situation. After his glucose rises, Mr. N becomes isolative, hopeless, and unable to cope with stressors. With considerable education about the importance of glycemic control, Mr. N is hopeful and future-oriented when he is discharged after 9 days of hospitalization. At outpatient evaluation, he continues to report euthymia with adequate glycemic control.

The authors’ observations

Patients with hyperglycemia may experience symptoms secondary to volume depletion and hyperosmolality. The severity of these symptoms generally is proportional to the extent and duration of the hyperosmolar state. Initially, most patients complain of polyuria and polydipsia, but in more severe cases, mental status changes may evolve and include lethargy, twitching, cloudiness, motor or sensory defects, seizures, and coma. Some evidence shows that hyperglycemic patients with hyperosmolality are symptomatic only if hypernatremia is present.¹³ Mr. N was hyponatremic, which resolved with aggressive hydration and insulin administration.

Traditionally, depression has been observed to worsen glycemic control in diabetic patients; discussion of increased glucose levels leading to worsened depression rarely has been reported. In a meta-analysis, Lustman et al⁷ revealed that depression is significantly associated with hyperglycemia. A review by Li et al¹⁴ demonstrated that depression is much more common in patients with diabetes compared with general population and 45% of diabetes patients with depression were undiagnosed. Calhoun et al¹⁵ showed that for every 1-unit increase in HbA_1c the odds of depressive symptoms increase by 22%. Researchers also found a positive relationship between depression and glycemic control in American Indians.¹⁵

Mr. N’s case is further evidence that the relationship between diabetes and depression is bidirectional and diagnosis and treatment of each illness impacts the other. Although this case does not confirm causality, it highlights the importance of aggressive approaches to screening and treatment of depression in patients with diabetes, and vice versa.

Related Resources

• Katon W, Russo J, Lin EH, et al. Depression and diabetes: factors associated with major depression at five-year follow-up. Psychosomatics. 2009; 50(6): 570-579.
• Biessels GJ, Luchsinger JA. Diabetes and the brain. New York, NY: Humana Press; 2009.

Drug Brand Names

• Fluoxetine • Prozac
• Furosemide • Lasix
• Insulin aspart • NovoLog
• Insulin glargine • Lantus
• Methyldopa • Aldomet
• Propranolol • Inderal
• Reserpine • Serpasil
• Spironolactone • Aldactone

Disclosure

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

CASE: Worsening depression

Mr. N, age 64, is a disabled factory worker with a complicated medical history. He has poorly controlled type II diabetes mellitus; obesity (body mass index 40 kg/m²); complicated cryptogenic cirrhosis with prior esophageal varices, portal gastropathy, splenomegaly, and no encephalopathy; surgically treated colon adenocarcinoma; and bilateral thalamic and right occipital infarcts with residual left homonymous hemianopsia and vertical gaze paresis. Mr. N sustained a perioperative stroke 18 months ago while undergoing a colectomy procedure for colon adenocarcinoma; an MRI done at that time showed the bilateral thalamic and right occipital infarcts. While in the internal medicine consultation clinic, Mr. N expresses suicidal and homicidal thoughts, which prompted the internal medicine team to refer him to the emergency department (ED). The team deems Mr. N’s medical problems stable except for diabetic dyscontrol.

In the ED, Mr. N says he feels sad, worthless, and “tired” of his complex family issues and multiple medical conditions. He says he’s had these feeling for at least a year, but his depression has worsened in the last few days. Mr. N is tearful while explaining his discouragement with following a diet for diabetes; earlier that day he ate an entire chocolate cake. He says all 3 of his children have ongoing substance abuse and relationship problems, but he is particularly focused on his youngest daughter, who is involved with a man who is addicted to drugs and physically abuses her and her children. Mr. N describes a detailed plan to shoot him and then commit suicide. This disclosure prompts the ED physician to admit Mr. N to ensure his safety and stabilize his mood.

Mr. N’s temperature is 36. 4°C (97. 5°F), blood pressure is 123/60 mm Hg, pulse is 81 beats per minute, respiratory rate is 24 breaths per minute, and oxygen saturation is 96% on ambient air. His physical exam is notable only for dysphoria and mild gynecomastia. He shows no evidence of acute cardiopulmonary, gastrointestinal, or other neurologic changes. His serum glucose is 650 mg/dL, and his recent hemoglobin A_1c (HbA_1c) is 10. 9%. His other laboratory tests include a hemoglobin of 11. 7 g/dL; white cell count, 3500/mm³; platelet count, 41, 000/mm³; sodium, 129 mEq/L; potassium, 5. 0 mEq/L; alkaline phosphatase, 90 U/L; aspartate aminotransferase, 23 U/L; alanine aminotransferase, 21 U/L; total bilirubin, 1. 8 mg/dL; creatinine, 1. 2 mg/dL; prothrombin time, 10. 4 sec; and arterial ammonia, <50 ?g/dL. Arterial blood gases are normal.

A year ago, his primary care physician prescribed fluoxetine, 20 mg/d, for fatigue and chronic back pain and neuropathic pain related to diabetes. We continue Mr. N’s outpatient prescription of fluoxetine, 20 mg/d, and low-dose acetaminophen as needed for pain. Furosemide, 40 mg/d, spironolactone, 100 mg/d, and propranolol sustained release, 60 mg/d, are maintained for complications of cirrhosis. Insulin aspart, 22 units with breakfast, 24 units with lunch, and 24 units with supper, also are administered routinely.

We consult with the internal medicine, ophthalmology, neurology, endocrinology, and diabetes services to assist in evaluating and managing Mr. N’s multiple medical conditions.

The authors’ observations

Depression and other forms of psychopathology may be underrecognized in geriatric patients because older adults may not report psychiatric symptoms that are secondary to physical conditions. Cognitive impairment in some older adults also may lead to underreporting of symptoms. Mr. N denies a history of depression, which we confirmed with his wife, daughter, and primary care physician. The late onset of his initial presentation prompted close investigation for a potential medical etiology (Table 1).^1,2

We considered post-stroke depression because shortly after Mr. N’s stroke, his neurologist described emotional lability and frustration related to his poor vision. Depression occurs in one-third of chronic stroke survivors and is prevalent among patients referred for neurologic rehabilitation.¹ Premorbid neuroticism³ and a history of mental illness are predictors of post-stroke depression. Stroke laterality is not related to risk of post-stroke depressive symptoms,³ but women have a higher risk of developing post-stroke depression.³

Table 1

When to consider medical causes of depressive symptoms

Diabetes and depression

Up to 30% of patients with type 2 diabetes mellitus report a lifetime history of major depression.² Depression increases the risk of hyperglycemia and accompanying long-term metabolic complications.^4,5 Few studies have explored the effects of poor glycemic control on depressive symptoms among diabetic patients.^6-9 A literature review revealed no large-scale study investigating worsened depressive symptoms in patients with poor glycemic control.^10,11

The cross-sectional difference between a single episode of major depression and adjustment disorder can be subtle. DSM-IV-TR describes the latter as a maladaptive reaction to an identifiable psychosocial stressor, or stressors, that occurs within 3 months of onset of that stressor (Table 2).¹² Because we did not deem Mr. N’s depressive symptoms, which were evident only when he was hyperglycemic, to be grossly disproportionate to his stressors, we diagnose him with major depression rather than adjustment disorder.

Table 2

DSM-IV-TR diagnostic criteria for adjustment disorder

EVALUATION: No psychiatric history

On admission, Mr. N is overwhelmed, tearful, and dysphoric when describing his situation. He displays no evidence of psychosis, but his judgment and insight are impaired. He shows no change in consciousness or ability to stay awake. Mr. N acknowledges hypersomnolence, anhedonia, anergia, and decreased concentration and continues to express suicidal and homicidal thoughts. He repeatedly denies any personal or family psychiatric history or personal substance abuse, including alcohol and nicotine.

TREATMENT: Glycemic control

Mr. N receives 1 L of saline in the ED and is encouraged to drink more water during hospitalization. With appropriate insulin dosing, Mr. N’s serum glucose levels improve from 650 to 426 mg/dL by the next morning. On his third hospital day, Mr. N’s glucose level is 155 mg/dL in the morning. With tighter glycemic control, his dysphoria improves. He is future-oriented, markedly less dysphoric, and denies homicidal or suicidal ideation. Mr. N is interested in participating in group therapy, and his insight and judgment regarding his homicidal and suicidal thoughts improve. He still doesn’t fully understand the importance of diabetic control, and he struggles with his diet.

On the fourth hospital day, Mr. N’s glucose level rises to 325 mg/dL in the early evening. Subsequently, his mood deteriorates; he becomes increasingly withdrawn and somnolent. With appropriate attention to his dietary intake and supplemental insulin, his serum glucose improves to the 100 to 200 mg/dL range overnight, and his mood improves. When the glucose is controlled, he attends group therapy, tends to his hygiene, denies feeling hopeless, and offers several ideas about how to manage his family situation. After his glucose rises, Mr. N becomes isolative, hopeless, and unable to cope with stressors. With considerable education about the importance of glycemic control, Mr. N is hopeful and future-oriented when he is discharged after 9 days of hospitalization. At outpatient evaluation, he continues to report euthymia with adequate glycemic control.

The authors’ observations

Patients with hyperglycemia may experience symptoms secondary to volume depletion and hyperosmolality. The severity of these symptoms generally is proportional to the extent and duration of the hyperosmolar state. Initially, most patients complain of polyuria and polydipsia, but in more severe cases, mental status changes may evolve and include lethargy, twitching, cloudiness, motor or sensory defects, seizures, and coma. Some evidence shows that hyperglycemic patients with hyperosmolality are symptomatic only if hypernatremia is present.¹³ Mr. N was hyponatremic, which resolved with aggressive hydration and insulin administration.

Traditionally, depression has been observed to worsen glycemic control in diabetic patients; discussion of increased glucose levels leading to worsened depression rarely has been reported. In a meta-analysis, Lustman et al⁷ revealed that depression is significantly associated with hyperglycemia. A review by Li et al¹⁴ demonstrated that depression is much more common in patients with diabetes compared with general population and 45% of diabetes patients with depression were undiagnosed. Calhoun et al¹⁵ showed that for every 1-unit increase in HbA_1c the odds of depressive symptoms increase by 22%. Researchers also found a positive relationship between depression and glycemic control in American Indians.¹⁵

Mr. N’s case is further evidence that the relationship between diabetes and depression is bidirectional and diagnosis and treatment of each illness impacts the other. Although this case does not confirm causality, it highlights the importance of aggressive approaches to screening and treatment of depression in patients with diabetes, and vice versa.

Related Resources

• Katon W, Russo J, Lin EH, et al. Depression and diabetes: factors associated with major depression at five-year follow-up. Psychosomatics. 2009; 50(6): 570-579.
• Biessels GJ, Luchsinger JA. Diabetes and the brain. New York, NY: Humana Press; 2009.

Drug Brand Names

• Fluoxetine • Prozac
• Furosemide • Lasix
• Insulin aspart • NovoLog
• Insulin glargine • Lantus
• Methyldopa • Aldomet
• Propranolol • Inderal
• Reserpine • Serpasil
• Spironolactone • Aldactone

Disclosure

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

CASE: Worsening depression

Mr. N, age 64, is a disabled factory worker with a complicated medical history. He has poorly controlled type II diabetes mellitus; obesity (body mass index 40 kg/m²); complicated cryptogenic cirrhosis with prior esophageal varices, portal gastropathy, splenomegaly, and no encephalopathy; surgically treated colon adenocarcinoma; and bilateral thalamic and right occipital infarcts with residual left homonymous hemianopsia and vertical gaze paresis. Mr. N sustained a perioperative stroke 18 months ago while undergoing a colectomy procedure for colon adenocarcinoma; an MRI done at that time showed the bilateral thalamic and right occipital infarcts. While in the internal medicine consultation clinic, Mr. N expresses suicidal and homicidal thoughts, which prompted the internal medicine team to refer him to the emergency department (ED). The team deems Mr. N’s medical problems stable except for diabetic dyscontrol.

In the ED, Mr. N says he feels sad, worthless, and “tired” of his complex family issues and multiple medical conditions. He says he’s had these feeling for at least a year, but his depression has worsened in the last few days. Mr. N is tearful while explaining his discouragement with following a diet for diabetes; earlier that day he ate an entire chocolate cake. He says all 3 of his children have ongoing substance abuse and relationship problems, but he is particularly focused on his youngest daughter, who is involved with a man who is addicted to drugs and physically abuses her and her children. Mr. N describes a detailed plan to shoot him and then commit suicide. This disclosure prompts the ED physician to admit Mr. N to ensure his safety and stabilize his mood.

Mr. N’s temperature is 36. 4°C (97. 5°F), blood pressure is 123/60 mm Hg, pulse is 81 beats per minute, respiratory rate is 24 breaths per minute, and oxygen saturation is 96% on ambient air. His physical exam is notable only for dysphoria and mild gynecomastia. He shows no evidence of acute cardiopulmonary, gastrointestinal, or other neurologic changes. His serum glucose is 650 mg/dL, and his recent hemoglobin A_1c (HbA_1c) is 10. 9%. His other laboratory tests include a hemoglobin of 11. 7 g/dL; white cell count, 3500/mm³; platelet count, 41, 000/mm³; sodium, 129 mEq/L; potassium, 5. 0 mEq/L; alkaline phosphatase, 90 U/L; aspartate aminotransferase, 23 U/L; alanine aminotransferase, 21 U/L; total bilirubin, 1. 8 mg/dL; creatinine, 1. 2 mg/dL; prothrombin time, 10. 4 sec; and arterial ammonia, <50 ?g/dL. Arterial blood gases are normal.

A year ago, his primary care physician prescribed fluoxetine, 20 mg/d, for fatigue and chronic back pain and neuropathic pain related to diabetes. We continue Mr. N’s outpatient prescription of fluoxetine, 20 mg/d, and low-dose acetaminophen as needed for pain. Furosemide, 40 mg/d, spironolactone, 100 mg/d, and propranolol sustained release, 60 mg/d, are maintained for complications of cirrhosis. Insulin aspart, 22 units with breakfast, 24 units with lunch, and 24 units with supper, also are administered routinely.

We consult with the internal medicine, ophthalmology, neurology, endocrinology, and diabetes services to assist in evaluating and managing Mr. N’s multiple medical conditions.

The authors’ observations

Depression and other forms of psychopathology may be underrecognized in geriatric patients because older adults may not report psychiatric symptoms that are secondary to physical conditions. Cognitive impairment in some older adults also may lead to underreporting of symptoms. Mr. N denies a history of depression, which we confirmed with his wife, daughter, and primary care physician. The late onset of his initial presentation prompted close investigation for a potential medical etiology (Table 1).^1,2

We considered post-stroke depression because shortly after Mr. N’s stroke, his neurologist described emotional lability and frustration related to his poor vision. Depression occurs in one-third of chronic stroke survivors and is prevalent among patients referred for neurologic rehabilitation.¹ Premorbid neuroticism³ and a history of mental illness are predictors of post-stroke depression. Stroke laterality is not related to risk of post-stroke depressive symptoms,³ but women have a higher risk of developing post-stroke depression.³

Table 1

When to consider medical causes of depressive symptoms

Diabetes and depression

Up to 30% of patients with type 2 diabetes mellitus report a lifetime history of major depression.² Depression increases the risk of hyperglycemia and accompanying long-term metabolic complications.^4,5 Few studies have explored the effects of poor glycemic control on depressive symptoms among diabetic patients.^6-9 A literature review revealed no large-scale study investigating worsened depressive symptoms in patients with poor glycemic control.^10,11

The cross-sectional difference between a single episode of major depression and adjustment disorder can be subtle. DSM-IV-TR describes the latter as a maladaptive reaction to an identifiable psychosocial stressor, or stressors, that occurs within 3 months of onset of that stressor (Table 2).¹² Because we did not deem Mr. N’s depressive symptoms, which were evident only when he was hyperglycemic, to be grossly disproportionate to his stressors, we diagnose him with major depression rather than adjustment disorder.

Table 2

DSM-IV-TR diagnostic criteria for adjustment disorder

EVALUATION: No psychiatric history

On admission, Mr. N is overwhelmed, tearful, and dysphoric when describing his situation. He displays no evidence of psychosis, but his judgment and insight are impaired. He shows no change in consciousness or ability to stay awake. Mr. N acknowledges hypersomnolence, anhedonia, anergia, and decreased concentration and continues to express suicidal and homicidal thoughts. He repeatedly denies any personal or family psychiatric history or personal substance abuse, including alcohol and nicotine.

TREATMENT: Glycemic control

Mr. N receives 1 L of saline in the ED and is encouraged to drink more water during hospitalization. With appropriate insulin dosing, Mr. N’s serum glucose levels improve from 650 to 426 mg/dL by the next morning. On his third hospital day, Mr. N’s glucose level is 155 mg/dL in the morning. With tighter glycemic control, his dysphoria improves. He is future-oriented, markedly less dysphoric, and denies homicidal or suicidal ideation. Mr. N is interested in participating in group therapy, and his insight and judgment regarding his homicidal and suicidal thoughts improve. He still doesn’t fully understand the importance of diabetic control, and he struggles with his diet.

On the fourth hospital day, Mr. N’s glucose level rises to 325 mg/dL in the early evening. Subsequently, his mood deteriorates; he becomes increasingly withdrawn and somnolent. With appropriate attention to his dietary intake and supplemental insulin, his serum glucose improves to the 100 to 200 mg/dL range overnight, and his mood improves. When the glucose is controlled, he attends group therapy, tends to his hygiene, denies feeling hopeless, and offers several ideas about how to manage his family situation. After his glucose rises, Mr. N becomes isolative, hopeless, and unable to cope with stressors. With considerable education about the importance of glycemic control, Mr. N is hopeful and future-oriented when he is discharged after 9 days of hospitalization. At outpatient evaluation, he continues to report euthymia with adequate glycemic control.

The authors’ observations

Patients with hyperglycemia may experience symptoms secondary to volume depletion and hyperosmolality. The severity of these symptoms generally is proportional to the extent and duration of the hyperosmolar state. Initially, most patients complain of polyuria and polydipsia, but in more severe cases, mental status changes may evolve and include lethargy, twitching, cloudiness, motor or sensory defects, seizures, and coma. Some evidence shows that hyperglycemic patients with hyperosmolality are symptomatic only if hypernatremia is present.¹³ Mr. N was hyponatremic, which resolved with aggressive hydration and insulin administration.

Traditionally, depression has been observed to worsen glycemic control in diabetic patients; discussion of increased glucose levels leading to worsened depression rarely has been reported. In a meta-analysis, Lustman et al⁷ revealed that depression is significantly associated with hyperglycemia. A review by Li et al¹⁴ demonstrated that depression is much more common in patients with diabetes compared with general population and 45% of diabetes patients with depression were undiagnosed. Calhoun et al¹⁵ showed that for every 1-unit increase in HbA_1c the odds of depressive symptoms increase by 22%. Researchers also found a positive relationship between depression and glycemic control in American Indians.¹⁵

Mr. N’s case is further evidence that the relationship between diabetes and depression is bidirectional and diagnosis and treatment of each illness impacts the other. Although this case does not confirm causality, it highlights the importance of aggressive approaches to screening and treatment of depression in patients with diabetes, and vice versa.

Related Resources

• Katon W, Russo J, Lin EH, et al. Depression and diabetes: factors associated with major depression at five-year follow-up. Psychosomatics. 2009; 50(6): 570-579.
• Biessels GJ, Luchsinger JA. Diabetes and the brain. New York, NY: Humana Press; 2009.

Drug Brand Names

• Fluoxetine • Prozac
• Furosemide • Lasix
• Insulin aspart • NovoLog
• Insulin glargine • Lantus
• Methyldopa • Aldomet
• Propranolol • Inderal
• Reserpine • Serpasil
• Spironolactone • Aldactone

Disclosure

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

In January 2011, the FDA approved vilazodone for the treatment of major depressive disorder (MDD) (Table 1).

Vilazodone was discovered by Merck KGaA in Germany.¹ In February 2001, Merck KGaA licensed vilazodone to GlaxoSmithKline. In April 2003, GlaxoSmithKline returned all rights to Merck KGaA because phase IIb clinical data did not support progression to phase III clinical trials. In September 2004, Genaissance Pharmaceuticals Inc. acquired an exclusive worldwide license from Merck KGaA to develop and commercialize vilazodone for depression treatment.² Subsequently, Clinical Data Inc. acquired Genaissance Pharmaceuticals Inc., including vilazodone, and proceeded with 2 phase III trials and a large safety trial resulting in FDA approval. In February 2011, Forest Laboratories Inc. acquired Clinical Data Inc. and will launch vilazodone in second quarter of 2011.

Table 1

Vilazodone: Fast facts

How it works

Similar to all antidepressants, vilazodone’s mechanism of action is not fully understood, but is thought to be related to its inhibition of serotonin (ie, 5-HT) reuptake and partial agonism of 5-HT1A receptors.³ Vilazodone technically is not a selective serotonin reuptake inhibitor (SSRI) because it has greater affinity for the 5-HT1A receptor (0.2nM) than it does for the 5-HT reuptake pump (0.5nM).⁴

Vilazodone was developed based on the theory that inhibition of 5-HT1A autoreceptor inhibition was responsible for SSRIs’ delayed (approximately 2 weeks) onset of antidepressant efficacy. Briefly, this theory is as follows: In humans, 5-HT1A receptors are primarily presynaptic in the raphe nuclei and postsynaptic 5-HT1A receptors predominate in the neocortex and limbic regions of the brain.⁵ Presynaptically, 5-HT1A are autoreceptors, ie, serotonin stimulation of these receptors results in inhibition of firing of 5-HT neurons, while postsynaptically they may be involved in downstream serotonergic effects such as sexual function.⁵ SSRIs are thought to work as antidepressants by increasing 5-HT concentration in the synapse but their initial effect is to turn off 5-HT neuronal firing as a result of increased concentration of 5-HT at the presynaptic 5-HT1A autoreceptor. Subsequently, these 5-HT1A autoreceptors subsensitize such that 5-HT neuronal firing rate returns to normal. The time course for this subsensitization parallels the onset of SSRI antidepressant efficacy. For several years, efforts have been made to antagonize the 5-HT1A presynaptic autoreceptors as a means of potentially shortening SSRIs’ onset of efficacy.^6-8

Pharmacokinetics

Vilazodone is absorbed in the gastrointestinal tract and reaches peak concentration at a median of 4 to 5 hours. Its bioavailability increases when taken with food such that Cmax (maximum concentration) is increased by 147% to 160%, and area under the curve is increased by 64% to 85%. Its absolute bioavailability in the presence of food is 72%.⁴ In systemic circulation, the drug is 96% to 99% protein-bound.³ Vilazodone is eliminated primarily through cytochrome P450 (CYP) 3A4 metabolism in the liver.³

Terminal half-life of vilazodone is 25 hours. In general, steady state is achieved in 4 to 5 times the half-life at a stable dose. However, dosing guidelines for vilazodone recommend titration over 2 weeks to achieve a target of 40 mg/d. Thus, steady state will not be achieved until the patient has been on the stable target dose for approximately 2.5 weeks.³

Efficacy

Vilazodone’ efficacy for MDD treatment was established in 2 pivotal 8-week, randomized, double-blind, placebo-controlled, but not active-controlled, trials (Table 2).^9-11 Study participants were outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score >22 and a HAM-D-17 item 1 (depressed mood) score >2.

In the first clinical trial, 410 patients were randomly assigned to vilazodone or placebo. In the vilazodone group, patients were started on 10 mg/d for 1 week, titrated to 20 mg/d for a second week, and then 40 mg/d for the remainder of the study. At week 8, the mean change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-D-17, Clinical Global Impression-Improvement scale (CGI-I), Clinical Global Impression-Severity scale (CGI-S), and Hamilton Anxiety scale (HAM-A) was statistically greater with vilazodone than placebo (P <.05).⁹ Compared with placebo, vilazodone-treated patients showed a statistically significant (P <. 05) improvement in MADRS and HAM-D-17 scores at week 1. Approximately 12% more vilazodone-treated patients achieved response (defined as ≥50% decrease in total score at end of treatment) on the primary efficacy measure, which was MADRS (40.4% vs 28.1%, P=.007), and the 2 secondary efficacy measures, which were HAM-D-17 (44.4% vs 32.7%, P =.011) and CGI-I (48.0 vs 32.7, P =.001). Remission rates (MADRS <10) were not reported in this study, but the authors stated that there was no statistical difference in remission rates between the vilazodone and placebo groups.⁹

In a second trial, which featured design and titration schedule identical to that of the first study, 481 patients were randomized to vilazodone or placebo.¹⁰ At week 8, the vilazodone-treated patients had significantly greater improvement in MADRS, HAM-D-17, HAM-A, CGI-S, and CGI-I score compared with the placebo group (P <.05). Approximately 14% more patients in the vilazodone group were MADRS responders compared with placebo (44% vs 30%, P =.002). Remission rates were not statistically different between patients taking vilazodone vs placebo (27% vs 20% respectively).¹⁰ Demonstrating a statistically significant difference between a 27% vs 20% remission rate would require a much larger number of patients than were included in this study.

Table 2

Efficacy of vilazodone in phase III clinical trials

Tolerability

Vilazodone’s safety was evaluated in 2, 177 patients (age 18 to 70) diagnosed with MDD who participated in clinical studies, including the two 8-week, randomized, doubleblind, placebo-controlled studies (N=891) and a 52-week, open-label study of 599 patients.¹² Overall, 7.1% of patients who received vilazodone discontinued treatment because of an adverse reaction, compared with 3.2% of placebo-treated patients in the double-blind studies.³ Diarrhea, nausea, and headache were the most commonly reported adverse events; the incidence of headache was similar to that in the placebo group (13.2% vs 14.2%).¹⁰ These adverse events are consistent with serotonin agonism, mild to moderate intensity, and occurred mainly during the first week of treatment.³

Doses up to 80 mg/d have not been associated with clinically significant changes in ECG parameters or laboratory parameters in serum chemistry hematology and urine analysis.^9,10 The drug had no effect on weight as measured by mean change from baseline.^9,10

In one 8-week trial, there were no substantial differences between vilazodone and placebo in Arizona Sexual Experience Scale (ASEX) scores at treatment end for either sex.⁹ ASEX is a 5-item scale used to assess sexual dysfunction; a score >18 indicates clinically significant sexual dysfunction. At baseline, mean ASEX scores among men were 15.8 in the placebo group and 16.5 in the vilazodone group. Among women, the mean ASEX score was 21.2 in both groups.⁹ Overall sexual function for men and women was similar for vilazodone and placebo, as measured by the Changes in Sexual Function Questionnaire.¹⁰ The most commonly reported sexual adverse effect was decreased libido.¹⁰

Contraindications

Vilazodone is contraindicated for concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping or starting an MAOI. Vilazodone is contraindicated in patients taking strong CYP3A4 inhibitors (eg, ketoconazole) because of increased vilazodone concentrations and resulting concentration-dependent adverse effects.³ Concomitant administration of strong CYP3A4 inducers (eg, rifampin) might result in a reduction in vilazodone levels leading to lack or loss of efficacy.¹³

As with other antidepressants, vilazodone carries a black-box warning about increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders.³ Vilazodone showed evidence of developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate, well-controlled studies of vilazodone in pregnant women and no human data regarding vilazodone concentrations in breast milk.³ Women taking vilazodone are advised to breastfeed only if the potential benefits outweigh the risks. Vilazodone is not recommended for use in pediatric patients.³

Similar to other antidepressants, vilazodone labeling carries warnings about serotonin syndrome, seizures, abnormal bleeding, activation of mania/hypomania, and hyponatremia.⁴

Dosing

Vilazodone is available as 10 mg, 20 mg, and 40 mg tablets. The recommended target dose for vilazodone is 40 mg/d, with a starting dose of 10 mg/d for 7 days, followed by 20 mg/d for 7 days, then 40 mg/d.³ The drug should be taken with food, but unlike other psychotropics, the manufacturer does not recommended a specific calorie amount.³ Dose tapering is recommended when the drug is discontinued.³

Dose should be reduced to 20 mg/d when vilazodone is coadministered with strong CYP3A4 inhibitors, such as azole antifungals, macrolides, protease inhibitors, and verapamil.¹³ No dosage adjustment is recommended based on age, mild or moderate liver impairment, or renal impairment of any severity.³ Vilazodone has not been studied in patients with severe hepatic impairment.³

How does vilazodone compare?

Ideally, it would be good to know how vilazodone compares with other marketed antidepressants. Unfortunately, there are no published head-to-head comparison data to address this matter. The number needed to treat with vilazodone is between 7 and 8 based on the data from the 2 phase III trials (Table 2).^9-11 This is comparable to other antidepressants. One phase III study showed a statistically greater reduction in depressive symptomatology in vilazodone-treated patients after 1 week, ⁹ but that was not replicated in the second trial.¹⁰

Related Resources

• Khan A. Vilazodone, a novel dual-acting serotonergic antidepressant for managing major depression. Expert Opin Investig Drugs. 2009;18(11):1753-1764.

Drug Brand Names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Verapamil • Isoptin
• Vilazodone • Viibryd

Disclosures

Drs. Kalia and Mittal report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Since January 2010, Dr. Preskorn has received grant/research support from Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Ipsen, Link Medicine, Pfizer Inc, Sunovion, Takeda, and Targacept. He has been a consultant to Abbott Laboratories, Allergan, Biovail, Boehringer Ingelheim, Eisai, Eli Lilly and Company, Evotec Johnson and Johnson, Labopharm, Merck, NovaDel Pharma, Orexigen, Prexa, Psylin Neurosciences Inc., and Sunovion. He is on the speakers bureau of Eisai, Pfizer Inc., and Sunovion.

In January 2011, the FDA approved vilazodone for the treatment of major depressive disorder (MDD) (Table 1).

Vilazodone was discovered by Merck KGaA in Germany.¹ In February 2001, Merck KGaA licensed vilazodone to GlaxoSmithKline. In April 2003, GlaxoSmithKline returned all rights to Merck KGaA because phase IIb clinical data did not support progression to phase III clinical trials. In September 2004, Genaissance Pharmaceuticals Inc. acquired an exclusive worldwide license from Merck KGaA to develop and commercialize vilazodone for depression treatment.² Subsequently, Clinical Data Inc. acquired Genaissance Pharmaceuticals Inc., including vilazodone, and proceeded with 2 phase III trials and a large safety trial resulting in FDA approval. In February 2011, Forest Laboratories Inc. acquired Clinical Data Inc. and will launch vilazodone in second quarter of 2011.

Table 1

Vilazodone: Fast facts

How it works

Similar to all antidepressants, vilazodone’s mechanism of action is not fully understood, but is thought to be related to its inhibition of serotonin (ie, 5-HT) reuptake and partial agonism of 5-HT1A receptors.³ Vilazodone technically is not a selective serotonin reuptake inhibitor (SSRI) because it has greater affinity for the 5-HT1A receptor (0.2nM) than it does for the 5-HT reuptake pump (0.5nM).⁴

Vilazodone was developed based on the theory that inhibition of 5-HT1A autoreceptor inhibition was responsible for SSRIs’ delayed (approximately 2 weeks) onset of antidepressant efficacy. Briefly, this theory is as follows: In humans, 5-HT1A receptors are primarily presynaptic in the raphe nuclei and postsynaptic 5-HT1A receptors predominate in the neocortex and limbic regions of the brain.⁵ Presynaptically, 5-HT1A are autoreceptors, ie, serotonin stimulation of these receptors results in inhibition of firing of 5-HT neurons, while postsynaptically they may be involved in downstream serotonergic effects such as sexual function.⁵ SSRIs are thought to work as antidepressants by increasing 5-HT concentration in the synapse but their initial effect is to turn off 5-HT neuronal firing as a result of increased concentration of 5-HT at the presynaptic 5-HT1A autoreceptor. Subsequently, these 5-HT1A autoreceptors subsensitize such that 5-HT neuronal firing rate returns to normal. The time course for this subsensitization parallels the onset of SSRI antidepressant efficacy. For several years, efforts have been made to antagonize the 5-HT1A presynaptic autoreceptors as a means of potentially shortening SSRIs’ onset of efficacy.^6-8

Pharmacokinetics

Vilazodone is absorbed in the gastrointestinal tract and reaches peak concentration at a median of 4 to 5 hours. Its bioavailability increases when taken with food such that Cmax (maximum concentration) is increased by 147% to 160%, and area under the curve is increased by 64% to 85%. Its absolute bioavailability in the presence of food is 72%.⁴ In systemic circulation, the drug is 96% to 99% protein-bound.³ Vilazodone is eliminated primarily through cytochrome P450 (CYP) 3A4 metabolism in the liver.³

Terminal half-life of vilazodone is 25 hours. In general, steady state is achieved in 4 to 5 times the half-life at a stable dose. However, dosing guidelines for vilazodone recommend titration over 2 weeks to achieve a target of 40 mg/d. Thus, steady state will not be achieved until the patient has been on the stable target dose for approximately 2.5 weeks.³

Efficacy

Vilazodone’ efficacy for MDD treatment was established in 2 pivotal 8-week, randomized, double-blind, placebo-controlled, but not active-controlled, trials (Table 2).^9-11 Study participants were outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score >22 and a HAM-D-17 item 1 (depressed mood) score >2.

In the first clinical trial, 410 patients were randomly assigned to vilazodone or placebo. In the vilazodone group, patients were started on 10 mg/d for 1 week, titrated to 20 mg/d for a second week, and then 40 mg/d for the remainder of the study. At week 8, the mean change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-D-17, Clinical Global Impression-Improvement scale (CGI-I), Clinical Global Impression-Severity scale (CGI-S), and Hamilton Anxiety scale (HAM-A) was statistically greater with vilazodone than placebo (P <.05).⁹ Compared with placebo, vilazodone-treated patients showed a statistically significant (P <. 05) improvement in MADRS and HAM-D-17 scores at week 1. Approximately 12% more vilazodone-treated patients achieved response (defined as ≥50% decrease in total score at end of treatment) on the primary efficacy measure, which was MADRS (40.4% vs 28.1%, P=.007), and the 2 secondary efficacy measures, which were HAM-D-17 (44.4% vs 32.7%, P =.011) and CGI-I (48.0 vs 32.7, P =.001). Remission rates (MADRS <10) were not reported in this study, but the authors stated that there was no statistical difference in remission rates between the vilazodone and placebo groups.⁹

In a second trial, which featured design and titration schedule identical to that of the first study, 481 patients were randomized to vilazodone or placebo.¹⁰ At week 8, the vilazodone-treated patients had significantly greater improvement in MADRS, HAM-D-17, HAM-A, CGI-S, and CGI-I score compared with the placebo group (P <.05). Approximately 14% more patients in the vilazodone group were MADRS responders compared with placebo (44% vs 30%, P =.002). Remission rates were not statistically different between patients taking vilazodone vs placebo (27% vs 20% respectively).¹⁰ Demonstrating a statistically significant difference between a 27% vs 20% remission rate would require a much larger number of patients than were included in this study.

Table 2

Efficacy of vilazodone in phase III clinical trials

Tolerability

Vilazodone’s safety was evaluated in 2, 177 patients (age 18 to 70) diagnosed with MDD who participated in clinical studies, including the two 8-week, randomized, doubleblind, placebo-controlled studies (N=891) and a 52-week, open-label study of 599 patients.¹² Overall, 7.1% of patients who received vilazodone discontinued treatment because of an adverse reaction, compared with 3.2% of placebo-treated patients in the double-blind studies.³ Diarrhea, nausea, and headache were the most commonly reported adverse events; the incidence of headache was similar to that in the placebo group (13.2% vs 14.2%).¹⁰ These adverse events are consistent with serotonin agonism, mild to moderate intensity, and occurred mainly during the first week of treatment.³

Doses up to 80 mg/d have not been associated with clinically significant changes in ECG parameters or laboratory parameters in serum chemistry hematology and urine analysis.^9,10 The drug had no effect on weight as measured by mean change from baseline.^9,10

In one 8-week trial, there were no substantial differences between vilazodone and placebo in Arizona Sexual Experience Scale (ASEX) scores at treatment end for either sex.⁹ ASEX is a 5-item scale used to assess sexual dysfunction; a score >18 indicates clinically significant sexual dysfunction. At baseline, mean ASEX scores among men were 15.8 in the placebo group and 16.5 in the vilazodone group. Among women, the mean ASEX score was 21.2 in both groups.⁹ Overall sexual function for men and women was similar for vilazodone and placebo, as measured by the Changes in Sexual Function Questionnaire.¹⁰ The most commonly reported sexual adverse effect was decreased libido.¹⁰

Contraindications

Vilazodone is contraindicated for concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping or starting an MAOI. Vilazodone is contraindicated in patients taking strong CYP3A4 inhibitors (eg, ketoconazole) because of increased vilazodone concentrations and resulting concentration-dependent adverse effects.³ Concomitant administration of strong CYP3A4 inducers (eg, rifampin) might result in a reduction in vilazodone levels leading to lack or loss of efficacy.¹³

As with other antidepressants, vilazodone carries a black-box warning about increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders.³ Vilazodone showed evidence of developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate, well-controlled studies of vilazodone in pregnant women and no human data regarding vilazodone concentrations in breast milk.³ Women taking vilazodone are advised to breastfeed only if the potential benefits outweigh the risks. Vilazodone is not recommended for use in pediatric patients.³

Similar to other antidepressants, vilazodone labeling carries warnings about serotonin syndrome, seizures, abnormal bleeding, activation of mania/hypomania, and hyponatremia.⁴

Dosing

Vilazodone is available as 10 mg, 20 mg, and 40 mg tablets. The recommended target dose for vilazodone is 40 mg/d, with a starting dose of 10 mg/d for 7 days, followed by 20 mg/d for 7 days, then 40 mg/d.³ The drug should be taken with food, but unlike other psychotropics, the manufacturer does not recommended a specific calorie amount.³ Dose tapering is recommended when the drug is discontinued.³

Dose should be reduced to 20 mg/d when vilazodone is coadministered with strong CYP3A4 inhibitors, such as azole antifungals, macrolides, protease inhibitors, and verapamil.¹³ No dosage adjustment is recommended based on age, mild or moderate liver impairment, or renal impairment of any severity.³ Vilazodone has not been studied in patients with severe hepatic impairment.³

How does vilazodone compare?

Ideally, it would be good to know how vilazodone compares with other marketed antidepressants. Unfortunately, there are no published head-to-head comparison data to address this matter. The number needed to treat with vilazodone is between 7 and 8 based on the data from the 2 phase III trials (Table 2).^9-11 This is comparable to other antidepressants. One phase III study showed a statistically greater reduction in depressive symptomatology in vilazodone-treated patients after 1 week, ⁹ but that was not replicated in the second trial.¹⁰

Related Resources

• Khan A. Vilazodone, a novel dual-acting serotonergic antidepressant for managing major depression. Expert Opin Investig Drugs. 2009;18(11):1753-1764.

Drug Brand Names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Verapamil • Isoptin
• Vilazodone • Viibryd

Disclosures

Drs. Kalia and Mittal report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Since January 2010, Dr. Preskorn has received grant/research support from Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Ipsen, Link Medicine, Pfizer Inc, Sunovion, Takeda, and Targacept. He has been a consultant to Abbott Laboratories, Allergan, Biovail, Boehringer Ingelheim, Eisai, Eli Lilly and Company, Evotec Johnson and Johnson, Labopharm, Merck, NovaDel Pharma, Orexigen, Prexa, Psylin Neurosciences Inc., and Sunovion. He is on the speakers bureau of Eisai, Pfizer Inc., and Sunovion.

In January 2011, the FDA approved vilazodone for the treatment of major depressive disorder (MDD) (Table 1).

Vilazodone was discovered by Merck KGaA in Germany.¹ In February 2001, Merck KGaA licensed vilazodone to GlaxoSmithKline. In April 2003, GlaxoSmithKline returned all rights to Merck KGaA because phase IIb clinical data did not support progression to phase III clinical trials. In September 2004, Genaissance Pharmaceuticals Inc. acquired an exclusive worldwide license from Merck KGaA to develop and commercialize vilazodone for depression treatment.² Subsequently, Clinical Data Inc. acquired Genaissance Pharmaceuticals Inc., including vilazodone, and proceeded with 2 phase III trials and a large safety trial resulting in FDA approval. In February 2011, Forest Laboratories Inc. acquired Clinical Data Inc. and will launch vilazodone in second quarter of 2011.

Table 1

Vilazodone: Fast facts

How it works

Similar to all antidepressants, vilazodone’s mechanism of action is not fully understood, but is thought to be related to its inhibition of serotonin (ie, 5-HT) reuptake and partial agonism of 5-HT1A receptors.³ Vilazodone technically is not a selective serotonin reuptake inhibitor (SSRI) because it has greater affinity for the 5-HT1A receptor (0.2nM) than it does for the 5-HT reuptake pump (0.5nM).⁴

Vilazodone was developed based on the theory that inhibition of 5-HT1A autoreceptor inhibition was responsible for SSRIs’ delayed (approximately 2 weeks) onset of antidepressant efficacy. Briefly, this theory is as follows: In humans, 5-HT1A receptors are primarily presynaptic in the raphe nuclei and postsynaptic 5-HT1A receptors predominate in the neocortex and limbic regions of the brain.⁵ Presynaptically, 5-HT1A are autoreceptors, ie, serotonin stimulation of these receptors results in inhibition of firing of 5-HT neurons, while postsynaptically they may be involved in downstream serotonergic effects such as sexual function.⁵ SSRIs are thought to work as antidepressants by increasing 5-HT concentration in the synapse but their initial effect is to turn off 5-HT neuronal firing as a result of increased concentration of 5-HT at the presynaptic 5-HT1A autoreceptor. Subsequently, these 5-HT1A autoreceptors subsensitize such that 5-HT neuronal firing rate returns to normal. The time course for this subsensitization parallels the onset of SSRI antidepressant efficacy. For several years, efforts have been made to antagonize the 5-HT1A presynaptic autoreceptors as a means of potentially shortening SSRIs’ onset of efficacy.^6-8

Pharmacokinetics

Vilazodone is absorbed in the gastrointestinal tract and reaches peak concentration at a median of 4 to 5 hours. Its bioavailability increases when taken with food such that Cmax (maximum concentration) is increased by 147% to 160%, and area under the curve is increased by 64% to 85%. Its absolute bioavailability in the presence of food is 72%.⁴ In systemic circulation, the drug is 96% to 99% protein-bound.³ Vilazodone is eliminated primarily through cytochrome P450 (CYP) 3A4 metabolism in the liver.³

Terminal half-life of vilazodone is 25 hours. In general, steady state is achieved in 4 to 5 times the half-life at a stable dose. However, dosing guidelines for vilazodone recommend titration over 2 weeks to achieve a target of 40 mg/d. Thus, steady state will not be achieved until the patient has been on the stable target dose for approximately 2.5 weeks.³

Efficacy

Vilazodone’ efficacy for MDD treatment was established in 2 pivotal 8-week, randomized, double-blind, placebo-controlled, but not active-controlled, trials (Table 2).^9-11 Study participants were outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score >22 and a HAM-D-17 item 1 (depressed mood) score >2.

In the first clinical trial, 410 patients were randomly assigned to vilazodone or placebo. In the vilazodone group, patients were started on 10 mg/d for 1 week, titrated to 20 mg/d for a second week, and then 40 mg/d for the remainder of the study. At week 8, the mean change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-D-17, Clinical Global Impression-Improvement scale (CGI-I), Clinical Global Impression-Severity scale (CGI-S), and Hamilton Anxiety scale (HAM-A) was statistically greater with vilazodone than placebo (P <.05).⁹ Compared with placebo, vilazodone-treated patients showed a statistically significant (P <. 05) improvement in MADRS and HAM-D-17 scores at week 1. Approximately 12% more vilazodone-treated patients achieved response (defined as ≥50% decrease in total score at end of treatment) on the primary efficacy measure, which was MADRS (40.4% vs 28.1%, P=.007), and the 2 secondary efficacy measures, which were HAM-D-17 (44.4% vs 32.7%, P =.011) and CGI-I (48.0 vs 32.7, P =.001). Remission rates (MADRS <10) were not reported in this study, but the authors stated that there was no statistical difference in remission rates between the vilazodone and placebo groups.⁹

In a second trial, which featured design and titration schedule identical to that of the first study, 481 patients were randomized to vilazodone or placebo.¹⁰ At week 8, the vilazodone-treated patients had significantly greater improvement in MADRS, HAM-D-17, HAM-A, CGI-S, and CGI-I score compared with the placebo group (P <.05). Approximately 14% more patients in the vilazodone group were MADRS responders compared with placebo (44% vs 30%, P =.002). Remission rates were not statistically different between patients taking vilazodone vs placebo (27% vs 20% respectively).¹⁰ Demonstrating a statistically significant difference between a 27% vs 20% remission rate would require a much larger number of patients than were included in this study.

Table 2

Efficacy of vilazodone in phase III clinical trials

Tolerability

Vilazodone’s safety was evaluated in 2, 177 patients (age 18 to 70) diagnosed with MDD who participated in clinical studies, including the two 8-week, randomized, doubleblind, placebo-controlled studies (N=891) and a 52-week, open-label study of 599 patients.¹² Overall, 7.1% of patients who received vilazodone discontinued treatment because of an adverse reaction, compared with 3.2% of placebo-treated patients in the double-blind studies.³ Diarrhea, nausea, and headache were the most commonly reported adverse events; the incidence of headache was similar to that in the placebo group (13.2% vs 14.2%).¹⁰ These adverse events are consistent with serotonin agonism, mild to moderate intensity, and occurred mainly during the first week of treatment.³

Doses up to 80 mg/d have not been associated with clinically significant changes in ECG parameters or laboratory parameters in serum chemistry hematology and urine analysis.^9,10 The drug had no effect on weight as measured by mean change from baseline.^9,10

In one 8-week trial, there were no substantial differences between vilazodone and placebo in Arizona Sexual Experience Scale (ASEX) scores at treatment end for either sex.⁹ ASEX is a 5-item scale used to assess sexual dysfunction; a score >18 indicates clinically significant sexual dysfunction. At baseline, mean ASEX scores among men were 15.8 in the placebo group and 16.5 in the vilazodone group. Among women, the mean ASEX score was 21.2 in both groups.⁹ Overall sexual function for men and women was similar for vilazodone and placebo, as measured by the Changes in Sexual Function Questionnaire.¹⁰ The most commonly reported sexual adverse effect was decreased libido.¹⁰

Contraindications

Vilazodone is contraindicated for concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping or starting an MAOI. Vilazodone is contraindicated in patients taking strong CYP3A4 inhibitors (eg, ketoconazole) because of increased vilazodone concentrations and resulting concentration-dependent adverse effects.³ Concomitant administration of strong CYP3A4 inducers (eg, rifampin) might result in a reduction in vilazodone levels leading to lack or loss of efficacy.¹³

As with other antidepressants, vilazodone carries a black-box warning about increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders.³ Vilazodone showed evidence of developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate, well-controlled studies of vilazodone in pregnant women and no human data regarding vilazodone concentrations in breast milk.³ Women taking vilazodone are advised to breastfeed only if the potential benefits outweigh the risks. Vilazodone is not recommended for use in pediatric patients.³

Similar to other antidepressants, vilazodone labeling carries warnings about serotonin syndrome, seizures, abnormal bleeding, activation of mania/hypomania, and hyponatremia.⁴

Dosing

Vilazodone is available as 10 mg, 20 mg, and 40 mg tablets. The recommended target dose for vilazodone is 40 mg/d, with a starting dose of 10 mg/d for 7 days, followed by 20 mg/d for 7 days, then 40 mg/d.³ The drug should be taken with food, but unlike other psychotropics, the manufacturer does not recommended a specific calorie amount.³ Dose tapering is recommended when the drug is discontinued.³

Dose should be reduced to 20 mg/d when vilazodone is coadministered with strong CYP3A4 inhibitors, such as azole antifungals, macrolides, protease inhibitors, and verapamil.¹³ No dosage adjustment is recommended based on age, mild or moderate liver impairment, or renal impairment of any severity.³ Vilazodone has not been studied in patients with severe hepatic impairment.³

How does vilazodone compare?

Ideally, it would be good to know how vilazodone compares with other marketed antidepressants. Unfortunately, there are no published head-to-head comparison data to address this matter. The number needed to treat with vilazodone is between 7 and 8 based on the data from the 2 phase III trials (Table 2).^9-11 This is comparable to other antidepressants. One phase III study showed a statistically greater reduction in depressive symptomatology in vilazodone-treated patients after 1 week, ⁹ but that was not replicated in the second trial.¹⁰

Related Resources

• Khan A. Vilazodone, a novel dual-acting serotonergic antidepressant for managing major depression. Expert Opin Investig Drugs. 2009;18(11):1753-1764.

Drug Brand Names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Verapamil • Isoptin
• Vilazodone • Viibryd

Disclosures

Drs. Kalia and Mittal report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Since January 2010, Dr. Preskorn has received grant/research support from Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Ipsen, Link Medicine, Pfizer Inc, Sunovion, Takeda, and Targacept. He has been a consultant to Abbott Laboratories, Allergan, Biovail, Boehringer Ingelheim, Eisai, Eli Lilly and Company, Evotec Johnson and Johnson, Labopharm, Merck, NovaDel Pharma, Orexigen, Prexa, Psylin Neurosciences Inc., and Sunovion. He is on the speakers bureau of Eisai, Pfizer Inc., and Sunovion.

Interictal psychosis of epilepsy (IPE) is schizophrenia-like psychosis associated with epilepsy that cannot be directly linked to an ictus. IPE often is indistinguishable from primary schizophrenia. This phenomenon commonly occurs in patients with a history of temporal lobe epilepsy (TLE); in those with frequent seizures; and in patients with a long history of epilepsy (>10 years).¹ Interictal psychosis rarely precedes seizure activity² and few cases have been reported. The epidemiology and clinical characteristics of IPE are poorly defined.³ We recently treated a patient with suspected IPE.

Mr. R, age 18, presented to our emergency department with his mother, who stated that her son was behaving strangely and had slow speech for 4 days. He had decreased social interaction, reduced appetite, poor hygiene, decreased sleep, and auditory hallucinations. Mr. R demonstrated hypervigilance and paranoia. He repeatedly checked rooms in his house for intruders. Mr. R also expressed suicidal ideation and exhibited cognitive decline of memory, attention, and fund of knowledge. His physical exam, routine laboratory investigations, CT, and MRI were within normal limits. Urine drug screen was positive for marijuana. We made a clinical diagnosis of acute psychosis.

Mr. R was admitted and started on ziprasidone, titrated to 160 mg/d; however, he could not tolerate this medication because of orthostatic hypotension. We discontinued ziprasidone and started risperidone, titrated to 4 mg/d. By day 4 Mr. R remained psychotic and marijuana intoxication was ruled out. EEG demonstrated rare intermittent left temporal sharp slow wave discharges and sharply contoured slow waves. This suggested an underlying seizure disorder, although Mr. R had no history of seizure.

The psychosis resolved 3 weeks later with risperidone, 2 mg/d, risperidone long-acting injection, 25 mg every 2 weeks, and carbamazepine, 400 mg/d. Mr. R was discharged home on these medications. He was noncompliant with treatment and continued to smoke marijuana. Four months later, Mr. R was rehospitalized for strange behavior. When seen in the outpatient clinic for follow-up, Mr. R admitted that he had his first witnessed seizure before his last hospitalization. Mr. R was restarted on risperidone, 4 mg/d, and risperidone long-acting injection, 25 mg every 2 weeks. To increase compliance, we switched carbamazepine to divalproex sodium extended-release, 500 mg/d. He remains stable, but continues to smoke marijuana.

Our case illustrates that IPE may be a presenting feature of TLE. Because IPE may occur in patients who do not have a history of TLE, EEG monitoring should be considered in the workup of new-onset psychosis.

Disclosure

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

Interictal psychosis of epilepsy (IPE) is schizophrenia-like psychosis associated with epilepsy that cannot be directly linked to an ictus. IPE often is indistinguishable from primary schizophrenia. This phenomenon commonly occurs in patients with a history of temporal lobe epilepsy (TLE); in those with frequent seizures; and in patients with a long history of epilepsy (>10 years).¹ Interictal psychosis rarely precedes seizure activity² and few cases have been reported. The epidemiology and clinical characteristics of IPE are poorly defined.³ We recently treated a patient with suspected IPE.

Mr. R, age 18, presented to our emergency department with his mother, who stated that her son was behaving strangely and had slow speech for 4 days. He had decreased social interaction, reduced appetite, poor hygiene, decreased sleep, and auditory hallucinations. Mr. R demonstrated hypervigilance and paranoia. He repeatedly checked rooms in his house for intruders. Mr. R also expressed suicidal ideation and exhibited cognitive decline of memory, attention, and fund of knowledge. His physical exam, routine laboratory investigations, CT, and MRI were within normal limits. Urine drug screen was positive for marijuana. We made a clinical diagnosis of acute psychosis.

Mr. R was admitted and started on ziprasidone, titrated to 160 mg/d; however, he could not tolerate this medication because of orthostatic hypotension. We discontinued ziprasidone and started risperidone, titrated to 4 mg/d. By day 4 Mr. R remained psychotic and marijuana intoxication was ruled out. EEG demonstrated rare intermittent left temporal sharp slow wave discharges and sharply contoured slow waves. This suggested an underlying seizure disorder, although Mr. R had no history of seizure.

The psychosis resolved 3 weeks later with risperidone, 2 mg/d, risperidone long-acting injection, 25 mg every 2 weeks, and carbamazepine, 400 mg/d. Mr. R was discharged home on these medications. He was noncompliant with treatment and continued to smoke marijuana. Four months later, Mr. R was rehospitalized for strange behavior. When seen in the outpatient clinic for follow-up, Mr. R admitted that he had his first witnessed seizure before his last hospitalization. Mr. R was restarted on risperidone, 4 mg/d, and risperidone long-acting injection, 25 mg every 2 weeks. To increase compliance, we switched carbamazepine to divalproex sodium extended-release, 500 mg/d. He remains stable, but continues to smoke marijuana.

Our case illustrates that IPE may be a presenting feature of TLE. Because IPE may occur in patients who do not have a history of TLE, EEG monitoring should be considered in the workup of new-onset psychosis.

Disclosure

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

Interictal psychosis of epilepsy (IPE) is schizophrenia-like psychosis associated with epilepsy that cannot be directly linked to an ictus. IPE often is indistinguishable from primary schizophrenia. This phenomenon commonly occurs in patients with a history of temporal lobe epilepsy (TLE); in those with frequent seizures; and in patients with a long history of epilepsy (>10 years).¹ Interictal psychosis rarely precedes seizure activity² and few cases have been reported. The epidemiology and clinical characteristics of IPE are poorly defined.³ We recently treated a patient with suspected IPE.

Mr. R, age 18, presented to our emergency department with his mother, who stated that her son was behaving strangely and had slow speech for 4 days. He had decreased social interaction, reduced appetite, poor hygiene, decreased sleep, and auditory hallucinations. Mr. R demonstrated hypervigilance and paranoia. He repeatedly checked rooms in his house for intruders. Mr. R also expressed suicidal ideation and exhibited cognitive decline of memory, attention, and fund of knowledge. His physical exam, routine laboratory investigations, CT, and MRI were within normal limits. Urine drug screen was positive for marijuana. We made a clinical diagnosis of acute psychosis.

Mr. R was admitted and started on ziprasidone, titrated to 160 mg/d; however, he could not tolerate this medication because of orthostatic hypotension. We discontinued ziprasidone and started risperidone, titrated to 4 mg/d. By day 4 Mr. R remained psychotic and marijuana intoxication was ruled out. EEG demonstrated rare intermittent left temporal sharp slow wave discharges and sharply contoured slow waves. This suggested an underlying seizure disorder, although Mr. R had no history of seizure.

The psychosis resolved 3 weeks later with risperidone, 2 mg/d, risperidone long-acting injection, 25 mg every 2 weeks, and carbamazepine, 400 mg/d. Mr. R was discharged home on these medications. He was noncompliant with treatment and continued to smoke marijuana. Four months later, Mr. R was rehospitalized for strange behavior. When seen in the outpatient clinic for follow-up, Mr. R admitted that he had his first witnessed seizure before his last hospitalization. Mr. R was restarted on risperidone, 4 mg/d, and risperidone long-acting injection, 25 mg every 2 weeks. To increase compliance, we switched carbamazepine to divalproex sodium extended-release, 500 mg/d. He remains stable, but continues to smoke marijuana.

Our case illustrates that IPE may be a presenting feature of TLE. Because IPE may occur in patients who do not have a history of TLE, EEG monitoring should be considered in the workup of new-onset psychosis.

Disclosure

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

Residents in psychiatry and other specialties experience depressive illness at rates similar to or higher than the general population. Residency training is a major psychosocial stressor.¹ Having to master a large body of medical knowledge while facing feared inadequacy or failure creates a demanding emotional climate for physicians in training. When added to other mood disorder risk factors, such as genetic vulnerability and fatigue, continuous performance demands can lead to the onset of a major depressive episode. Assisting the newest members of our profession by providing needed mental health treatment can be challenging but rewarding.

Are residents ‘special’ patients?

Some residents who realize they are depressed are tempted to self-diagnose and self-prescribe or obtain informal consultation from peers or family members who are physicians. The best treatment for depressed residents is to provide the same meticulous, excellent, and thoughtful care that you provide for your nonphysician patients. Many depressed residents who seek psychiatric treatment are relieved to share their symptoms and stresses with a professional who is there to treat, not teach, them.²

Residents from nonpsychiatric specialties may be assessed and treated by psychiatry faculty at their home institutions or by providers in the community. For psychiatrists who supervise residents, establishing liaisons with private practice clinicians who can offer rapid treatment access for physicians in training can be effective. To avoid conflicts of interest, it is crucial that psychiatry residents are treated by providers other than their own faculty.

Factors that may lead residents to avoid seeking treatment include:

• The culture of medicine reinforces the stereotype that physicians are “strong” and “tough,” implying that the need for depression treatment is a weakness.
• Fear of stigma can extend to fear of receiving negative evaluations by supervisors if depression is acknowledged.
• Residents have logistic difficulties participating in treatment—a busy and inflexible schedule makes it hard to attend appointments.
• Altruism can hinder some residents from obtaining self-care. These residents may perceive a “good doctor” as one who is self-sacrificing for his or her patients.

Treatment

The same collaborative approach to establishing a healthy therapeutic relationship with nonphysician patients is equally effective with physicians in training. Residents usually are open to using evidence-based combined modalities, eg, pharmacotherapy and specific structured psychotherapies such as cognitive-behavioral therapy or interpersonal psychotherapy.

Occasionally a resident will lobby for special treatment. For example, a resident may insist that the psychiatrist rearrange other patients’ appointments to accommodate the resident’s schedule. Also, residents may be unwilling or unable to see themselves in the patient role. They may attempt to define their treatment in singular and distinctive ways, setting themselves apart from nonphysician patients. These barriers can be overcome by setting appropriate boundaries with patients early in treatment. It is the psychiatrist’s responsibility to gently but firmly set limits with residents so that treatment can be effective.

Disclosure

Dr. Gay reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Residents in psychiatry and other specialties experience depressive illness at rates similar to or higher than the general population. Residency training is a major psychosocial stressor.¹ Having to master a large body of medical knowledge while facing feared inadequacy or failure creates a demanding emotional climate for physicians in training. When added to other mood disorder risk factors, such as genetic vulnerability and fatigue, continuous performance demands can lead to the onset of a major depressive episode. Assisting the newest members of our profession by providing needed mental health treatment can be challenging but rewarding.

Are residents ‘special’ patients?

Some residents who realize they are depressed are tempted to self-diagnose and self-prescribe or obtain informal consultation from peers or family members who are physicians. The best treatment for depressed residents is to provide the same meticulous, excellent, and thoughtful care that you provide for your nonphysician patients. Many depressed residents who seek psychiatric treatment are relieved to share their symptoms and stresses with a professional who is there to treat, not teach, them.²

Residents from nonpsychiatric specialties may be assessed and treated by psychiatry faculty at their home institutions or by providers in the community. For psychiatrists who supervise residents, establishing liaisons with private practice clinicians who can offer rapid treatment access for physicians in training can be effective. To avoid conflicts of interest, it is crucial that psychiatry residents are treated by providers other than their own faculty.

Factors that may lead residents to avoid seeking treatment include:

• The culture of medicine reinforces the stereotype that physicians are “strong” and “tough,” implying that the need for depression treatment is a weakness.
• Fear of stigma can extend to fear of receiving negative evaluations by supervisors if depression is acknowledged.
• Residents have logistic difficulties participating in treatment—a busy and inflexible schedule makes it hard to attend appointments.
• Altruism can hinder some residents from obtaining self-care. These residents may perceive a “good doctor” as one who is self-sacrificing for his or her patients.

Treatment

The same collaborative approach to establishing a healthy therapeutic relationship with nonphysician patients is equally effective with physicians in training. Residents usually are open to using evidence-based combined modalities, eg, pharmacotherapy and specific structured psychotherapies such as cognitive-behavioral therapy or interpersonal psychotherapy.

Occasionally a resident will lobby for special treatment. For example, a resident may insist that the psychiatrist rearrange other patients’ appointments to accommodate the resident’s schedule. Also, residents may be unwilling or unable to see themselves in the patient role. They may attempt to define their treatment in singular and distinctive ways, setting themselves apart from nonphysician patients. These barriers can be overcome by setting appropriate boundaries with patients early in treatment. It is the psychiatrist’s responsibility to gently but firmly set limits with residents so that treatment can be effective.

Disclosure

Dr. Gay reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Residents in psychiatry and other specialties experience depressive illness at rates similar to or higher than the general population. Residency training is a major psychosocial stressor.¹ Having to master a large body of medical knowledge while facing feared inadequacy or failure creates a demanding emotional climate for physicians in training. When added to other mood disorder risk factors, such as genetic vulnerability and fatigue, continuous performance demands can lead to the onset of a major depressive episode. Assisting the newest members of our profession by providing needed mental health treatment can be challenging but rewarding.

Are residents ‘special’ patients?

Some residents who realize they are depressed are tempted to self-diagnose and self-prescribe or obtain informal consultation from peers or family members who are physicians. The best treatment for depressed residents is to provide the same meticulous, excellent, and thoughtful care that you provide for your nonphysician patients. Many depressed residents who seek psychiatric treatment are relieved to share their symptoms and stresses with a professional who is there to treat, not teach, them.²

Residents from nonpsychiatric specialties may be assessed and treated by psychiatry faculty at their home institutions or by providers in the community. For psychiatrists who supervise residents, establishing liaisons with private practice clinicians who can offer rapid treatment access for physicians in training can be effective. To avoid conflicts of interest, it is crucial that psychiatry residents are treated by providers other than their own faculty.

Factors that may lead residents to avoid seeking treatment include:

• The culture of medicine reinforces the stereotype that physicians are “strong” and “tough,” implying that the need for depression treatment is a weakness.
• Fear of stigma can extend to fear of receiving negative evaluations by supervisors if depression is acknowledged.
• Residents have logistic difficulties participating in treatment—a busy and inflexible schedule makes it hard to attend appointments.
• Altruism can hinder some residents from obtaining self-care. These residents may perceive a “good doctor” as one who is self-sacrificing for his or her patients.

Treatment

The same collaborative approach to establishing a healthy therapeutic relationship with nonphysician patients is equally effective with physicians in training. Residents usually are open to using evidence-based combined modalities, eg, pharmacotherapy and specific structured psychotherapies such as cognitive-behavioral therapy or interpersonal psychotherapy.

Occasionally a resident will lobby for special treatment. For example, a resident may insist that the psychiatrist rearrange other patients’ appointments to accommodate the resident’s schedule. Also, residents may be unwilling or unable to see themselves in the patient role. They may attempt to define their treatment in singular and distinctive ways, setting themselves apart from nonphysician patients. These barriers can be overcome by setting appropriate boundaries with patients early in treatment. It is the psychiatrist’s responsibility to gently but firmly set limits with residents so that treatment can be effective.

Disclosure

Dr. Gay reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although self-harm behaviors such as burning or cutting are common among adolescents, they are a source of concern for parents and friends, and challenging to treat. Treatments have focused on distracting stimuli such as ice or the sting of a rubber band snapped on the wrist. Tattooing may be an alternative somatic strategy that can decrease self-harm and counter negative body image.^1,2

In a study of 423 individuals with body modification (tattoos and piercings), 27% admitted to cutting themselves during childhood.³ This study’s authors concluded that these practices became a substitute for self-harm, helped patients overcome traumatic experiences, and improved satisfaction with body image.

In line with these observations, we decided to offer temporary tattooing to residents in our 60-bed child and adolescent treatment center. Patients were age 6 to 20 and 70% were female. We received consent from all patients’ guardians after explaining the temporary, nontoxic nature of the ink or decals.

Our first trials were with adolescent females with a history of cutting, but we offered temporary tattooing to all patients within a few months. Overall, 7 females and 3 males, all of whom had an axis I mood disorder, participated in temporary tattooing as an alternative to self-harm. We noted borderline personality traits in female patients who engaged in severe self-harm. Patients either drew on themselves or, with therapist supervision, “tattooed” other patients using self-selected designs.

One older teenage girl used cutting to manage flashbacks of sexual abuse from a family member. She had multiple scars from the cutting despite outpatient, hospital, and residential treatment over several years without symptom improvement. After 1 year of tattooing, her cutting episodes decreased from several times per month to once every 3 months. She also reported an improvement in positive perception of her body image from 0 on a 1-to-10 scale on admission to 5 at 1 year.

A younger teenage female without visible scars used cutting to manage feelings of being ugly associated with memories of sexual abuse. She reported that over 3 months, drawing tattoos improved her feelings about her body from 0/10 to 4/10, and she no longer reported thoughts of cutting or self-harm. Over 3 months, a male teenager without scars who cut himself when distressed about female relationships instead used tattoos to draw his conflicted feelings on his arm.

Tattoo designs included:

• flowers, vines, and roses
• patients’ psychological issues
• 2 faces for a patient dealing with internal and external relationship conflicts
• 2 flags to represent melding different cultures
• 2 hearts fused to represent issues with the intensities of love
• foreign words to indicate secrecy and alienation
• fantasy daydreams reflected as unicorns and dolphins.

Patients’ conversations with their therapists about the tattoos enabled detailed discussions about abuse, body image, and relationships.

Parents and some of our staff initially were concerned that temporary tattoos would increase self-harm or high-risk behaviors. This did not occur, perhaps because patients felt the designs helped them visually express feelings and conflicts.

Our clinical experience indicates that temporary tattooing may be a method of discussing and altering self-harm behaviors and negative body image in adolescent inpatients. Further evaluation of this strategy is warranted.

Disclosure

Dr. Masters reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although self-harm behaviors such as burning or cutting are common among adolescents, they are a source of concern for parents and friends, and challenging to treat. Treatments have focused on distracting stimuli such as ice or the sting of a rubber band snapped on the wrist. Tattooing may be an alternative somatic strategy that can decrease self-harm and counter negative body image.^1,2

In a study of 423 individuals with body modification (tattoos and piercings), 27% admitted to cutting themselves during childhood.³ This study’s authors concluded that these practices became a substitute for self-harm, helped patients overcome traumatic experiences, and improved satisfaction with body image.

In line with these observations, we decided to offer temporary tattooing to residents in our 60-bed child and adolescent treatment center. Patients were age 6 to 20 and 70% were female. We received consent from all patients’ guardians after explaining the temporary, nontoxic nature of the ink or decals.

Our first trials were with adolescent females with a history of cutting, but we offered temporary tattooing to all patients within a few months. Overall, 7 females and 3 males, all of whom had an axis I mood disorder, participated in temporary tattooing as an alternative to self-harm. We noted borderline personality traits in female patients who engaged in severe self-harm. Patients either drew on themselves or, with therapist supervision, “tattooed” other patients using self-selected designs.

One older teenage girl used cutting to manage flashbacks of sexual abuse from a family member. She had multiple scars from the cutting despite outpatient, hospital, and residential treatment over several years without symptom improvement. After 1 year of tattooing, her cutting episodes decreased from several times per month to once every 3 months. She also reported an improvement in positive perception of her body image from 0 on a 1-to-10 scale on admission to 5 at 1 year.

A younger teenage female without visible scars used cutting to manage feelings of being ugly associated with memories of sexual abuse. She reported that over 3 months, drawing tattoos improved her feelings about her body from 0/10 to 4/10, and she no longer reported thoughts of cutting or self-harm. Over 3 months, a male teenager without scars who cut himself when distressed about female relationships instead used tattoos to draw his conflicted feelings on his arm.

Tattoo designs included:

• flowers, vines, and roses
• patients’ psychological issues
• 2 faces for a patient dealing with internal and external relationship conflicts
• 2 flags to represent melding different cultures
• 2 hearts fused to represent issues with the intensities of love
• foreign words to indicate secrecy and alienation
• fantasy daydreams reflected as unicorns and dolphins.

Patients’ conversations with their therapists about the tattoos enabled detailed discussions about abuse, body image, and relationships.

Parents and some of our staff initially were concerned that temporary tattoos would increase self-harm or high-risk behaviors. This did not occur, perhaps because patients felt the designs helped them visually express feelings and conflicts.

Our clinical experience indicates that temporary tattooing may be a method of discussing and altering self-harm behaviors and negative body image in adolescent inpatients. Further evaluation of this strategy is warranted.

Disclosure

Dr. Masters reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although self-harm behaviors such as burning or cutting are common among adolescents, they are a source of concern for parents and friends, and challenging to treat. Treatments have focused on distracting stimuli such as ice or the sting of a rubber band snapped on the wrist. Tattooing may be an alternative somatic strategy that can decrease self-harm and counter negative body image.^1,2

In a study of 423 individuals with body modification (tattoos and piercings), 27% admitted to cutting themselves during childhood.³ This study’s authors concluded that these practices became a substitute for self-harm, helped patients overcome traumatic experiences, and improved satisfaction with body image.

In line with these observations, we decided to offer temporary tattooing to residents in our 60-bed child and adolescent treatment center. Patients were age 6 to 20 and 70% were female. We received consent from all patients’ guardians after explaining the temporary, nontoxic nature of the ink or decals.

Our first trials were with adolescent females with a history of cutting, but we offered temporary tattooing to all patients within a few months. Overall, 7 females and 3 males, all of whom had an axis I mood disorder, participated in temporary tattooing as an alternative to self-harm. We noted borderline personality traits in female patients who engaged in severe self-harm. Patients either drew on themselves or, with therapist supervision, “tattooed” other patients using self-selected designs.

One older teenage girl used cutting to manage flashbacks of sexual abuse from a family member. She had multiple scars from the cutting despite outpatient, hospital, and residential treatment over several years without symptom improvement. After 1 year of tattooing, her cutting episodes decreased from several times per month to once every 3 months. She also reported an improvement in positive perception of her body image from 0 on a 1-to-10 scale on admission to 5 at 1 year.

A younger teenage female without visible scars used cutting to manage feelings of being ugly associated with memories of sexual abuse. She reported that over 3 months, drawing tattoos improved her feelings about her body from 0/10 to 4/10, and she no longer reported thoughts of cutting or self-harm. Over 3 months, a male teenager without scars who cut himself when distressed about female relationships instead used tattoos to draw his conflicted feelings on his arm.

Tattoo designs included:

• flowers, vines, and roses
• patients’ psychological issues
• 2 faces for a patient dealing with internal and external relationship conflicts
• 2 flags to represent melding different cultures
• 2 hearts fused to represent issues with the intensities of love
• foreign words to indicate secrecy and alienation
• fantasy daydreams reflected as unicorns and dolphins.

Patients’ conversations with their therapists about the tattoos enabled detailed discussions about abuse, body image, and relationships.

Parents and some of our staff initially were concerned that temporary tattoos would increase self-harm or high-risk behaviors. This did not occur, perhaps because patients felt the designs helped them visually express feelings and conflicts.

Our clinical experience indicates that temporary tattooing may be a method of discussing and altering self-harm behaviors and negative body image in adolescent inpatients. Further evaluation of this strategy is warranted.

Disclosure

Dr. Masters reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Substance use and high-risk sexual behaviors are common among persons with severe mental illness and make them vulnerable to human immunodeficiency virus (HIV) infection.^1-3 The prevalence of HIV is 3 times higher among these patients compared with individuals who are not mentally ill. This article reviews risk factors for HIV transmission, HIV screening recommendations, and current testing options, including the fourth-generation HIV test.

According to the World Health Organization, in 2009:

• 33 million people were infected with HIV
• there were 2.6 million new infections
• 1.8 million people died from causes related to acquired immune deficiency syndrome (AIDS).⁴

In the United States, approximately 1 million people are living with HIV; 55, 000 new cases were diagnosed in North America in 2009.⁵ The demographics of those infected with HIV in the United States have changed substantially. Most newly infected individuals are African American, and younger adults have higher rates of new infections.⁶ With the introduction of standardized antiviral medication combinations and federal programs to provide universal access to medications in the mid 1990s, the number of AIDS cases and mortality dropped, but there have not been similar gains in the past decade.⁶

In countries With access to antiviral medications, medical advances in HIV treatment have transformed an infection with a high mortality rate into a chronic illness. However, the rate of new cases has not changed significantly in the past 10 years. Early detection and treatment initiation reduces high-risk behavior and subsequent transmission in patients with HIV. Evidence suggests that detecting HIV in the acute phase of the illness, when the viral load is high, reduces HIV transmission.^1,5,6

HIV screening

HIV screening should be part of routine psychiatric practice, especially in community and forensic settings. We recommend that all psychiatrists understand HIV screening guidelines from the Centers for Disease Control and Prevention (CDC)⁷ and the American College of Physicians (ACP).⁸ The CDC (2006)⁷ and ACP (2009)⁸ guidelines recommend HIV screening for:

• all patients age 13 to 64, unless the prevalence of undiagnosed HIV infection in your patients has been documented to be <0. 1%⁷
• all patients seeking treatment for sexually transmitted diseases, including each visit for a new complaint⁷
• all pregnant women⁷
• any patient who received a blood transfusion between 1978 and 1985.⁸

Rescreening frequency is determined on an individual basis, taking into consideration the patient’s risk of contracting HIV. The ACP guidelines recommend using rapid tests when available.⁸ Although the false positive rates are higher with rapid tests, the benefits of early detection and reducing transmission outweigh the cost of confirming positive tests.⁸

The fourth-generation test

The gold standard for HIV screening is the enzyme-linked immunosorbent assay antibody test followed by a western blot.⁸ This has a high sensitivity and specificity but there is a window of time between infection and detectable antibodies in serum during which patients have high virus levels (Figure).⁹ The combined antibody and antigen p24 test is a fourth-generation screening tool that detects HIV in the acute phase of the illness without requiring expensive ribonucleic acid viral tests.¹⁰ The fourth-generation test’s capacity to detect infection during the antibody-negative window when infectivity is highest may help decrease HIV transmission.¹¹

Figure When can HIV tests detect the virus?
EIA: enzyme immunoassay; HIV: human immunodeficiency virus; RNA: ribonucleic acid
Source: Adapted from reference 9

Psychiatrists’ role

Because psychiatrists routinely interact with patients who have an increased risk of HIV, they may be uniquely qualified to help these individuals. Psychiatrists often are comfortable discussing patients’ sexual and substance use history, which allows them to uncover and effectively address high-risk behaviors with appropriate testing and counseling. If testing confirms HIV infection, psychiatrists also can discuss altering high-risk behaviors (Table),^1,2 which has significant implications not only for patients, but also for public health.

Table

HIV transmission risk factors

Related Resource

• Centers for Disease Control and Prevention. HIV/AIDS. www.cdc.gov/hiv.

Disclosure

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

Substance use and high-risk sexual behaviors are common among persons with severe mental illness and make them vulnerable to human immunodeficiency virus (HIV) infection.^1-3 The prevalence of HIV is 3 times higher among these patients compared with individuals who are not mentally ill. This article reviews risk factors for HIV transmission, HIV screening recommendations, and current testing options, including the fourth-generation HIV test.

According to the World Health Organization, in 2009:

• 33 million people were infected with HIV
• there were 2.6 million new infections
• 1.8 million people died from causes related to acquired immune deficiency syndrome (AIDS).⁴

In the United States, approximately 1 million people are living with HIV; 55, 000 new cases were diagnosed in North America in 2009.⁵ The demographics of those infected with HIV in the United States have changed substantially. Most newly infected individuals are African American, and younger adults have higher rates of new infections.⁶ With the introduction of standardized antiviral medication combinations and federal programs to provide universal access to medications in the mid 1990s, the number of AIDS cases and mortality dropped, but there have not been similar gains in the past decade.⁶

In countries With access to antiviral medications, medical advances in HIV treatment have transformed an infection with a high mortality rate into a chronic illness. However, the rate of new cases has not changed significantly in the past 10 years. Early detection and treatment initiation reduces high-risk behavior and subsequent transmission in patients with HIV. Evidence suggests that detecting HIV in the acute phase of the illness, when the viral load is high, reduces HIV transmission.^1,5,6

HIV screening

HIV screening should be part of routine psychiatric practice, especially in community and forensic settings. We recommend that all psychiatrists understand HIV screening guidelines from the Centers for Disease Control and Prevention (CDC)⁷ and the American College of Physicians (ACP).⁸ The CDC (2006)⁷ and ACP (2009)⁸ guidelines recommend HIV screening for:

• all patients age 13 to 64, unless the prevalence of undiagnosed HIV infection in your patients has been documented to be <0. 1%⁷
• all patients seeking treatment for sexually transmitted diseases, including each visit for a new complaint⁷
• all pregnant women⁷
• any patient who received a blood transfusion between 1978 and 1985.⁸

Rescreening frequency is determined on an individual basis, taking into consideration the patient’s risk of contracting HIV. The ACP guidelines recommend using rapid tests when available.⁸ Although the false positive rates are higher with rapid tests, the benefits of early detection and reducing transmission outweigh the cost of confirming positive tests.⁸

The fourth-generation test

The gold standard for HIV screening is the enzyme-linked immunosorbent assay antibody test followed by a western blot.⁸ This has a high sensitivity and specificity but there is a window of time between infection and detectable antibodies in serum during which patients have high virus levels (Figure).⁹ The combined antibody and antigen p24 test is a fourth-generation screening tool that detects HIV in the acute phase of the illness without requiring expensive ribonucleic acid viral tests.¹⁰ The fourth-generation test’s capacity to detect infection during the antibody-negative window when infectivity is highest may help decrease HIV transmission.¹¹

Figure When can HIV tests detect the virus?
EIA: enzyme immunoassay; HIV: human immunodeficiency virus; RNA: ribonucleic acid
Source: Adapted from reference 9

Psychiatrists’ role

Because psychiatrists routinely interact with patients who have an increased risk of HIV, they may be uniquely qualified to help these individuals. Psychiatrists often are comfortable discussing patients’ sexual and substance use history, which allows them to uncover and effectively address high-risk behaviors with appropriate testing and counseling. If testing confirms HIV infection, psychiatrists also can discuss altering high-risk behaviors (Table),^1,2 which has significant implications not only for patients, but also for public health.

Table

HIV transmission risk factors

Related Resource

• Centers for Disease Control and Prevention. HIV/AIDS. www.cdc.gov/hiv.

Disclosure

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

Substance use and high-risk sexual behaviors are common among persons with severe mental illness and make them vulnerable to human immunodeficiency virus (HIV) infection.^1-3 The prevalence of HIV is 3 times higher among these patients compared with individuals who are not mentally ill. This article reviews risk factors for HIV transmission, HIV screening recommendations, and current testing options, including the fourth-generation HIV test.

According to the World Health Organization, in 2009:

• 33 million people were infected with HIV
• there were 2.6 million new infections
• 1.8 million people died from causes related to acquired immune deficiency syndrome (AIDS).⁴

In the United States, approximately 1 million people are living with HIV; 55, 000 new cases were diagnosed in North America in 2009.⁵ The demographics of those infected with HIV in the United States have changed substantially. Most newly infected individuals are African American, and younger adults have higher rates of new infections.⁶ With the introduction of standardized antiviral medication combinations and federal programs to provide universal access to medications in the mid 1990s, the number of AIDS cases and mortality dropped, but there have not been similar gains in the past decade.⁶

In countries With access to antiviral medications, medical advances in HIV treatment have transformed an infection with a high mortality rate into a chronic illness. However, the rate of new cases has not changed significantly in the past 10 years. Early detection and treatment initiation reduces high-risk behavior and subsequent transmission in patients with HIV. Evidence suggests that detecting HIV in the acute phase of the illness, when the viral load is high, reduces HIV transmission.^1,5,6

HIV screening

HIV screening should be part of routine psychiatric practice, especially in community and forensic settings. We recommend that all psychiatrists understand HIV screening guidelines from the Centers for Disease Control and Prevention (CDC)⁷ and the American College of Physicians (ACP).⁸ The CDC (2006)⁷ and ACP (2009)⁸ guidelines recommend HIV screening for:

• all patients age 13 to 64, unless the prevalence of undiagnosed HIV infection in your patients has been documented to be <0. 1%⁷
• all patients seeking treatment for sexually transmitted diseases, including each visit for a new complaint⁷
• all pregnant women⁷
• any patient who received a blood transfusion between 1978 and 1985.⁸

Rescreening frequency is determined on an individual basis, taking into consideration the patient’s risk of contracting HIV. The ACP guidelines recommend using rapid tests when available.⁸ Although the false positive rates are higher with rapid tests, the benefits of early detection and reducing transmission outweigh the cost of confirming positive tests.⁸

The fourth-generation test

The gold standard for HIV screening is the enzyme-linked immunosorbent assay antibody test followed by a western blot.⁸ This has a high sensitivity and specificity but there is a window of time between infection and detectable antibodies in serum during which patients have high virus levels (Figure).⁹ The combined antibody and antigen p24 test is a fourth-generation screening tool that detects HIV in the acute phase of the illness without requiring expensive ribonucleic acid viral tests.¹⁰ The fourth-generation test’s capacity to detect infection during the antibody-negative window when infectivity is highest may help decrease HIV transmission.¹¹

Figure When can HIV tests detect the virus?
EIA: enzyme immunoassay; HIV: human immunodeficiency virus; RNA: ribonucleic acid
Source: Adapted from reference 9

Psychiatrists’ role

Because psychiatrists routinely interact with patients who have an increased risk of HIV, they may be uniquely qualified to help these individuals. Psychiatrists often are comfortable discussing patients’ sexual and substance use history, which allows them to uncover and effectively address high-risk behaviors with appropriate testing and counseling. If testing confirms HIV infection, psychiatrists also can discuss altering high-risk behaviors (Table),^1,2 which has significant implications not only for patients, but also for public health.

Table

HIV transmission risk factors

Related Resource

• Centers for Disease Control and Prevention. HIV/AIDS. www.cdc.gov/hiv.

Disclosure

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

I needed an intellectual oasis to deal with the anguish and frustration triggered by the monumental amount of misleading information that was included in the well-written article “Not all mood swings are bipolar disorder” (Current Psychiatry, February 2011, p. 38-52). Fortunately, a commentary by Dr. Irene Abramovich (“Breaking the box,” Comments & Controversies, Current Psychiatry, February 2011, p. 59) appeared as a therapeutic elixir. I believe that the “mood swings” article is filled with examples of how dangerous “cookbook” medicine can be.

Dr. Kowatch and colleagues use an expression that can be applied to the so-called diagnoses oppositional defiant disorder (ODD) and conduct disorder (CD): “Mood swings are analogous to a fever in pediatrics—they indicate something potentially is wrong with the patient, but they are not diagnostic as an isolated symptom. “ A similar concept was my position in a debate titled “Childhood conduct disorder and oppositional-defiant disorders are common manifestations of bipolar disorder” in which I argued that ODD and CD are behavioral expressions of genuine diagnoses.¹ Besides bipolar disorder, I also have seen obsessive-compulsive disorder, social anxiety disorder, and even sexual abuse labeled as “ODD” because the child refuses to be around people (such as a classroom) or is distracted by intrusive thoughts or flashbacks and turns hostile when reproached in front of the class.

In my view, Dr. Kowatch and colleagues give undeserved credit to the behavioral scales (the “cookbooks” of psychiatry) to make diagnoses and seem to miss warning signs in patients’ family history, ie, “history of depression and anxiety” (many times this translates as agitated/dysphoric mania) and “drinking problems, “ which frequently is found in undiagnosed bipolar spectrum patients who use alcohol to “shoot down” racing thoughts that interfere with normal sleep.

From January 2010 to February 2011, I reviewed charts and interviewed patients and families of 1, 654 patients with diagnoses of attention-deficit/hyperactivity disorder co-morbid with ODD, bipolar disorder, generalized anxiety disorder, and even 2 diagnoses that are not allowed by DSM rules: autism and mental retardation. The data from this study, which covers 12 counties that represent the 5 geographical areas of Florida, are being analyzed. In the meantime, I refer readers to my poster presentation from the 2010 U. S. Psychiatric and Mental Health Congress “Extinction of oppositional-defiant symptoms following treatment with mood stabilizers. “² In this study 44 patients were followed for at least 5 years (10 patients were observed for 7 years and a similar number for 6) and none had “oppositional” behavior after the diagnoses were treated. One caveat is that I placed antipsychotics in the same category as conventional mood stabilizers because 5 patients considered to be “inattentive” and “oppositional” actually had schizophrenia.

I oppose the authors’ assertion that “it can be difficult to differentiate the mood swings and symptoms of ODD from those of pediatric BD. “ My experience is that it is simple if we consider all diagnostic possibilities and obtain a thorough family history, which usually includes alcoholism, cannabis abuse, moodiness, suicide completion, unstable lifestyle, etc.

Manuel Mota-Castillo, MD
Assistant Clinical Professor
St. Matthews University
Voluntary Faculty
University of Central Florida
Lake Mary, FL

References

1. Mota-Castillo M, Steiner H. Childhood conduct disorder and oppositional-defiant disorder are common manifestations of bipolar disorder pro and con. Journal of Bipolar Disorders: Reviews and Commentaries. 2005;3:3,15-17.

2. Mota-Castillo M. Extinction of oppositional-defiant symptoms following treatment with mood stabilizers. Poster presented at: 23rd Annual U.S. Psychiatric and Mental Health Congress; November 20 2010; Orlando, FL.

The authors respond

We never suggested that clinicians use “cookbook medicine. “ The “behavioral scales” we recommended in our article are well-validated and reliable tools that allow a clinician to effectively elicit a great deal of useful information from patients and their parents about presenting problems and symptoms. This information can be used with other clinical information to make an accurate diagnosis and subsequent treatment plan.

The purpose of our article was to share our experiences in the differential diagnosis of mood swings in children and adolescents and to suggest that there are other diagnoses that cause mood swings besides bipolar disorder. Although a family history of mood disorders is important, it is also important to recognize that a recent, state-of-the-art study by Birmaher et al¹ reported that 10% of children of parents with bipolar disorder had a bipolar spectrum disorder. That means that 90% did not have bipolar disorder. It is important to remember this when evaluating children of parents with bipolar disorder. Although these children’s risk for developing bipolar disorder is increased compared with the general population, it is more likely that they will not develop bipolar disorder.

Robert A. Kowatch, MD, PhD
Professor of Psychiatry and Pediatrics

Erin Monroe, CNS
Clinical Nurse Specialist
Division of Psychiatry

Sergio V. Delgado, MD
Associate Professor of Psychiatry
and Pediatrics
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH