Evidence-Based Reviews

Although selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed¹ and are better tolerated than older antidepressants, side effects such as sexual dysfunction limit patient acceptance of these medications. DSM-IV-TR categorizes medication-induced sexual dysfunction as a type of substance-induced sexual dysfunction.² These dysfunctions are characterized by impairment of various sexual response phases (Table 1).^2,3

Estimating the true incidence and prevalence of SSRI-related sexual dysfunction can be difficult. Zimmerman et al⁴ compared psychiatrists’ clinical assessments of depressed patients receiving ongoing treatment with results of a standardized side effects questionnaire and found that even though psychiatrists regularly inquired about sexual side effects, on the questionnaire patients reported higher rates of almost all sexual dysfunctions. The incidence of SSRI-induced sexual dysfunction also can be difficult to ascertain because some sexual dysfunctions frequently accompany a primary psychiatric disorder⁵ or physical illness. Balon⁶ suggested that the incidence of SSRI-associated sexual dysfunction is 30% to 50%, although others have reported higher incidences.

Few quality studies have focused on identifying the exact nature and causes of SSRI treatment-emergent sexual dysfunction. This article describes mechanisms that may be fundamental to SSRI-associated sexual dysfunction.

Table 1

Sexual dysfunction and the sexual response cycle

Not just serotonin

Although SSRIs are relatively selective for the serotonergic system, they affect other neurotransmitter systems as well (Table 2).⁷ For example, at high dosages paroxetine is believed to block norepinephrine reuptake, and it has a clinically significant anticholinergic effect. Also, sertraline is a potent reuptake inhibitor of dopamine.⁸ Therefore, our discussion will include these neurotransmitters.

In their dual control model of male sexual response, Bancroft et al⁹ discuss the interplay between excitatory and inhibitory mechanisms at the central and peripheral levels. For example, they describe the role of norepinephrine mediation in the central arousal system via the disinhibition of dopaminergic and a possible testosterone mechanism. They also point to possible inhibition of central sexual arousal by neuropeptidergic and serotonergic mechanisms.

Evidence linking serotonin to sexual dysfunction is inconclusive because there are no exclusively serotonergic agents. Drugs frequently used to test these hypotheses often affect other neurotransmitters, which means conclusions are not specific to serotonin. Animal studies of the impact of serotonin agonist and antagonist agents on mounting and ejaculation have reported inconsistent results.¹⁰ Differential roles of 5-HT1 and 5-HT2 receptor activation on sexual behavior may explain some of these inconsistencies.⁸ However, 1 study found that antiserotonergic pharmacologic agents enhance sexual excitation in laboratory animals,¹¹ and a separate study showed that severing serotonergic axons in the medial forebrain bundle in male rats facilitated ejaculation.¹²

Monteiro et al¹³ found a high incidence of anorgasmia in previously orgasmic patients after they received clomipramine, which may be partially attributed to the drug’s serotonergic action. This prompted researchers to hypothesize that central serotonergic tone inhibits sexual behavior. However, based on current evidence, it would be best to consider serotonin as having a modulating effect¹⁰—as opposed to a complete inhibitory effect—on human sexual behavior.

Regarding the parasympathetic system, it was long believed that cholinergic innervations mediate penile erection. However, a more plausible hypothesis may be that parasympathetic cholinergic transmission at best has a modulating effect when other neurotransmitters—primarily the adrenergic system—are affected by concomitant pharmacologic interventions. Segraves¹⁰ proposed that cholinergic potentiating of adrenergic activity may be primarily responsible for bethanechol-induced reversal of SSRI-induced sexual dysfunction.

The adrenergic system is believed to play a role in penile erection and ejaculation.¹⁰ Adrenergic fibers innervate the vas deferens, seminal vesicles, trigone of the urinary bladder, and proximal urethra.¹⁴ Penile contractile and erectile tissue is richly innervated by the adrenergic nerve fibers.¹⁰ Ejaculation is mediated by α1-adrenergic receptors.¹⁰

Table 2

Neurotransmitters affected by SSRIs

The role of nitric oxide synthase

The advent of sildenafil underscored the importance of nitric oxide-mediated relaxation pathways in treating erectile dysfunction. Nitric oxide plays an important role in mediating the penile vasculature changes essential for erection and also is hypothesized to promote penile smooth muscle relaxation via cyclic guanosine monophosphate, there-by contributing to physiologic erection.¹⁵ Paroxetine is known to inhibit nitric oxide synthase, which reduces nitric oxide levels. The exact mechanism of this interaction remains unclear; however, it is hypothesized that 3 nitric oxide synthase isoenzymes are structurally similar to cytochrome P450 (CYP450). Paroxetine is a strong CYP2D6 inhibitor, which contributes to low nitric oxide levels in patients taking the drug.¹⁶

SSRIs and sexual response

Because decreased libido is part of depressive psychopathology,⁵ it is difficult to attribute loss of sexual desire directly to SSRIs. Nonetheless, SSRIs are associated with a risk of clinically significant loss of sexual desire that may resemble moderate to severe hypoactive sexual desire disorder.¹⁷ Reduced mesolimbic dopaminergic activity as a result of inhibitory serotonergic midbrain raphe nuclei projections is 1 possible cause.¹⁸ This hypothesis has lead investigators to examine drug targets in the CNS for hypoactive sexual desire disorder that would inhibit serotonergic tone and lead to brain dopaminergic system stimulation.

Another putative hypothesis for SSRI-induced loss of sexual desire is the role of 5-HT1A receptor-mediated norepinephrine neurotransmission. Because the sympathetic nervous system is believed to be involved in genital arousal in women, a small study analyzed the effect of sympathetic activation on SSRI-induced sexual dysfunction.¹⁹ Women who received paroxetine and sertraline—both are highly selective for 5-HT1A—showed improvement in sexual arousal and orgasm after taking ephedrine before sexual activity.¹⁹ Women who took fluoxetine, which is less selective for 5-HT1A, show no change or decreased sexual function.

SSRIs are associated with reduced nocturnal penile erections and severe erectile dysfunction, but the relationship is not robust.¹⁷ SSRI-induced suppression of rapid eye movement sleep²⁰ may partially explain reduced nocturnal and early morning erections. Supraspinal areas and preganglionic sacral neurons involved in sexual excitement also are reported to have substantial serotonergic activity, which suggests that serotonin has a direct role in erectile dysfunction at a comparative peripheral level.²¹ However, a recent study¹⁷ found no difference in flaccid and peak systolic velocity when comparing patients taking SSRIs with those who do not. This indicates that SSRIs’ affect on spontaneous and sexually aroused erections may be mediated at both central and peripheral levels.

Delayed ejaculation frequently is associated with SSRIs¹⁷ and usually is not caused by depressive psychopathology.²² Animal studies show that increased serotonergic tone predicts ejaculatory latency by acting as an inhibitor at the hypothalamus level.²³ In contrast, noradrenergic tone enhances ejaculation.²⁴ Antidepressants that increase noradrenaline levels and serotonin levels—such as serotonin-norepinephrine reuptake inhibitors—induce milder ejaculatory delay.¹⁷

A recent study¹⁷ found impaired climax and reduced libido in partners of patients using SSRIs. Patients receiving SSRIs report less frequent sexual intercourse and heightened guilt associated with masturbation, and SSRIs are associated with psychosocial factors such as higher stress at work and increased risk of conflicts with partners and other family members.¹⁷ In addition to biologic mechanisms, these psychosocial and intra-couple factors might contribute to SSRI-associated sexual dysfunction. However, because the temporal association between SSRI use and psychosocial dysfunction is ambiguous, this hypothesis should be interpreted with caution.

SSRIs have been associated with lower serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone.²⁵ However, these findings need to be replicated before drawing firm conclusions on intermediary role of hormones in SSRI-emergent sexual dysfunction.

Be aware that other medications may contribute to sexual dysfunction experienced by a patient receiving an SSRI (Table 3).²⁶

Table 3

Other than SSRIs, which medications can cause sexual dysfunction?

SSRIs for premature ejaculation?

Because SSRIs can cause delayed ejaculation, they have been used off-label to treat premature ejaculation.²⁷ For this purpose, paroxetine and sertraline have been prescribed with daily or on-demand dosing before sexual intercourse²⁸ and daily fluoxetine has been used.²⁹ However, none of these SSRIs is FDA-approved for treating premature ejaculation, daily dosing of SSRIs exposes patients to undesirable side effects, and inconsistent use of paroxetine can lead to discontinuation syndrome.

These concerns have lead researchers to seek an SSRI that could be used on as-needed basis and would not cause some of the deleterious side effects associated with current SSRIs. The short-acting SSRI dapoxetine is in FDA review for treating premature ejaculation; the drug is approved for this use in several countries outside the United States.³⁰

Sexual health education

Because sexual dysfunction can be caused by underlying psychopathology or physical illness, it is essential to obtain a detailed sexual history at your patient’s initial assessment and at every follow-up visit. Patients and providers may be guarded when discussing sexual health, which can be a barrier to providing comprehensive health care. The organizations listed in Related Resources can provide information and materials to help patients and health care providers better understand sexual health. Addressing the importance of sexual health in a comprehensive, culturally sensitive manner can substantially improve our patients’ medication compliance and prognosis.

Related Resources

• American Association of Sexuality Educators, Counselors, and Therapists. www.aasect.org.
• Sexual Medicine and Wellness Center. www.methodistsexualwellness.com.
• The Sexual Health Network. www.sexualhealth.com.
• International Society for the Study of Women’s Sexual Health. www.isswsh.org.

Drug Brand Names

• Bethanechol • Urecholine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Dapoxetine • Priligy
• Digoxin • Lanoxin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sildenafil • Viagra

Disclosure

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

Although selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed¹ and are better tolerated than older antidepressants, side effects such as sexual dysfunction limit patient acceptance of these medications. DSM-IV-TR categorizes medication-induced sexual dysfunction as a type of substance-induced sexual dysfunction.² These dysfunctions are characterized by impairment of various sexual response phases (Table 1).^2,3

Estimating the true incidence and prevalence of SSRI-related sexual dysfunction can be difficult. Zimmerman et al⁴ compared psychiatrists’ clinical assessments of depressed patients receiving ongoing treatment with results of a standardized side effects questionnaire and found that even though psychiatrists regularly inquired about sexual side effects, on the questionnaire patients reported higher rates of almost all sexual dysfunctions. The incidence of SSRI-induced sexual dysfunction also can be difficult to ascertain because some sexual dysfunctions frequently accompany a primary psychiatric disorder⁵ or physical illness. Balon⁶ suggested that the incidence of SSRI-associated sexual dysfunction is 30% to 50%, although others have reported higher incidences.

Few quality studies have focused on identifying the exact nature and causes of SSRI treatment-emergent sexual dysfunction. This article describes mechanisms that may be fundamental to SSRI-associated sexual dysfunction.

Table 1

Sexual dysfunction and the sexual response cycle

Not just serotonin

Although SSRIs are relatively selective for the serotonergic system, they affect other neurotransmitter systems as well (Table 2).⁷ For example, at high dosages paroxetine is believed to block norepinephrine reuptake, and it has a clinically significant anticholinergic effect. Also, sertraline is a potent reuptake inhibitor of dopamine.⁸ Therefore, our discussion will include these neurotransmitters.

In their dual control model of male sexual response, Bancroft et al⁹ discuss the interplay between excitatory and inhibitory mechanisms at the central and peripheral levels. For example, they describe the role of norepinephrine mediation in the central arousal system via the disinhibition of dopaminergic and a possible testosterone mechanism. They also point to possible inhibition of central sexual arousal by neuropeptidergic and serotonergic mechanisms.

Evidence linking serotonin to sexual dysfunction is inconclusive because there are no exclusively serotonergic agents. Drugs frequently used to test these hypotheses often affect other neurotransmitters, which means conclusions are not specific to serotonin. Animal studies of the impact of serotonin agonist and antagonist agents on mounting and ejaculation have reported inconsistent results.¹⁰ Differential roles of 5-HT1 and 5-HT2 receptor activation on sexual behavior may explain some of these inconsistencies.⁸ However, 1 study found that antiserotonergic pharmacologic agents enhance sexual excitation in laboratory animals,¹¹ and a separate study showed that severing serotonergic axons in the medial forebrain bundle in male rats facilitated ejaculation.¹²

Monteiro et al¹³ found a high incidence of anorgasmia in previously orgasmic patients after they received clomipramine, which may be partially attributed to the drug’s serotonergic action. This prompted researchers to hypothesize that central serotonergic tone inhibits sexual behavior. However, based on current evidence, it would be best to consider serotonin as having a modulating effect¹⁰—as opposed to a complete inhibitory effect—on human sexual behavior.

Regarding the parasympathetic system, it was long believed that cholinergic innervations mediate penile erection. However, a more plausible hypothesis may be that parasympathetic cholinergic transmission at best has a modulating effect when other neurotransmitters—primarily the adrenergic system—are affected by concomitant pharmacologic interventions. Segraves¹⁰ proposed that cholinergic potentiating of adrenergic activity may be primarily responsible for bethanechol-induced reversal of SSRI-induced sexual dysfunction.

The adrenergic system is believed to play a role in penile erection and ejaculation.¹⁰ Adrenergic fibers innervate the vas deferens, seminal vesicles, trigone of the urinary bladder, and proximal urethra.¹⁴ Penile contractile and erectile tissue is richly innervated by the adrenergic nerve fibers.¹⁰ Ejaculation is mediated by α1-adrenergic receptors.¹⁰

Table 2

Neurotransmitters affected by SSRIs

The role of nitric oxide synthase

The advent of sildenafil underscored the importance of nitric oxide-mediated relaxation pathways in treating erectile dysfunction. Nitric oxide plays an important role in mediating the penile vasculature changes essential for erection and also is hypothesized to promote penile smooth muscle relaxation via cyclic guanosine monophosphate, there-by contributing to physiologic erection.¹⁵ Paroxetine is known to inhibit nitric oxide synthase, which reduces nitric oxide levels. The exact mechanism of this interaction remains unclear; however, it is hypothesized that 3 nitric oxide synthase isoenzymes are structurally similar to cytochrome P450 (CYP450). Paroxetine is a strong CYP2D6 inhibitor, which contributes to low nitric oxide levels in patients taking the drug.¹⁶

SSRIs and sexual response

Because decreased libido is part of depressive psychopathology,⁵ it is difficult to attribute loss of sexual desire directly to SSRIs. Nonetheless, SSRIs are associated with a risk of clinically significant loss of sexual desire that may resemble moderate to severe hypoactive sexual desire disorder.¹⁷ Reduced mesolimbic dopaminergic activity as a result of inhibitory serotonergic midbrain raphe nuclei projections is 1 possible cause.¹⁸ This hypothesis has lead investigators to examine drug targets in the CNS for hypoactive sexual desire disorder that would inhibit serotonergic tone and lead to brain dopaminergic system stimulation.

Another putative hypothesis for SSRI-induced loss of sexual desire is the role of 5-HT1A receptor-mediated norepinephrine neurotransmission. Because the sympathetic nervous system is believed to be involved in genital arousal in women, a small study analyzed the effect of sympathetic activation on SSRI-induced sexual dysfunction.¹⁹ Women who received paroxetine and sertraline—both are highly selective for 5-HT1A—showed improvement in sexual arousal and orgasm after taking ephedrine before sexual activity.¹⁹ Women who took fluoxetine, which is less selective for 5-HT1A, show no change or decreased sexual function.

SSRIs are associated with reduced nocturnal penile erections and severe erectile dysfunction, but the relationship is not robust.¹⁷ SSRI-induced suppression of rapid eye movement sleep²⁰ may partially explain reduced nocturnal and early morning erections. Supraspinal areas and preganglionic sacral neurons involved in sexual excitement also are reported to have substantial serotonergic activity, which suggests that serotonin has a direct role in erectile dysfunction at a comparative peripheral level.²¹ However, a recent study¹⁷ found no difference in flaccid and peak systolic velocity when comparing patients taking SSRIs with those who do not. This indicates that SSRIs’ affect on spontaneous and sexually aroused erections may be mediated at both central and peripheral levels.

Delayed ejaculation frequently is associated with SSRIs¹⁷ and usually is not caused by depressive psychopathology.²² Animal studies show that increased serotonergic tone predicts ejaculatory latency by acting as an inhibitor at the hypothalamus level.²³ In contrast, noradrenergic tone enhances ejaculation.²⁴ Antidepressants that increase noradrenaline levels and serotonin levels—such as serotonin-norepinephrine reuptake inhibitors—induce milder ejaculatory delay.¹⁷

A recent study¹⁷ found impaired climax and reduced libido in partners of patients using SSRIs. Patients receiving SSRIs report less frequent sexual intercourse and heightened guilt associated with masturbation, and SSRIs are associated with psychosocial factors such as higher stress at work and increased risk of conflicts with partners and other family members.¹⁷ In addition to biologic mechanisms, these psychosocial and intra-couple factors might contribute to SSRI-associated sexual dysfunction. However, because the temporal association between SSRI use and psychosocial dysfunction is ambiguous, this hypothesis should be interpreted with caution.

SSRIs have been associated with lower serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone.²⁵ However, these findings need to be replicated before drawing firm conclusions on intermediary role of hormones in SSRI-emergent sexual dysfunction.

Be aware that other medications may contribute to sexual dysfunction experienced by a patient receiving an SSRI (Table 3).²⁶

Table 3

Other than SSRIs, which medications can cause sexual dysfunction?

SSRIs for premature ejaculation?

Because SSRIs can cause delayed ejaculation, they have been used off-label to treat premature ejaculation.²⁷ For this purpose, paroxetine and sertraline have been prescribed with daily or on-demand dosing before sexual intercourse²⁸ and daily fluoxetine has been used.²⁹ However, none of these SSRIs is FDA-approved for treating premature ejaculation, daily dosing of SSRIs exposes patients to undesirable side effects, and inconsistent use of paroxetine can lead to discontinuation syndrome.

These concerns have lead researchers to seek an SSRI that could be used on as-needed basis and would not cause some of the deleterious side effects associated with current SSRIs. The short-acting SSRI dapoxetine is in FDA review for treating premature ejaculation; the drug is approved for this use in several countries outside the United States.³⁰

Sexual health education

Because sexual dysfunction can be caused by underlying psychopathology or physical illness, it is essential to obtain a detailed sexual history at your patient’s initial assessment and at every follow-up visit. Patients and providers may be guarded when discussing sexual health, which can be a barrier to providing comprehensive health care. The organizations listed in Related Resources can provide information and materials to help patients and health care providers better understand sexual health. Addressing the importance of sexual health in a comprehensive, culturally sensitive manner can substantially improve our patients’ medication compliance and prognosis.

Related Resources

• American Association of Sexuality Educators, Counselors, and Therapists. www.aasect.org.
• Sexual Medicine and Wellness Center. www.methodistsexualwellness.com.
• The Sexual Health Network. www.sexualhealth.com.
• International Society for the Study of Women’s Sexual Health. www.isswsh.org.

Drug Brand Names

• Bethanechol • Urecholine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Dapoxetine • Priligy
• Digoxin • Lanoxin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sildenafil • Viagra

Disclosure

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

Although selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed¹ and are better tolerated than older antidepressants, side effects such as sexual dysfunction limit patient acceptance of these medications. DSM-IV-TR categorizes medication-induced sexual dysfunction as a type of substance-induced sexual dysfunction.² These dysfunctions are characterized by impairment of various sexual response phases (Table 1).^2,3

Estimating the true incidence and prevalence of SSRI-related sexual dysfunction can be difficult. Zimmerman et al⁴ compared psychiatrists’ clinical assessments of depressed patients receiving ongoing treatment with results of a standardized side effects questionnaire and found that even though psychiatrists regularly inquired about sexual side effects, on the questionnaire patients reported higher rates of almost all sexual dysfunctions. The incidence of SSRI-induced sexual dysfunction also can be difficult to ascertain because some sexual dysfunctions frequently accompany a primary psychiatric disorder⁵ or physical illness. Balon⁶ suggested that the incidence of SSRI-associated sexual dysfunction is 30% to 50%, although others have reported higher incidences.

Few quality studies have focused on identifying the exact nature and causes of SSRI treatment-emergent sexual dysfunction. This article describes mechanisms that may be fundamental to SSRI-associated sexual dysfunction.

Table 1

Sexual dysfunction and the sexual response cycle

Not just serotonin

Although SSRIs are relatively selective for the serotonergic system, they affect other neurotransmitter systems as well (Table 2).⁷ For example, at high dosages paroxetine is believed to block norepinephrine reuptake, and it has a clinically significant anticholinergic effect. Also, sertraline is a potent reuptake inhibitor of dopamine.⁸ Therefore, our discussion will include these neurotransmitters.

In their dual control model of male sexual response, Bancroft et al⁹ discuss the interplay between excitatory and inhibitory mechanisms at the central and peripheral levels. For example, they describe the role of norepinephrine mediation in the central arousal system via the disinhibition of dopaminergic and a possible testosterone mechanism. They also point to possible inhibition of central sexual arousal by neuropeptidergic and serotonergic mechanisms.

Evidence linking serotonin to sexual dysfunction is inconclusive because there are no exclusively serotonergic agents. Drugs frequently used to test these hypotheses often affect other neurotransmitters, which means conclusions are not specific to serotonin. Animal studies of the impact of serotonin agonist and antagonist agents on mounting and ejaculation have reported inconsistent results.¹⁰ Differential roles of 5-HT1 and 5-HT2 receptor activation on sexual behavior may explain some of these inconsistencies.⁸ However, 1 study found that antiserotonergic pharmacologic agents enhance sexual excitation in laboratory animals,¹¹ and a separate study showed that severing serotonergic axons in the medial forebrain bundle in male rats facilitated ejaculation.¹²

Monteiro et al¹³ found a high incidence of anorgasmia in previously orgasmic patients after they received clomipramine, which may be partially attributed to the drug’s serotonergic action. This prompted researchers to hypothesize that central serotonergic tone inhibits sexual behavior. However, based on current evidence, it would be best to consider serotonin as having a modulating effect¹⁰—as opposed to a complete inhibitory effect—on human sexual behavior.

Regarding the parasympathetic system, it was long believed that cholinergic innervations mediate penile erection. However, a more plausible hypothesis may be that parasympathetic cholinergic transmission at best has a modulating effect when other neurotransmitters—primarily the adrenergic system—are affected by concomitant pharmacologic interventions. Segraves¹⁰ proposed that cholinergic potentiating of adrenergic activity may be primarily responsible for bethanechol-induced reversal of SSRI-induced sexual dysfunction.

The adrenergic system is believed to play a role in penile erection and ejaculation.¹⁰ Adrenergic fibers innervate the vas deferens, seminal vesicles, trigone of the urinary bladder, and proximal urethra.¹⁴ Penile contractile and erectile tissue is richly innervated by the adrenergic nerve fibers.¹⁰ Ejaculation is mediated by α1-adrenergic receptors.¹⁰

Table 2

Neurotransmitters affected by SSRIs

The role of nitric oxide synthase

The advent of sildenafil underscored the importance of nitric oxide-mediated relaxation pathways in treating erectile dysfunction. Nitric oxide plays an important role in mediating the penile vasculature changes essential for erection and also is hypothesized to promote penile smooth muscle relaxation via cyclic guanosine monophosphate, there-by contributing to physiologic erection.¹⁵ Paroxetine is known to inhibit nitric oxide synthase, which reduces nitric oxide levels. The exact mechanism of this interaction remains unclear; however, it is hypothesized that 3 nitric oxide synthase isoenzymes are structurally similar to cytochrome P450 (CYP450). Paroxetine is a strong CYP2D6 inhibitor, which contributes to low nitric oxide levels in patients taking the drug.¹⁶

SSRIs and sexual response

Because decreased libido is part of depressive psychopathology,⁵ it is difficult to attribute loss of sexual desire directly to SSRIs. Nonetheless, SSRIs are associated with a risk of clinically significant loss of sexual desire that may resemble moderate to severe hypoactive sexual desire disorder.¹⁷ Reduced mesolimbic dopaminergic activity as a result of inhibitory serotonergic midbrain raphe nuclei projections is 1 possible cause.¹⁸ This hypothesis has lead investigators to examine drug targets in the CNS for hypoactive sexual desire disorder that would inhibit serotonergic tone and lead to brain dopaminergic system stimulation.

Another putative hypothesis for SSRI-induced loss of sexual desire is the role of 5-HT1A receptor-mediated norepinephrine neurotransmission. Because the sympathetic nervous system is believed to be involved in genital arousal in women, a small study analyzed the effect of sympathetic activation on SSRI-induced sexual dysfunction.¹⁹ Women who received paroxetine and sertraline—both are highly selective for 5-HT1A—showed improvement in sexual arousal and orgasm after taking ephedrine before sexual activity.¹⁹ Women who took fluoxetine, which is less selective for 5-HT1A, show no change or decreased sexual function.

SSRIs are associated with reduced nocturnal penile erections and severe erectile dysfunction, but the relationship is not robust.¹⁷ SSRI-induced suppression of rapid eye movement sleep²⁰ may partially explain reduced nocturnal and early morning erections. Supraspinal areas and preganglionic sacral neurons involved in sexual excitement also are reported to have substantial serotonergic activity, which suggests that serotonin has a direct role in erectile dysfunction at a comparative peripheral level.²¹ However, a recent study¹⁷ found no difference in flaccid and peak systolic velocity when comparing patients taking SSRIs with those who do not. This indicates that SSRIs’ affect on spontaneous and sexually aroused erections may be mediated at both central and peripheral levels.

Delayed ejaculation frequently is associated with SSRIs¹⁷ and usually is not caused by depressive psychopathology.²² Animal studies show that increased serotonergic tone predicts ejaculatory latency by acting as an inhibitor at the hypothalamus level.²³ In contrast, noradrenergic tone enhances ejaculation.²⁴ Antidepressants that increase noradrenaline levels and serotonin levels—such as serotonin-norepinephrine reuptake inhibitors—induce milder ejaculatory delay.¹⁷

A recent study¹⁷ found impaired climax and reduced libido in partners of patients using SSRIs. Patients receiving SSRIs report less frequent sexual intercourse and heightened guilt associated with masturbation, and SSRIs are associated with psychosocial factors such as higher stress at work and increased risk of conflicts with partners and other family members.¹⁷ In addition to biologic mechanisms, these psychosocial and intra-couple factors might contribute to SSRI-associated sexual dysfunction. However, because the temporal association between SSRI use and psychosocial dysfunction is ambiguous, this hypothesis should be interpreted with caution.

SSRIs have been associated with lower serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone.²⁵ However, these findings need to be replicated before drawing firm conclusions on intermediary role of hormones in SSRI-emergent sexual dysfunction.

Be aware that other medications may contribute to sexual dysfunction experienced by a patient receiving an SSRI (Table 3).²⁶

Table 3

Other than SSRIs, which medications can cause sexual dysfunction?

SSRIs for premature ejaculation?

Because SSRIs can cause delayed ejaculation, they have been used off-label to treat premature ejaculation.²⁷ For this purpose, paroxetine and sertraline have been prescribed with daily or on-demand dosing before sexual intercourse²⁸ and daily fluoxetine has been used.²⁹ However, none of these SSRIs is FDA-approved for treating premature ejaculation, daily dosing of SSRIs exposes patients to undesirable side effects, and inconsistent use of paroxetine can lead to discontinuation syndrome.

These concerns have lead researchers to seek an SSRI that could be used on as-needed basis and would not cause some of the deleterious side effects associated with current SSRIs. The short-acting SSRI dapoxetine is in FDA review for treating premature ejaculation; the drug is approved for this use in several countries outside the United States.³⁰

Sexual health education

Because sexual dysfunction can be caused by underlying psychopathology or physical illness, it is essential to obtain a detailed sexual history at your patient’s initial assessment and at every follow-up visit. Patients and providers may be guarded when discussing sexual health, which can be a barrier to providing comprehensive health care. The organizations listed in Related Resources can provide information and materials to help patients and health care providers better understand sexual health. Addressing the importance of sexual health in a comprehensive, culturally sensitive manner can substantially improve our patients’ medication compliance and prognosis.

Related Resources

• American Association of Sexuality Educators, Counselors, and Therapists. www.aasect.org.
• Sexual Medicine and Wellness Center. www.methodistsexualwellness.com.
• The Sexual Health Network. www.sexualhealth.com.
• International Society for the Study of Women’s Sexual Health. www.isswsh.org.

Drug Brand Names

• Bethanechol • Urecholine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Dapoxetine • Priligy
• Digoxin • Lanoxin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sildenafil • Viagra

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/therapeutic-neuromodulation.html#comments

The brain is an electrochemical organ, and its activity can be modulated for therapeutic purposes by electrical, pharmacologic, or combined approaches. In general, neuromodulation induces electrical current in peripheral or central nervous tissue, which is accomplished by various techniques, including:

• electroconvulsive therapy (ECT)
• vagus nerve stimulation (VNS)
• transcranial magnetic stimulation (TMS)
• deep brain stimulation (DBS).

It is thought that therapeutic benefit occurs by regulating functional disturbances in relevant distributed neural circuits.¹ Depending on the stimulation method, the frequencies chosen may excite or inhibit different or the same areas of the brain in varying patterns. Unlike medication, neuromodulation impacts the brain episodically, which may mitigate adaptation to the therapy’s beneficial effects and avoid systemic adverse effects.

Neuromodulation techniques are categorized based on their risk level as invasive or noninvasive and seizurogenic or nonseizurogenic (Table 1). Although these and other approaches are being considered for various neuropsychiatric disorders (Table 2), the most common application is for severe, treatment-resistant depression. Therefore, this article focuses on FDA-approved neuromodulation treatments for depression, with limited discussion of other indications.

Table 1

Therapeutic neuromodulation: Categorization based on risk

Table 2

Approved and investigational indications of neuromodulation

ECT: Oldest and most effective

ECT has remained the most effective therapeutic neuromodulation technique for more than 7 decades. It is indicated primarily for severe depressive episodes (eg, psychotic, melancholic), particularly in older patients.

ECT delivers electrical current to the CNS that is sufficient to produce a seizure. Under modified conditions, a typical course of 6 to 12 sessions can resolve severe depressive episodes and may also benefit other disorders, such as bipolar mania and acute psychosis. Although ECT is potentially life-saving, its use was markedly curtailed with the advent of effective antidepressants in the 1950s. Multiple factors impede its use, including:

• access and expertise are limited in many areas
• cognition is at least temporarily adversely affected
• relapse rates after acute benefit are high
• cost
• public perception often is negative.

Studies are addressing several of these concerns. For example, the National Institute of Mental Health-sponsored Consortium on Research with ECT (CORE) group is considering how to more effectively maintain acute benefits of ECT. They compared the potential merits of maintenance ECT with maintenance pharmacotherapy (nortriptyline plus lithium) over 6 months. Although the 2 strategies had comparable results, retention rates were <50% and about one-third relapsed in both groups.^2,3 Potential alternative strategies include a more frequent ECT maintenance schedule and/or combining maintenance ECT with medication(s).

Magnetic seizure therapy (MST) and focal electrically administered seizure therapy (FEAST) are attempts to produce similar efficacy and less cognitive disruption compared with ECT.^4,5 Work also continues on electrode placement (eg, bifrontal) and alteration of waveform characteristics (eg, ultra-brief) to maintain or enhance efficacy while minimizing adverse effects.^6,7

Stimulating the vagus nerve

VNS was introduced for treating refractory epilepsy in 1997. In 2005, it became the first FDA-approved implantable device for managing chronic or recurrent treatment-resistant depression.

The vagus nerve is the principal parasympathetic, efferent tract regulating heart rate, intestinal motility, and gastric acid secretion. Information about pain, hunger, and satiety is conveyed by these fibers to the median raphe nucleus and locus coeruleus, brain regions with significant serotonergic and noradrenergic innervation. These neurotransmitters also are believed to play a pivotal role in major depression.

With VNS, a pacemaker-like pulse generator is surgically implanted subcutaneously in the patient’s upper left chest. Wires extend from this device to the left vagus nerve (80% of whose fibers are afferent) located in the neck, to which the pulse generator sends electrical signals every few seconds (Table 3). The right vagus nerve is not used because it provides parasympathetic innervation to the heart. A clinician adjusts stimulation parameters using a computer and a noninvasive handheld device. Common adverse effects include voice alteration or hoarseness, cough, and shortness of breath, which occur during active stimulation because of the proximity of the electrodes to the laryngeal and pharyngeal branches of the vagus nerve. These effects may improve by adjusting stimulation intensity. The device permits a wide range of duty cycles, but preclinical animal studies indicate that >50% activation periods may damage the vagus nerve. If patients become too uncomfortable, they may deactivate the device with a magnet held over the implantation area.

Two open-label studies evaluated VNS to treat major depression. The first involved 10 weeks of stimulation in 59 subjects with chronic or recurrent, nonpsychotic, unipolar or bipolar depression who failed at least 2 adequate antidepressant trials in the current episode.⁸ Stable doses of concomitant antidepressants or mood stabilizers were allowed. After 3 months, 18 (31%) patients responded within an average of 45.5 days, and nearly 15% achieved remission. Response was defined as 50% reduction in baseline Hamilton Depression Rating Scale-28 (HDRS-28) score; remission was defined as HDRS-28 score ≤10. Further, clinical response did not differ between unipolar and bipolar depression patients.

In the second trial, 74 patients with treatment-resistant depression received fixed dose antidepressants and VNS for 3 months, followed by 9 months of flexibly dosed VNS and antidepressants.⁹ At 3 months, response (≥50% reduction in HDRS-28 score) and remission (HDRS-28 score <10) rates were 37% and 17%, respectively, and increased to 53% and 33% at 1 year.

A sham-controlled trial of VNS in 235 depressed patients used similar inclusion and exclusion criteria as in the open-label study by Sackeim et al.^8,10 Two weeks after device implantation, patients were randomized to active treatment (stimulator turned on) or sham control (stimulator left off). At 3 months, the primary outcome measure—response rate based on HDRS-24 score—did not differ significantly between the active and control groups (15% vs 10%, respectively). There was, however, a significantly greater improvement in Inventory of Depressive Symptomatology-Self Report Scale scores with active VNS vs sham VNS.

Patients on sham treatment then were switched to active treatment and both groups were followed for 12 additional months, at which time response and remission rates nearly doubled for both groups.¹¹ In a post-hoc analysis, the same investigators found significant improvement with VNS compared with a naturalistic, matched control group with similar treatment-resistant depression.¹² The FDA considered this adequate to support efficacy and approved the device for chronic or recurrent treatment-resistant depression in an episode not responsive to at least 4 adequate treatment trials with pharmacotherapy or ECT. Perhaps because post-hoc analyses typically are not sufficient to gain FDA approval, most insurance companies do not reimburse for VNS treatment of depression, and VNS is not frequently used for refractory depression.

Table 3

Vagus nerve stimulation treatment parameters

A newer option: TMS

TMS is the most recently FDA-approved therapeutic neuromodulation technique for treating depression. In October 2008, a TMS device became available for patients failing to respond to 1 adequate antidepressant trial during the current episode.

TMS delivers intense, intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The pulse intensity is similar to that produced by MRI. The coil usually is placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC) and pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the adjacent cerebral cortex, as well as distal effects in other relevant neural circuits (Table 4). TMS typically is administered on an outpatient basis. A standard treatment course for depression consists of 5 treatment sessions per week for 4 to 8 weeks, depending on symptom severity and how quickly patients respond.

TMS initially was examined in several small, open-label studies that looked at various treatment parameters and stimulation sites. Several sham-controlled studies generally found TMS efficacious and further refined treatment administration. Its role in treating depression—and possibly other psychiatric disorders—has been supported by 2 recent meta-analyses.^13,14

O’Reardon et al¹⁵ conducted the largest double-blind trial of active vs sham TMS (N=301) for moderately treatment-resistant major depression. This study began with a 4- to 6-week, blinded, randomized phase followed by 6 weeks of open-label TMS for initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressants. This trial utilized the most aggressive treatment parameters to date (ie, 10 Hz; 75 4-second trains; 26-second inter-train interval; 120% motor threshold) delivering 3,000 pulses per treatment over an average of 24 sessions. Compared with the sham procedure, patients who received active TMS showed significantly higher response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, remission rate—defined as a MADRS score <10—was significantly higher in the active treatment group (14%) compared with the sham procedure (6%). A post-hoc analysis found that the most robust benefit occurred in patients with only 1 failed adequate antidepressant trial (effect size=0.83).¹⁶ This administration protocol was well tolerated, with no deaths or seizures and a low rate of discontinuation because of adverse events (5%).¹⁷ The most common adverse effects were application site pain or discomfort and headaches.

Recently, the second largest (N=190) sham-controlled trial of TMS for treatment-resistant major depression was published.¹⁸ This National Institute of Mental Health-sponsored, multiphase study included an initial 2-week, treatment-free period; 3 weeks of daily treatments over the left DLPFC using the same device and parameters as in the O’Reardon study; and an additional 3 weeks of treatment in patients who were improving. Those not responding to initial treatment were crossed over to open-label active TMS. This study advanced TMS development by:

• using a novel somatosensory system that produced similar sensations with sham and active TMS
• assessing the success of maintaining the blind
• establishing a rigorous clinical rating system
• utilizing MRI-guided adjustment of coil placement in a subset of patients.

The authors concluded that active TMS was significantly better than sham treatment in achieving remission (14% vs 5%). In addition, the raters, treaters, and patients were effectively blinded to the treatment condition. MRI-assisted coil placement found that in 33% of the sample, site placement determined by standardized assessment was over the premotor cortex rather than the prefrontal cortex, so the coil was moved 1 additional cm anteriorly in these patients. Similar to those observed by O’Reardon et al, adverse effects of active TMS were generally mild to moderate, did not differ by treatment condition, and led to a low discontinuation rate (5.5%).

Table 4

Treatment parameters of transcranial magnetic stimulation

Deep brain stimulation

DBS is a “functional neurosurgical” procedure that delivers electrical current directly to specific areas within the brain.¹⁹ Its mechanism of action remains uncertain; depolarization blockade, synaptic inhibition, and “neural jamming” are leading hypotheses. In contrast to conventional ablative surgeries, DBS is reversible and adjustable. Implantation involves positioning pacemaker-like battery devices subcutaneously in the left and right upper chest. Electrodes attached to wires are run subcutaneously behind the ears and, with stereotactic guidance, placed through burr holes in the skull into specific CNS areas implicated in the pathophysiology of conditions such as Parkinson’s disease, refractory depression, and severe obsessive-compulsive disorder (OCD).

Antidepressant effects. The FDA recently approved DBS under its humanitarian device exemption program for intractable, severe, disabling OCD based on promising results from open and blind trials that stimulated areas such as the internal capsule and adjacent ventral striatum.^20-22 These studies reported that DBS of the caudate nucleus for OCD and subthalamic nucleus for Parkinson’s disease also produced antidepressant effects. Subsequently, trials targeting the subgenual region (Brodmann’s area 25), the ventral capsule/ventral striatum, and nucleus accumbens demonstrated antidepressant effects.^23-27 Pending the results of ongoing pilot trials, large, multi-center studies using different devices and target areas are being planned to clarify the role of DBS for patients with severe, disabling, refractory depression.

Adverse effects of DBS can be:

• surgical-related (eg, seizure, bleeding, infection)
• device-related (eg, lead breakage, malfunction)
• stimulation-related (eg, paresthesia, dysarthria, memory disruption, cognitive changes, psychiatric symptoms).

The most serious risk is intracranial bleeding, which occurs in 2% to 3% of patients. Clearly, the risk-benefit ratio must be carefully considered.

Cost and reimbursement

Cost of treatment and potential for third-party reimbursement are important considerations for any risk-benefit analysis. Many patients who seek neuromodulation treatments will not have insurance or other coverage entitlements.^28-30 Further, newer treatments are not routinely covered by insurance; however, individual case coverage may be allowed and some device manufacturers have programs to assist providers and patients obtain coverage.^28-30 Even ECT, which has long been a covered treatment for major depression, is still considered investigational for other disorders. Thus, it is important to pre-certify with the patient’s health insurance provider before initiating treatment.

Coverage, however, is not the only consideration when weighing cost effectiveness. Economic studies can assist with clinical and ethical decisions relating to treatment choice.³¹ These studies, however, need to be critically evaluated (eg, what costs were included in the analysis). Although direct costs are easier to evaluate, indirect costs—such as the patient’s ability to continue to work while receiving the treatment, caretaker availability during treatment, and whether treatment is an inpatient or outpatient procedure—are more difficult to evaluate and should be discussed with the patient. Because these specialized options have the potential to further benefit patients with depression and other neuropsychiatric disorders, it is essential to balance the pressures of cost containment with the need for more effective and better tolerated treatments.^32-34

Related Resource

• Brunoni AR, Teng CT, Correa C, et al. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Arq Neuropsiquiatr. 2010;68(3):433-451.

Drug Brand Names

• Lithium • Eskalith, Lithobid
• Nortriptyline • Aventyl, Pamelor

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/therapeutic-neuromodulation.html#comments

The brain is an electrochemical organ, and its activity can be modulated for therapeutic purposes by electrical, pharmacologic, or combined approaches. In general, neuromodulation induces electrical current in peripheral or central nervous tissue, which is accomplished by various techniques, including:

• electroconvulsive therapy (ECT)
• vagus nerve stimulation (VNS)
• transcranial magnetic stimulation (TMS)
• deep brain stimulation (DBS).

It is thought that therapeutic benefit occurs by regulating functional disturbances in relevant distributed neural circuits.¹ Depending on the stimulation method, the frequencies chosen may excite or inhibit different or the same areas of the brain in varying patterns. Unlike medication, neuromodulation impacts the brain episodically, which may mitigate adaptation to the therapy’s beneficial effects and avoid systemic adverse effects.

Neuromodulation techniques are categorized based on their risk level as invasive or noninvasive and seizurogenic or nonseizurogenic (Table 1). Although these and other approaches are being considered for various neuropsychiatric disorders (Table 2), the most common application is for severe, treatment-resistant depression. Therefore, this article focuses on FDA-approved neuromodulation treatments for depression, with limited discussion of other indications.

Table 1

Therapeutic neuromodulation: Categorization based on risk

Table 2

Approved and investigational indications of neuromodulation

ECT: Oldest and most effective

ECT has remained the most effective therapeutic neuromodulation technique for more than 7 decades. It is indicated primarily for severe depressive episodes (eg, psychotic, melancholic), particularly in older patients.

ECT delivers electrical current to the CNS that is sufficient to produce a seizure. Under modified conditions, a typical course of 6 to 12 sessions can resolve severe depressive episodes and may also benefit other disorders, such as bipolar mania and acute psychosis. Although ECT is potentially life-saving, its use was markedly curtailed with the advent of effective antidepressants in the 1950s. Multiple factors impede its use, including:

• access and expertise are limited in many areas
• cognition is at least temporarily adversely affected
• relapse rates after acute benefit are high
• cost
• public perception often is negative.

Studies are addressing several of these concerns. For example, the National Institute of Mental Health-sponsored Consortium on Research with ECT (CORE) group is considering how to more effectively maintain acute benefits of ECT. They compared the potential merits of maintenance ECT with maintenance pharmacotherapy (nortriptyline plus lithium) over 6 months. Although the 2 strategies had comparable results, retention rates were <50% and about one-third relapsed in both groups.^2,3 Potential alternative strategies include a more frequent ECT maintenance schedule and/or combining maintenance ECT with medication(s).

Magnetic seizure therapy (MST) and focal electrically administered seizure therapy (FEAST) are attempts to produce similar efficacy and less cognitive disruption compared with ECT.^4,5 Work also continues on electrode placement (eg, bifrontal) and alteration of waveform characteristics (eg, ultra-brief) to maintain or enhance efficacy while minimizing adverse effects.^6,7

Stimulating the vagus nerve

VNS was introduced for treating refractory epilepsy in 1997. In 2005, it became the first FDA-approved implantable device for managing chronic or recurrent treatment-resistant depression.

The vagus nerve is the principal parasympathetic, efferent tract regulating heart rate, intestinal motility, and gastric acid secretion. Information about pain, hunger, and satiety is conveyed by these fibers to the median raphe nucleus and locus coeruleus, brain regions with significant serotonergic and noradrenergic innervation. These neurotransmitters also are believed to play a pivotal role in major depression.

With VNS, a pacemaker-like pulse generator is surgically implanted subcutaneously in the patient’s upper left chest. Wires extend from this device to the left vagus nerve (80% of whose fibers are afferent) located in the neck, to which the pulse generator sends electrical signals every few seconds (Table 3). The right vagus nerve is not used because it provides parasympathetic innervation to the heart. A clinician adjusts stimulation parameters using a computer and a noninvasive handheld device. Common adverse effects include voice alteration or hoarseness, cough, and shortness of breath, which occur during active stimulation because of the proximity of the electrodes to the laryngeal and pharyngeal branches of the vagus nerve. These effects may improve by adjusting stimulation intensity. The device permits a wide range of duty cycles, but preclinical animal studies indicate that >50% activation periods may damage the vagus nerve. If patients become too uncomfortable, they may deactivate the device with a magnet held over the implantation area.

Two open-label studies evaluated VNS to treat major depression. The first involved 10 weeks of stimulation in 59 subjects with chronic or recurrent, nonpsychotic, unipolar or bipolar depression who failed at least 2 adequate antidepressant trials in the current episode.⁸ Stable doses of concomitant antidepressants or mood stabilizers were allowed. After 3 months, 18 (31%) patients responded within an average of 45.5 days, and nearly 15% achieved remission. Response was defined as 50% reduction in baseline Hamilton Depression Rating Scale-28 (HDRS-28) score; remission was defined as HDRS-28 score ≤10. Further, clinical response did not differ between unipolar and bipolar depression patients.

In the second trial, 74 patients with treatment-resistant depression received fixed dose antidepressants and VNS for 3 months, followed by 9 months of flexibly dosed VNS and antidepressants.⁹ At 3 months, response (≥50% reduction in HDRS-28 score) and remission (HDRS-28 score <10) rates were 37% and 17%, respectively, and increased to 53% and 33% at 1 year.

A sham-controlled trial of VNS in 235 depressed patients used similar inclusion and exclusion criteria as in the open-label study by Sackeim et al.^8,10 Two weeks after device implantation, patients were randomized to active treatment (stimulator turned on) or sham control (stimulator left off). At 3 months, the primary outcome measure—response rate based on HDRS-24 score—did not differ significantly between the active and control groups (15% vs 10%, respectively). There was, however, a significantly greater improvement in Inventory of Depressive Symptomatology-Self Report Scale scores with active VNS vs sham VNS.

Patients on sham treatment then were switched to active treatment and both groups were followed for 12 additional months, at which time response and remission rates nearly doubled for both groups.¹¹ In a post-hoc analysis, the same investigators found significant improvement with VNS compared with a naturalistic, matched control group with similar treatment-resistant depression.¹² The FDA considered this adequate to support efficacy and approved the device for chronic or recurrent treatment-resistant depression in an episode not responsive to at least 4 adequate treatment trials with pharmacotherapy or ECT. Perhaps because post-hoc analyses typically are not sufficient to gain FDA approval, most insurance companies do not reimburse for VNS treatment of depression, and VNS is not frequently used for refractory depression.

Table 3

Vagus nerve stimulation treatment parameters

A newer option: TMS

TMS is the most recently FDA-approved therapeutic neuromodulation technique for treating depression. In October 2008, a TMS device became available for patients failing to respond to 1 adequate antidepressant trial during the current episode.

TMS delivers intense, intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The pulse intensity is similar to that produced by MRI. The coil usually is placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC) and pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the adjacent cerebral cortex, as well as distal effects in other relevant neural circuits (Table 4). TMS typically is administered on an outpatient basis. A standard treatment course for depression consists of 5 treatment sessions per week for 4 to 8 weeks, depending on symptom severity and how quickly patients respond.

TMS initially was examined in several small, open-label studies that looked at various treatment parameters and stimulation sites. Several sham-controlled studies generally found TMS efficacious and further refined treatment administration. Its role in treating depression—and possibly other psychiatric disorders—has been supported by 2 recent meta-analyses.^13,14

O’Reardon et al¹⁵ conducted the largest double-blind trial of active vs sham TMS (N=301) for moderately treatment-resistant major depression. This study began with a 4- to 6-week, blinded, randomized phase followed by 6 weeks of open-label TMS for initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressants. This trial utilized the most aggressive treatment parameters to date (ie, 10 Hz; 75 4-second trains; 26-second inter-train interval; 120% motor threshold) delivering 3,000 pulses per treatment over an average of 24 sessions. Compared with the sham procedure, patients who received active TMS showed significantly higher response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, remission rate—defined as a MADRS score <10—was significantly higher in the active treatment group (14%) compared with the sham procedure (6%). A post-hoc analysis found that the most robust benefit occurred in patients with only 1 failed adequate antidepressant trial (effect size=0.83).¹⁶ This administration protocol was well tolerated, with no deaths or seizures and a low rate of discontinuation because of adverse events (5%).¹⁷ The most common adverse effects were application site pain or discomfort and headaches.

Recently, the second largest (N=190) sham-controlled trial of TMS for treatment-resistant major depression was published.¹⁸ This National Institute of Mental Health-sponsored, multiphase study included an initial 2-week, treatment-free period; 3 weeks of daily treatments over the left DLPFC using the same device and parameters as in the O’Reardon study; and an additional 3 weeks of treatment in patients who were improving. Those not responding to initial treatment were crossed over to open-label active TMS. This study advanced TMS development by:

• using a novel somatosensory system that produced similar sensations with sham and active TMS
• assessing the success of maintaining the blind
• establishing a rigorous clinical rating system
• utilizing MRI-guided adjustment of coil placement in a subset of patients.

The authors concluded that active TMS was significantly better than sham treatment in achieving remission (14% vs 5%). In addition, the raters, treaters, and patients were effectively blinded to the treatment condition. MRI-assisted coil placement found that in 33% of the sample, site placement determined by standardized assessment was over the premotor cortex rather than the prefrontal cortex, so the coil was moved 1 additional cm anteriorly in these patients. Similar to those observed by O’Reardon et al, adverse effects of active TMS were generally mild to moderate, did not differ by treatment condition, and led to a low discontinuation rate (5.5%).

Table 4

Treatment parameters of transcranial magnetic stimulation

Deep brain stimulation

DBS is a “functional neurosurgical” procedure that delivers electrical current directly to specific areas within the brain.¹⁹ Its mechanism of action remains uncertain; depolarization blockade, synaptic inhibition, and “neural jamming” are leading hypotheses. In contrast to conventional ablative surgeries, DBS is reversible and adjustable. Implantation involves positioning pacemaker-like battery devices subcutaneously in the left and right upper chest. Electrodes attached to wires are run subcutaneously behind the ears and, with stereotactic guidance, placed through burr holes in the skull into specific CNS areas implicated in the pathophysiology of conditions such as Parkinson’s disease, refractory depression, and severe obsessive-compulsive disorder (OCD).

Antidepressant effects. The FDA recently approved DBS under its humanitarian device exemption program for intractable, severe, disabling OCD based on promising results from open and blind trials that stimulated areas such as the internal capsule and adjacent ventral striatum.^20-22 These studies reported that DBS of the caudate nucleus for OCD and subthalamic nucleus for Parkinson’s disease also produced antidepressant effects. Subsequently, trials targeting the subgenual region (Brodmann’s area 25), the ventral capsule/ventral striatum, and nucleus accumbens demonstrated antidepressant effects.^23-27 Pending the results of ongoing pilot trials, large, multi-center studies using different devices and target areas are being planned to clarify the role of DBS for patients with severe, disabling, refractory depression.

Adverse effects of DBS can be:

• surgical-related (eg, seizure, bleeding, infection)
• device-related (eg, lead breakage, malfunction)
• stimulation-related (eg, paresthesia, dysarthria, memory disruption, cognitive changes, psychiatric symptoms).

The most serious risk is intracranial bleeding, which occurs in 2% to 3% of patients. Clearly, the risk-benefit ratio must be carefully considered.

Cost and reimbursement

Cost of treatment and potential for third-party reimbursement are important considerations for any risk-benefit analysis. Many patients who seek neuromodulation treatments will not have insurance or other coverage entitlements.^28-30 Further, newer treatments are not routinely covered by insurance; however, individual case coverage may be allowed and some device manufacturers have programs to assist providers and patients obtain coverage.^28-30 Even ECT, which has long been a covered treatment for major depression, is still considered investigational for other disorders. Thus, it is important to pre-certify with the patient’s health insurance provider before initiating treatment.

Coverage, however, is not the only consideration when weighing cost effectiveness. Economic studies can assist with clinical and ethical decisions relating to treatment choice.³¹ These studies, however, need to be critically evaluated (eg, what costs were included in the analysis). Although direct costs are easier to evaluate, indirect costs—such as the patient’s ability to continue to work while receiving the treatment, caretaker availability during treatment, and whether treatment is an inpatient or outpatient procedure—are more difficult to evaluate and should be discussed with the patient. Because these specialized options have the potential to further benefit patients with depression and other neuropsychiatric disorders, it is essential to balance the pressures of cost containment with the need for more effective and better tolerated treatments.^32-34

Related Resource

• Brunoni AR, Teng CT, Correa C, et al. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Arq Neuropsiquiatr. 2010;68(3):433-451.

Drug Brand Names

• Lithium • Eskalith, Lithobid
• Nortriptyline • Aventyl, Pamelor

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/therapeutic-neuromodulation.html#comments

The brain is an electrochemical organ, and its activity can be modulated for therapeutic purposes by electrical, pharmacologic, or combined approaches. In general, neuromodulation induces electrical current in peripheral or central nervous tissue, which is accomplished by various techniques, including:

• electroconvulsive therapy (ECT)
• vagus nerve stimulation (VNS)
• transcranial magnetic stimulation (TMS)
• deep brain stimulation (DBS).

It is thought that therapeutic benefit occurs by regulating functional disturbances in relevant distributed neural circuits.¹ Depending on the stimulation method, the frequencies chosen may excite or inhibit different or the same areas of the brain in varying patterns. Unlike medication, neuromodulation impacts the brain episodically, which may mitigate adaptation to the therapy’s beneficial effects and avoid systemic adverse effects.

Neuromodulation techniques are categorized based on their risk level as invasive or noninvasive and seizurogenic or nonseizurogenic (Table 1). Although these and other approaches are being considered for various neuropsychiatric disorders (Table 2), the most common application is for severe, treatment-resistant depression. Therefore, this article focuses on FDA-approved neuromodulation treatments for depression, with limited discussion of other indications.

Table 1

Therapeutic neuromodulation: Categorization based on risk

Table 2

Approved and investigational indications of neuromodulation

ECT: Oldest and most effective

ECT has remained the most effective therapeutic neuromodulation technique for more than 7 decades. It is indicated primarily for severe depressive episodes (eg, psychotic, melancholic), particularly in older patients.

ECT delivers electrical current to the CNS that is sufficient to produce a seizure. Under modified conditions, a typical course of 6 to 12 sessions can resolve severe depressive episodes and may also benefit other disorders, such as bipolar mania and acute psychosis. Although ECT is potentially life-saving, its use was markedly curtailed with the advent of effective antidepressants in the 1950s. Multiple factors impede its use, including:

• access and expertise are limited in many areas
• cognition is at least temporarily adversely affected
• relapse rates after acute benefit are high
• cost
• public perception often is negative.

Studies are addressing several of these concerns. For example, the National Institute of Mental Health-sponsored Consortium on Research with ECT (CORE) group is considering how to more effectively maintain acute benefits of ECT. They compared the potential merits of maintenance ECT with maintenance pharmacotherapy (nortriptyline plus lithium) over 6 months. Although the 2 strategies had comparable results, retention rates were <50% and about one-third relapsed in both groups.^2,3 Potential alternative strategies include a more frequent ECT maintenance schedule and/or combining maintenance ECT with medication(s).

Magnetic seizure therapy (MST) and focal electrically administered seizure therapy (FEAST) are attempts to produce similar efficacy and less cognitive disruption compared with ECT.^4,5 Work also continues on electrode placement (eg, bifrontal) and alteration of waveform characteristics (eg, ultra-brief) to maintain or enhance efficacy while minimizing adverse effects.^6,7

Stimulating the vagus nerve

VNS was introduced for treating refractory epilepsy in 1997. In 2005, it became the first FDA-approved implantable device for managing chronic or recurrent treatment-resistant depression.

The vagus nerve is the principal parasympathetic, efferent tract regulating heart rate, intestinal motility, and gastric acid secretion. Information about pain, hunger, and satiety is conveyed by these fibers to the median raphe nucleus and locus coeruleus, brain regions with significant serotonergic and noradrenergic innervation. These neurotransmitters also are believed to play a pivotal role in major depression.

With VNS, a pacemaker-like pulse generator is surgically implanted subcutaneously in the patient’s upper left chest. Wires extend from this device to the left vagus nerve (80% of whose fibers are afferent) located in the neck, to which the pulse generator sends electrical signals every few seconds (Table 3). The right vagus nerve is not used because it provides parasympathetic innervation to the heart. A clinician adjusts stimulation parameters using a computer and a noninvasive handheld device. Common adverse effects include voice alteration or hoarseness, cough, and shortness of breath, which occur during active stimulation because of the proximity of the electrodes to the laryngeal and pharyngeal branches of the vagus nerve. These effects may improve by adjusting stimulation intensity. The device permits a wide range of duty cycles, but preclinical animal studies indicate that >50% activation periods may damage the vagus nerve. If patients become too uncomfortable, they may deactivate the device with a magnet held over the implantation area.

Two open-label studies evaluated VNS to treat major depression. The first involved 10 weeks of stimulation in 59 subjects with chronic or recurrent, nonpsychotic, unipolar or bipolar depression who failed at least 2 adequate antidepressant trials in the current episode.⁸ Stable doses of concomitant antidepressants or mood stabilizers were allowed. After 3 months, 18 (31%) patients responded within an average of 45.5 days, and nearly 15% achieved remission. Response was defined as 50% reduction in baseline Hamilton Depression Rating Scale-28 (HDRS-28) score; remission was defined as HDRS-28 score ≤10. Further, clinical response did not differ between unipolar and bipolar depression patients.

In the second trial, 74 patients with treatment-resistant depression received fixed dose antidepressants and VNS for 3 months, followed by 9 months of flexibly dosed VNS and antidepressants.⁹ At 3 months, response (≥50% reduction in HDRS-28 score) and remission (HDRS-28 score <10) rates were 37% and 17%, respectively, and increased to 53% and 33% at 1 year.

A sham-controlled trial of VNS in 235 depressed patients used similar inclusion and exclusion criteria as in the open-label study by Sackeim et al.^8,10 Two weeks after device implantation, patients were randomized to active treatment (stimulator turned on) or sham control (stimulator left off). At 3 months, the primary outcome measure—response rate based on HDRS-24 score—did not differ significantly between the active and control groups (15% vs 10%, respectively). There was, however, a significantly greater improvement in Inventory of Depressive Symptomatology-Self Report Scale scores with active VNS vs sham VNS.

Patients on sham treatment then were switched to active treatment and both groups were followed for 12 additional months, at which time response and remission rates nearly doubled for both groups.¹¹ In a post-hoc analysis, the same investigators found significant improvement with VNS compared with a naturalistic, matched control group with similar treatment-resistant depression.¹² The FDA considered this adequate to support efficacy and approved the device for chronic or recurrent treatment-resistant depression in an episode not responsive to at least 4 adequate treatment trials with pharmacotherapy or ECT. Perhaps because post-hoc analyses typically are not sufficient to gain FDA approval, most insurance companies do not reimburse for VNS treatment of depression, and VNS is not frequently used for refractory depression.

Table 3

Vagus nerve stimulation treatment parameters

A newer option: TMS

TMS is the most recently FDA-approved therapeutic neuromodulation technique for treating depression. In October 2008, a TMS device became available for patients failing to respond to 1 adequate antidepressant trial during the current episode.

TMS delivers intense, intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The pulse intensity is similar to that produced by MRI. The coil usually is placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC) and pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the adjacent cerebral cortex, as well as distal effects in other relevant neural circuits (Table 4). TMS typically is administered on an outpatient basis. A standard treatment course for depression consists of 5 treatment sessions per week for 4 to 8 weeks, depending on symptom severity and how quickly patients respond.

TMS initially was examined in several small, open-label studies that looked at various treatment parameters and stimulation sites. Several sham-controlled studies generally found TMS efficacious and further refined treatment administration. Its role in treating depression—and possibly other psychiatric disorders—has been supported by 2 recent meta-analyses.^13,14

O’Reardon et al¹⁵ conducted the largest double-blind trial of active vs sham TMS (N=301) for moderately treatment-resistant major depression. This study began with a 4- to 6-week, blinded, randomized phase followed by 6 weeks of open-label TMS for initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressants. This trial utilized the most aggressive treatment parameters to date (ie, 10 Hz; 75 4-second trains; 26-second inter-train interval; 120% motor threshold) delivering 3,000 pulses per treatment over an average of 24 sessions. Compared with the sham procedure, patients who received active TMS showed significantly higher response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, remission rate—defined as a MADRS score <10—was significantly higher in the active treatment group (14%) compared with the sham procedure (6%). A post-hoc analysis found that the most robust benefit occurred in patients with only 1 failed adequate antidepressant trial (effect size=0.83).¹⁶ This administration protocol was well tolerated, with no deaths or seizures and a low rate of discontinuation because of adverse events (5%).¹⁷ The most common adverse effects were application site pain or discomfort and headaches.

Recently, the second largest (N=190) sham-controlled trial of TMS for treatment-resistant major depression was published.¹⁸ This National Institute of Mental Health-sponsored, multiphase study included an initial 2-week, treatment-free period; 3 weeks of daily treatments over the left DLPFC using the same device and parameters as in the O’Reardon study; and an additional 3 weeks of treatment in patients who were improving. Those not responding to initial treatment were crossed over to open-label active TMS. This study advanced TMS development by:

• using a novel somatosensory system that produced similar sensations with sham and active TMS
• assessing the success of maintaining the blind
• establishing a rigorous clinical rating system
• utilizing MRI-guided adjustment of coil placement in a subset of patients.

The authors concluded that active TMS was significantly better than sham treatment in achieving remission (14% vs 5%). In addition, the raters, treaters, and patients were effectively blinded to the treatment condition. MRI-assisted coil placement found that in 33% of the sample, site placement determined by standardized assessment was over the premotor cortex rather than the prefrontal cortex, so the coil was moved 1 additional cm anteriorly in these patients. Similar to those observed by O’Reardon et al, adverse effects of active TMS were generally mild to moderate, did not differ by treatment condition, and led to a low discontinuation rate (5.5%).

Table 4

Treatment parameters of transcranial magnetic stimulation

Deep brain stimulation

DBS is a “functional neurosurgical” procedure that delivers electrical current directly to specific areas within the brain.¹⁹ Its mechanism of action remains uncertain; depolarization blockade, synaptic inhibition, and “neural jamming” are leading hypotheses. In contrast to conventional ablative surgeries, DBS is reversible and adjustable. Implantation involves positioning pacemaker-like battery devices subcutaneously in the left and right upper chest. Electrodes attached to wires are run subcutaneously behind the ears and, with stereotactic guidance, placed through burr holes in the skull into specific CNS areas implicated in the pathophysiology of conditions such as Parkinson’s disease, refractory depression, and severe obsessive-compulsive disorder (OCD).

Antidepressant effects. The FDA recently approved DBS under its humanitarian device exemption program for intractable, severe, disabling OCD based on promising results from open and blind trials that stimulated areas such as the internal capsule and adjacent ventral striatum.^20-22 These studies reported that DBS of the caudate nucleus for OCD and subthalamic nucleus for Parkinson’s disease also produced antidepressant effects. Subsequently, trials targeting the subgenual region (Brodmann’s area 25), the ventral capsule/ventral striatum, and nucleus accumbens demonstrated antidepressant effects.^23-27 Pending the results of ongoing pilot trials, large, multi-center studies using different devices and target areas are being planned to clarify the role of DBS for patients with severe, disabling, refractory depression.

Adverse effects of DBS can be:

• surgical-related (eg, seizure, bleeding, infection)
• device-related (eg, lead breakage, malfunction)
• stimulation-related (eg, paresthesia, dysarthria, memory disruption, cognitive changes, psychiatric symptoms).

The most serious risk is intracranial bleeding, which occurs in 2% to 3% of patients. Clearly, the risk-benefit ratio must be carefully considered.

Cost and reimbursement

Cost of treatment and potential for third-party reimbursement are important considerations for any risk-benefit analysis. Many patients who seek neuromodulation treatments will not have insurance or other coverage entitlements.^28-30 Further, newer treatments are not routinely covered by insurance; however, individual case coverage may be allowed and some device manufacturers have programs to assist providers and patients obtain coverage.^28-30 Even ECT, which has long been a covered treatment for major depression, is still considered investigational for other disorders. Thus, it is important to pre-certify with the patient’s health insurance provider before initiating treatment.

Coverage, however, is not the only consideration when weighing cost effectiveness. Economic studies can assist with clinical and ethical decisions relating to treatment choice.³¹ These studies, however, need to be critically evaluated (eg, what costs were included in the analysis). Although direct costs are easier to evaluate, indirect costs—such as the patient’s ability to continue to work while receiving the treatment, caretaker availability during treatment, and whether treatment is an inpatient or outpatient procedure—are more difficult to evaluate and should be discussed with the patient. Because these specialized options have the potential to further benefit patients with depression and other neuropsychiatric disorders, it is essential to balance the pressures of cost containment with the need for more effective and better tolerated treatments.^32-34

Related Resource

• Brunoni AR, Teng CT, Correa C, et al. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Arq Neuropsiquiatr. 2010;68(3):433-451.

Drug Brand Names

• Lithium • Eskalith, Lithobid
• Nortriptyline • Aventyl, Pamelor

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/depression-treatment-for-women-with.html#comments

Psychological distress among patients with breast cancer is common and is linked to worse clinical outcomes. Depressive and anxiety symptoms affect up to 40% of breast cancer patients,¹ and depression is associated with a higher relative risk of mortality in individuals with breast cancer.² Psychotropic medications and psychotherapy used to treat depression in patients without carcinoma also are appropriate and effective for breast cancer patients. However, some patients present distinct challenges to standard treatment. For example, growing evidence suggests that some selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen, a chemotherapeutic agent. This article discusses challenges in diagnosing and treating depression in breast cancer patients and reviews evidence supporting appropriate psychiatric care.

Increased vulnerability

In 10% to 30% of women, a breast cancer diagnosis may lead to increased vulnerability to depressive disorders, including adjustment disorders with depressed mood, major depressive disorder (MDD), and mood disorders related to general medical conditions.^3,4 The risk of developing a depressive disorder is highest in the year after receiving the breast cancer diagnosis.⁴

A woman’s risk of developing a depressive disorder may depend on the type of cancer treatment she receives. For example, breast asymmetry is common after breast conserving surgery. Waljee et al⁵ found that women with breast asymmetry had increased fears of cancer recurrence and more feelings of self-consciousness. More pronounced asymmetry led to a higher incidence of depressive symptoms. However, among 90 patients undergoing bilateral prophylactic mastectomy, the rate of depression had not changed 1 year after the procedure.⁶ Chemotherapy, particularly at high doses, is a risk factor for depression.^4,7,8

Self-blame for developing breast cancer can affect mood. In 2007, Friedman et al⁹ determined that higher levels of self-blame correlated with higher levels of depression and decreased quality of life. Women often blamed themselves for various reasons, including:

• poor coping skills
• anxiety about their health and treatments
• inability to express emotions
• delays in medical consultation.

Exacerbated symptoms and side effects. Women with depression often experience increased side effects from cancer treatments, and the subjective experience of these effects—including hot flashes, cognitive impairment, pain, and sexual dysfunction—likely is intensified.⁴ Somatic symptoms of depression may be exacerbated by cancer treatment side effects or mistaken for effects of the treatment. When somatic symptoms of depression are mistaken for treatment side effects, depression—and the opportunity to treat it—can be overlooked.¹⁰

Depression may be a risk factor for poor adherence to cancer treatment. In a quantitative review of studies correlating depression and medical treatment noncompliance, DiMatteo et al¹¹ determined that compared with nondepressed patients, those with depression were 3 times more likely to not adhere to treatment recommendations; this review was not limited to cancer patients. Depressive symptoms—notably poor concentration and amotivation—can create the impression that a patient is poorly adherent. Women with comorbid depression and breast cancer may have difficulty understanding treatment recommendations or remembering daily treatment goals.⁴

Appropriate screening tools

Factors that may increase a breast cancer patient’s risk for developing a psychiatric disorder are listed in Table 1.¹⁰ Many depression screening tools are available; below we describe 3 commonly used for patients with breast cancer.

The National Comprehensive Cancer Center Distress Thermometer allows patients to rate their overall distress level over the past week on a scale from 0 to 10, using a visual analogue.¹² The Distress Thermometer has been validated for several cancer populations and in different parts of the world. A score of 7 has both good sensitivity and specificity for detecting depression in breast cancer patients. Consider a complete psychiatric evaluation for patients with scores ≥7.¹³

The Profile of Mood States questionnaire¹⁴ is a reliable, valid 65-item questionnaire often used in studies of mood dysregulation and breast cancer. Subscales include depression-dejection, tension-anxiety, anger-hostility, confusion-bewilderment, vigor-activity, and fatigue-inertia. Using a 5-point Likert scale, patients rate their symptoms over the past week. Subscale scores are then added to a total mood disturbance score.^14,15

The Hospital Anxiety and Depression Scale (HADS) is a sensitive, reliable 14-item scale that is commonly used to study depression and anxiety in patients with breast cancer.¹⁶ HADS includes two 7-item subscales—anxiety and depression—and answers are scored on a 4-point Likert scale. Patients are asked to respond quickly and avoid thinking too long about their answers.

Table 1

Risk factors for psychiatric distress related to breast cancer

Psychotherapeutic options

Behavioral therapies can diminish symptoms of depression, according to a review of studies and practice guidelines on managing depression in cancer patients.¹⁷ Group interventions, in particular, can be valuable. Anderson et al¹⁸ found that group cohesion, member connectedness, and more sessions correlated with decreased psychological distress.

Psychoeducation aims to provide medical information and discuss cancer’s causes, prognosis, and treatment strategies. Group settings can help improve communication and problem-solving skills. In a randomized controlled trial (RCT) of 203 women with breast cancer, psychoeducational group treatment reduced depression, anger, and fatigue.¹⁹

Cognitive-behavioral therapy (CBT) helps patients identify and restructure negative thoughts and increase positive, adaptive behaviors. Hunter et al²⁰ noted significant improvement in depressed mood, anxiety, and sleep in 17 women experiencing menopausal symptoms who received group CBT after completing breast cancer treatment. In 1 study, 124 patients with metastatic breast cancer who received 8 weekly sessions of group CBT reported reduced depression and mood disturbance and improved self-esteem compared with a no-therapy control group.²¹

Supportive-expressive therapy (SET) is a manual-based therapy that focuses on increasing social support, improving symptom control, and enhancing communication between the patient and treatment team. Affective expression helps lead the therapist to issues that should be addressed. Evidence on the effectiveness of SET for patients with breast cancer is mixed. A study of 357 women with breast cancer who were randomly assigned to 12-week group SET or an educational control condition found no evidence that SET reduced distress.²² However, a trial of 485 women with advanced breast cancer who were randomly assigned to group SET plus relaxation therapy or relaxation therapy alone showed that SET improved quality of life, including protection against depression.²³

Mindfulness-based stress reduction (MBSR) is a standardized form of meditation and yoga. Clinicians teach patients visualization, breathing exercises, and meditation to help them become aware of the body’s reaction to stress and how to regulate it. In an RCT of 84 female breast cancer survivors, a 6-week MBSR program diminished depressive symptoms, improved physical functioning, and reduced fear of cancer recurrence.²⁴

Evidence for antidepressants

SSRIs. Expert consensus guidelines on treating depression in women recommend an SSRI as a first-line agent.²⁵ In RCTs, fluoxetine, paroxetine, and sertraline were more effective than placebo in treating depression and related symptoms specifically in women with breast cancer (Table 2).^26-28

The interaction between SSRIs and chemotherapy agents is a concern. Tamoxifen decreases the rate of death from breast cancer in hormone receptor positive breast cancers.²⁹ Endoxifen, a potent anti-estrogen, is an active metabolite of tamoxifen via cytochrome P450 (CYP) 2D6. Goetz et al³⁰ demonstrated that women with decreased or inhibited metabolism via CYP2D6 had significantly shorter times to breast cancer recurrence, compared with women with extensive CYP2D6 metabolism.

SSRIs can varyingly inhibit CYP2D6. In a prospective trial of 158 breast cancer patients receiving tamoxifen, paroxetine and fluoxetine were found to be strong inhibitors of CYP2D6 and led to low levels of endoxifen.³¹ In contrast, weaker inhibitors, including sertraline and citalopram, led to intermediate levels of endoxifen. In a retrospective cohort study, Kelly et al³² demonstrated that women treated with paroxetine, in combination with tamoxifen, had an increased risk of death compared with women treated with other SSRIs or venlafaxine and tamoxifen. They estimated that paroxetine use in women treated with tamoxifen would lead to 1 additional breast cancer death per 20 women within 5 years of discontinuing tamoxifen.

According to American Psychiatric Association practice guidelines for treatment of MDD, depressed breast cancer patients who receive tamoxifen generally should be treated with an antidepressant that has minimal effect on CYP2D6 metabolism, such as citalopram, escitalopram, venlafaxine, or desvenlafaxine.³³

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be used to treat depressive disorders. In addition, venlafaxine may be helpful in treating post-mastectomy pain syndrome. Approximately one-half of patients who undergo mastectomy or breast reconstruction may experience a postoperative pain syndrome.³⁴ The most common symptom is a burning, stabbing pain in the axilla, arm, and chest wall of the affected side. This pain is worsened by movement and is poorly responsive to opioids.³⁵

In a 10-week RCT of 13 patients with neuropathic pain after breast cancer treatment, venlafaxine significantly improved pain relief compared with placebo, although the drug did not affect depression or anxiety.³⁶ In a study of 100 patients given venlafaxine or placebo for 2 weeks starting the night before undergoing partial or radical mastectomy with axillary dissection, those receiving venlafaxine had a significantly lower incidence of pain in the chest wall, arm, and axillary region, and scores of pain with movement were decreased.³⁷ There was no difference in opioid usage between groups.

Tricyclic antidepressants have been demonstrated to be effective in breast cancer patients. Side effects—notably anticholinergic effects—limit their use as antidepressants, especially when compared with SSRI treatment. In a study that randomly assigned 179 women with breast cancer to paroxetine, 20 to 40 mg/d, or amitriptyline, 75 to 150 mg/d, anticholinergic effects were almost twice as frequent in the amitriptyline group (19%) compared with paroxetine (11%).³⁸ In a 4-week double-blind, placebo-controlled crossover trial of 15 breast cancer patients, amitriptyline significantly relieved neuropathic pain, but its adverse effects made most patients unwilling to use the medication regularly.³⁹

Table 2

Evidence supporting SSRI use in patients with breast cancer*

Related Resources

• American Cancer Society. www.cancer.org.
• National Comprehensive Cancer network. www.nccn.org.

Drug Brand Names

• Amitripyline • Elavil
• Citalopram • Celexa
• Desvenlafaxine • Pristiq
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Venlafaxine • Effexor

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/depression-treatment-for-women-with.html#comments

Psychological distress among patients with breast cancer is common and is linked to worse clinical outcomes. Depressive and anxiety symptoms affect up to 40% of breast cancer patients,¹ and depression is associated with a higher relative risk of mortality in individuals with breast cancer.² Psychotropic medications and psychotherapy used to treat depression in patients without carcinoma also are appropriate and effective for breast cancer patients. However, some patients present distinct challenges to standard treatment. For example, growing evidence suggests that some selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen, a chemotherapeutic agent. This article discusses challenges in diagnosing and treating depression in breast cancer patients and reviews evidence supporting appropriate psychiatric care.

Increased vulnerability

In 10% to 30% of women, a breast cancer diagnosis may lead to increased vulnerability to depressive disorders, including adjustment disorders with depressed mood, major depressive disorder (MDD), and mood disorders related to general medical conditions.^3,4 The risk of developing a depressive disorder is highest in the year after receiving the breast cancer diagnosis.⁴

A woman’s risk of developing a depressive disorder may depend on the type of cancer treatment she receives. For example, breast asymmetry is common after breast conserving surgery. Waljee et al⁵ found that women with breast asymmetry had increased fears of cancer recurrence and more feelings of self-consciousness. More pronounced asymmetry led to a higher incidence of depressive symptoms. However, among 90 patients undergoing bilateral prophylactic mastectomy, the rate of depression had not changed 1 year after the procedure.⁶ Chemotherapy, particularly at high doses, is a risk factor for depression.^4,7,8

Self-blame for developing breast cancer can affect mood. In 2007, Friedman et al⁹ determined that higher levels of self-blame correlated with higher levels of depression and decreased quality of life. Women often blamed themselves for various reasons, including:

• poor coping skills
• anxiety about their health and treatments
• inability to express emotions
• delays in medical consultation.

Exacerbated symptoms and side effects. Women with depression often experience increased side effects from cancer treatments, and the subjective experience of these effects—including hot flashes, cognitive impairment, pain, and sexual dysfunction—likely is intensified.⁴ Somatic symptoms of depression may be exacerbated by cancer treatment side effects or mistaken for effects of the treatment. When somatic symptoms of depression are mistaken for treatment side effects, depression—and the opportunity to treat it—can be overlooked.¹⁰

Depression may be a risk factor for poor adherence to cancer treatment. In a quantitative review of studies correlating depression and medical treatment noncompliance, DiMatteo et al¹¹ determined that compared with nondepressed patients, those with depression were 3 times more likely to not adhere to treatment recommendations; this review was not limited to cancer patients. Depressive symptoms—notably poor concentration and amotivation—can create the impression that a patient is poorly adherent. Women with comorbid depression and breast cancer may have difficulty understanding treatment recommendations or remembering daily treatment goals.⁴

Appropriate screening tools

Factors that may increase a breast cancer patient’s risk for developing a psychiatric disorder are listed in Table 1.¹⁰ Many depression screening tools are available; below we describe 3 commonly used for patients with breast cancer.

The National Comprehensive Cancer Center Distress Thermometer allows patients to rate their overall distress level over the past week on a scale from 0 to 10, using a visual analogue.¹² The Distress Thermometer has been validated for several cancer populations and in different parts of the world. A score of 7 has both good sensitivity and specificity for detecting depression in breast cancer patients. Consider a complete psychiatric evaluation for patients with scores ≥7.¹³

The Profile of Mood States questionnaire¹⁴ is a reliable, valid 65-item questionnaire often used in studies of mood dysregulation and breast cancer. Subscales include depression-dejection, tension-anxiety, anger-hostility, confusion-bewilderment, vigor-activity, and fatigue-inertia. Using a 5-point Likert scale, patients rate their symptoms over the past week. Subscale scores are then added to a total mood disturbance score.^14,15

The Hospital Anxiety and Depression Scale (HADS) is a sensitive, reliable 14-item scale that is commonly used to study depression and anxiety in patients with breast cancer.¹⁶ HADS includes two 7-item subscales—anxiety and depression—and answers are scored on a 4-point Likert scale. Patients are asked to respond quickly and avoid thinking too long about their answers.

Table 1

Risk factors for psychiatric distress related to breast cancer

Psychotherapeutic options

Behavioral therapies can diminish symptoms of depression, according to a review of studies and practice guidelines on managing depression in cancer patients.¹⁷ Group interventions, in particular, can be valuable. Anderson et al¹⁸ found that group cohesion, member connectedness, and more sessions correlated with decreased psychological distress.

Psychoeducation aims to provide medical information and discuss cancer’s causes, prognosis, and treatment strategies. Group settings can help improve communication and problem-solving skills. In a randomized controlled trial (RCT) of 203 women with breast cancer, psychoeducational group treatment reduced depression, anger, and fatigue.¹⁹

Cognitive-behavioral therapy (CBT) helps patients identify and restructure negative thoughts and increase positive, adaptive behaviors. Hunter et al²⁰ noted significant improvement in depressed mood, anxiety, and sleep in 17 women experiencing menopausal symptoms who received group CBT after completing breast cancer treatment. In 1 study, 124 patients with metastatic breast cancer who received 8 weekly sessions of group CBT reported reduced depression and mood disturbance and improved self-esteem compared with a no-therapy control group.²¹

Supportive-expressive therapy (SET) is a manual-based therapy that focuses on increasing social support, improving symptom control, and enhancing communication between the patient and treatment team. Affective expression helps lead the therapist to issues that should be addressed. Evidence on the effectiveness of SET for patients with breast cancer is mixed. A study of 357 women with breast cancer who were randomly assigned to 12-week group SET or an educational control condition found no evidence that SET reduced distress.²² However, a trial of 485 women with advanced breast cancer who were randomly assigned to group SET plus relaxation therapy or relaxation therapy alone showed that SET improved quality of life, including protection against depression.²³

Mindfulness-based stress reduction (MBSR) is a standardized form of meditation and yoga. Clinicians teach patients visualization, breathing exercises, and meditation to help them become aware of the body’s reaction to stress and how to regulate it. In an RCT of 84 female breast cancer survivors, a 6-week MBSR program diminished depressive symptoms, improved physical functioning, and reduced fear of cancer recurrence.²⁴

Evidence for antidepressants

SSRIs. Expert consensus guidelines on treating depression in women recommend an SSRI as a first-line agent.²⁵ In RCTs, fluoxetine, paroxetine, and sertraline were more effective than placebo in treating depression and related symptoms specifically in women with breast cancer (Table 2).^26-28

The interaction between SSRIs and chemotherapy agents is a concern. Tamoxifen decreases the rate of death from breast cancer in hormone receptor positive breast cancers.²⁹ Endoxifen, a potent anti-estrogen, is an active metabolite of tamoxifen via cytochrome P450 (CYP) 2D6. Goetz et al³⁰ demonstrated that women with decreased or inhibited metabolism via CYP2D6 had significantly shorter times to breast cancer recurrence, compared with women with extensive CYP2D6 metabolism.

SSRIs can varyingly inhibit CYP2D6. In a prospective trial of 158 breast cancer patients receiving tamoxifen, paroxetine and fluoxetine were found to be strong inhibitors of CYP2D6 and led to low levels of endoxifen.³¹ In contrast, weaker inhibitors, including sertraline and citalopram, led to intermediate levels of endoxifen. In a retrospective cohort study, Kelly et al³² demonstrated that women treated with paroxetine, in combination with tamoxifen, had an increased risk of death compared with women treated with other SSRIs or venlafaxine and tamoxifen. They estimated that paroxetine use in women treated with tamoxifen would lead to 1 additional breast cancer death per 20 women within 5 years of discontinuing tamoxifen.

According to American Psychiatric Association practice guidelines for treatment of MDD, depressed breast cancer patients who receive tamoxifen generally should be treated with an antidepressant that has minimal effect on CYP2D6 metabolism, such as citalopram, escitalopram, venlafaxine, or desvenlafaxine.³³

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be used to treat depressive disorders. In addition, venlafaxine may be helpful in treating post-mastectomy pain syndrome. Approximately one-half of patients who undergo mastectomy or breast reconstruction may experience a postoperative pain syndrome.³⁴ The most common symptom is a burning, stabbing pain in the axilla, arm, and chest wall of the affected side. This pain is worsened by movement and is poorly responsive to opioids.³⁵

In a 10-week RCT of 13 patients with neuropathic pain after breast cancer treatment, venlafaxine significantly improved pain relief compared with placebo, although the drug did not affect depression or anxiety.³⁶ In a study of 100 patients given venlafaxine or placebo for 2 weeks starting the night before undergoing partial or radical mastectomy with axillary dissection, those receiving venlafaxine had a significantly lower incidence of pain in the chest wall, arm, and axillary region, and scores of pain with movement were decreased.³⁷ There was no difference in opioid usage between groups.

Tricyclic antidepressants have been demonstrated to be effective in breast cancer patients. Side effects—notably anticholinergic effects—limit their use as antidepressants, especially when compared with SSRI treatment. In a study that randomly assigned 179 women with breast cancer to paroxetine, 20 to 40 mg/d, or amitriptyline, 75 to 150 mg/d, anticholinergic effects were almost twice as frequent in the amitriptyline group (19%) compared with paroxetine (11%).³⁸ In a 4-week double-blind, placebo-controlled crossover trial of 15 breast cancer patients, amitriptyline significantly relieved neuropathic pain, but its adverse effects made most patients unwilling to use the medication regularly.³⁹

Table 2

Evidence supporting SSRI use in patients with breast cancer*

Related Resources

• American Cancer Society. www.cancer.org.
• National Comprehensive Cancer network. www.nccn.org.

Drug Brand Names

• Amitripyline • Elavil
• Citalopram • Celexa
• Desvenlafaxine • Pristiq
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Venlafaxine • Effexor

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/depression-treatment-for-women-with.html#comments

Psychological distress among patients with breast cancer is common and is linked to worse clinical outcomes. Depressive and anxiety symptoms affect up to 40% of breast cancer patients,¹ and depression is associated with a higher relative risk of mortality in individuals with breast cancer.² Psychotropic medications and psychotherapy used to treat depression in patients without carcinoma also are appropriate and effective for breast cancer patients. However, some patients present distinct challenges to standard treatment. For example, growing evidence suggests that some selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen, a chemotherapeutic agent. This article discusses challenges in diagnosing and treating depression in breast cancer patients and reviews evidence supporting appropriate psychiatric care.

Increased vulnerability

In 10% to 30% of women, a breast cancer diagnosis may lead to increased vulnerability to depressive disorders, including adjustment disorders with depressed mood, major depressive disorder (MDD), and mood disorders related to general medical conditions.^3,4 The risk of developing a depressive disorder is highest in the year after receiving the breast cancer diagnosis.⁴

A woman’s risk of developing a depressive disorder may depend on the type of cancer treatment she receives. For example, breast asymmetry is common after breast conserving surgery. Waljee et al⁵ found that women with breast asymmetry had increased fears of cancer recurrence and more feelings of self-consciousness. More pronounced asymmetry led to a higher incidence of depressive symptoms. However, among 90 patients undergoing bilateral prophylactic mastectomy, the rate of depression had not changed 1 year after the procedure.⁶ Chemotherapy, particularly at high doses, is a risk factor for depression.^4,7,8

Self-blame for developing breast cancer can affect mood. In 2007, Friedman et al⁹ determined that higher levels of self-blame correlated with higher levels of depression and decreased quality of life. Women often blamed themselves for various reasons, including:

• poor coping skills
• anxiety about their health and treatments
• inability to express emotions
• delays in medical consultation.

Exacerbated symptoms and side effects. Women with depression often experience increased side effects from cancer treatments, and the subjective experience of these effects—including hot flashes, cognitive impairment, pain, and sexual dysfunction—likely is intensified.⁴ Somatic symptoms of depression may be exacerbated by cancer treatment side effects or mistaken for effects of the treatment. When somatic symptoms of depression are mistaken for treatment side effects, depression—and the opportunity to treat it—can be overlooked.¹⁰

Depression may be a risk factor for poor adherence to cancer treatment. In a quantitative review of studies correlating depression and medical treatment noncompliance, DiMatteo et al¹¹ determined that compared with nondepressed patients, those with depression were 3 times more likely to not adhere to treatment recommendations; this review was not limited to cancer patients. Depressive symptoms—notably poor concentration and amotivation—can create the impression that a patient is poorly adherent. Women with comorbid depression and breast cancer may have difficulty understanding treatment recommendations or remembering daily treatment goals.⁴

Appropriate screening tools

Factors that may increase a breast cancer patient’s risk for developing a psychiatric disorder are listed in Table 1.¹⁰ Many depression screening tools are available; below we describe 3 commonly used for patients with breast cancer.

The National Comprehensive Cancer Center Distress Thermometer allows patients to rate their overall distress level over the past week on a scale from 0 to 10, using a visual analogue.¹² The Distress Thermometer has been validated for several cancer populations and in different parts of the world. A score of 7 has both good sensitivity and specificity for detecting depression in breast cancer patients. Consider a complete psychiatric evaluation for patients with scores ≥7.¹³

The Profile of Mood States questionnaire¹⁴ is a reliable, valid 65-item questionnaire often used in studies of mood dysregulation and breast cancer. Subscales include depression-dejection, tension-anxiety, anger-hostility, confusion-bewilderment, vigor-activity, and fatigue-inertia. Using a 5-point Likert scale, patients rate their symptoms over the past week. Subscale scores are then added to a total mood disturbance score.^14,15

The Hospital Anxiety and Depression Scale (HADS) is a sensitive, reliable 14-item scale that is commonly used to study depression and anxiety in patients with breast cancer.¹⁶ HADS includes two 7-item subscales—anxiety and depression—and answers are scored on a 4-point Likert scale. Patients are asked to respond quickly and avoid thinking too long about their answers.

Table 1

Risk factors for psychiatric distress related to breast cancer

Psychotherapeutic options

Behavioral therapies can diminish symptoms of depression, according to a review of studies and practice guidelines on managing depression in cancer patients.¹⁷ Group interventions, in particular, can be valuable. Anderson et al¹⁸ found that group cohesion, member connectedness, and more sessions correlated with decreased psychological distress.

Psychoeducation aims to provide medical information and discuss cancer’s causes, prognosis, and treatment strategies. Group settings can help improve communication and problem-solving skills. In a randomized controlled trial (RCT) of 203 women with breast cancer, psychoeducational group treatment reduced depression, anger, and fatigue.¹⁹

Cognitive-behavioral therapy (CBT) helps patients identify and restructure negative thoughts and increase positive, adaptive behaviors. Hunter et al²⁰ noted significant improvement in depressed mood, anxiety, and sleep in 17 women experiencing menopausal symptoms who received group CBT after completing breast cancer treatment. In 1 study, 124 patients with metastatic breast cancer who received 8 weekly sessions of group CBT reported reduced depression and mood disturbance and improved self-esteem compared with a no-therapy control group.²¹

Supportive-expressive therapy (SET) is a manual-based therapy that focuses on increasing social support, improving symptom control, and enhancing communication between the patient and treatment team. Affective expression helps lead the therapist to issues that should be addressed. Evidence on the effectiveness of SET for patients with breast cancer is mixed. A study of 357 women with breast cancer who were randomly assigned to 12-week group SET or an educational control condition found no evidence that SET reduced distress.²² However, a trial of 485 women with advanced breast cancer who were randomly assigned to group SET plus relaxation therapy or relaxation therapy alone showed that SET improved quality of life, including protection against depression.²³

Mindfulness-based stress reduction (MBSR) is a standardized form of meditation and yoga. Clinicians teach patients visualization, breathing exercises, and meditation to help them become aware of the body’s reaction to stress and how to regulate it. In an RCT of 84 female breast cancer survivors, a 6-week MBSR program diminished depressive symptoms, improved physical functioning, and reduced fear of cancer recurrence.²⁴

Evidence for antidepressants

SSRIs. Expert consensus guidelines on treating depression in women recommend an SSRI as a first-line agent.²⁵ In RCTs, fluoxetine, paroxetine, and sertraline were more effective than placebo in treating depression and related symptoms specifically in women with breast cancer (Table 2).^26-28

The interaction between SSRIs and chemotherapy agents is a concern. Tamoxifen decreases the rate of death from breast cancer in hormone receptor positive breast cancers.²⁹ Endoxifen, a potent anti-estrogen, is an active metabolite of tamoxifen via cytochrome P450 (CYP) 2D6. Goetz et al³⁰ demonstrated that women with decreased or inhibited metabolism via CYP2D6 had significantly shorter times to breast cancer recurrence, compared with women with extensive CYP2D6 metabolism.

SSRIs can varyingly inhibit CYP2D6. In a prospective trial of 158 breast cancer patients receiving tamoxifen, paroxetine and fluoxetine were found to be strong inhibitors of CYP2D6 and led to low levels of endoxifen.³¹ In contrast, weaker inhibitors, including sertraline and citalopram, led to intermediate levels of endoxifen. In a retrospective cohort study, Kelly et al³² demonstrated that women treated with paroxetine, in combination with tamoxifen, had an increased risk of death compared with women treated with other SSRIs or venlafaxine and tamoxifen. They estimated that paroxetine use in women treated with tamoxifen would lead to 1 additional breast cancer death per 20 women within 5 years of discontinuing tamoxifen.

According to American Psychiatric Association practice guidelines for treatment of MDD, depressed breast cancer patients who receive tamoxifen generally should be treated with an antidepressant that has minimal effect on CYP2D6 metabolism, such as citalopram, escitalopram, venlafaxine, or desvenlafaxine.³³

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be used to treat depressive disorders. In addition, venlafaxine may be helpful in treating post-mastectomy pain syndrome. Approximately one-half of patients who undergo mastectomy or breast reconstruction may experience a postoperative pain syndrome.³⁴ The most common symptom is a burning, stabbing pain in the axilla, arm, and chest wall of the affected side. This pain is worsened by movement and is poorly responsive to opioids.³⁵

In a 10-week RCT of 13 patients with neuropathic pain after breast cancer treatment, venlafaxine significantly improved pain relief compared with placebo, although the drug did not affect depression or anxiety.³⁶ In a study of 100 patients given venlafaxine or placebo for 2 weeks starting the night before undergoing partial or radical mastectomy with axillary dissection, those receiving venlafaxine had a significantly lower incidence of pain in the chest wall, arm, and axillary region, and scores of pain with movement were decreased.³⁷ There was no difference in opioid usage between groups.

Tricyclic antidepressants have been demonstrated to be effective in breast cancer patients. Side effects—notably anticholinergic effects—limit their use as antidepressants, especially when compared with SSRI treatment. In a study that randomly assigned 179 women with breast cancer to paroxetine, 20 to 40 mg/d, or amitriptyline, 75 to 150 mg/d, anticholinergic effects were almost twice as frequent in the amitriptyline group (19%) compared with paroxetine (11%).³⁸ In a 4-week double-blind, placebo-controlled crossover trial of 15 breast cancer patients, amitriptyline significantly relieved neuropathic pain, but its adverse effects made most patients unwilling to use the medication regularly.³⁹

Table 2

Evidence supporting SSRI use in patients with breast cancer*

Related Resources

• American Cancer Society. www.cancer.org.
• National Comprehensive Cancer network. www.nccn.org.

Drug Brand Names

• Amitripyline • Elavil
• Citalopram • Celexa
• Desvenlafaxine • Pristiq
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Venlafaxine • Effexor

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/parricide-characteristics-of-sons-and.html#comments

Mr. B, age 37, is single and lives with his elderly mother. Since being diagnosed with schizophrenia in his early 20s, he has been intermittently compliant with antipsychotic therapy. When unmedicated, Mr. B develops paranoid delusions and becomes preoccupied with the idea that his mother is plotting to kill him. He has been hospitalized twice in the last 5 years for physical aggression toward his mother. In the last 10 years, Mr. B has been placed in several group homes, but when he takes his medications, he is able to convince his mother to allow him to live with her.

During his most recent stay in his mother’s home, Mr. B again stops taking his psychotropic medications and decompensates. His mother becomes concerned about her son’s paranoid behavior—such as trying to listen in on her telephone conversations and smelling his food before he eats it—and considers having her son involuntarily committed. One day, after she prepares Mr. B a sandwich, he decides the meat is poisoned. When his mother tries to convince him to eat the sandwich, Mr. B becomes enraged and stabs her 54 times with a kitchen knife.

Mr. B is arrested without resistance. He is adjudicated incompetent to stand trial and is restored to competency within 3 months. Mr. B is found not guilty by reason of insanity (NGRI) and is civilly committed to a state psychiatric facility.

Parricide—killing one’s parents—once was referred to as “the schizophrenic crime,”¹ but is now recognized as being more complex.² In the United States, parricides accounted for 2% of all homicides from 1976 to 1998,³ which is consistent with studies from France⁴ and the United Kingdom.⁵ Parricide’s scandalous nature has long attracted the public’s fascination (see this article at CurrentPsychiatry.com).

This article primarily focuses on the interplay of the diagnostic and demographic factors seen in adults who kill their biological parents but briefly notes differences seen in juvenile perpetrators and those who kill their stepparents. Knowledge of these characteristics can help clinicians identify and more safely manage patients who may be at risk of harming their parents.

Box

A limited evidence base

The common themes found in the literature on parricide should be interpreted cautiously because of the limitations of this research. The number of individuals assessed in these studies often is small, which limits the statistical power of the findings. Studies often are conducted in forensic hospitals, which excludes those who are imprisoned or commit suicide following the acts. Finally, most individuals studied were diagnosed with a psychiatric disorder after the crime, which makes it difficult to distinguish the primary illness from the crime’s effect on a person’s mental state. Additionally, some individuals may be tempted to exaggerate or feign psychiatric symptoms in an effort to be found NGRI or granted leniency during sentencing. Despite these limitations, several conclusions can be drawn from these investigations.

The sex of the victims and perpetrators needs to be carefully considered when reviewing characteristics of those who commit parricide. Killing a mother is matricide, and killing a father is patricide.

Sons who kill their parents

Men are more likely to kill their parents than women.^6-9 In a study of 5,488 cases of parricide in the United States, 4,738 (86%) of perpetrators were male.³ Common characteristics of men who commit parricide are listed in Table 1.^5,8,10-14

Matricide by sons. Although sons kill their fathers more often than their mothers,¹⁵ authors writing about parricide commonly focus on men who commit matricide. Wertham described sons who kill their mothers in terms of the “Orestes Complex,” which refers to ambivalent feelings toward the mother that ultimately manifest in homicidal rage. He noted that many matricides are committed with excessive force, occur in the bedroom, and are precipitated by trivial reasons. Wertham stated that these crimes represent the son’s unconscious hatred for his mother superimposed on sexual desire for her.¹⁶ Sigmund Freud argued that matricide served as a displacement defense against incestuous impulses.¹⁷

In 5 studies that looked at sons who killed their mothers (n=13 to 58),^5,10-13 most of which examined men residing in forensic hospitals after the crime, perpetrators were noted to be immature, dependent, and passive. In a study of 16 men with schizophrenia who committed matricide, subjects perceived themselves as “weak, small, inadequate, hopeless, doubtful about sexual identity, dependent, and unable to accept a separate, adult male role.”¹¹ Mothers generally were domineering, demanding, and possessive.

Based on our literature review, most men who committed matricide had a schizophrenia diagnosis (weighted mean 72%, range 50% to 100%); other diagnoses included depression and personality disorders. Many men were experiencing psychosis shortly before the crime, and their acts were influenced by persecutory delusions and/or auditory hallucinations. Approximately one-quarter of sons killed their mothers for altruistic reasons, such as to relieve actual or perceived suffering.

Nearly all men in these 5 studies were single and lived with their mothers before killing them, and many of the perpetrators’ fathers were absent. Mothers often were the only victims of their sons’ violent acts. In addition to delusional beliefs, sons were motivated to kill their mothers for various reasons, including threatened separation or minor arguments (eg, over food or money). Many of these homicides took place in the home. Sharp or blunt objects were the most common weapons, but guns and strangulation/asphyxiation also were used. Approximately one-half of the men used excessive violence; for example, 1 victim had 177 stab wounds. After the crimes, the perpetrators generally expressed remorse or relief.

Patricide by sons. Psychoanalysts may consider the Oedipal Complex to be the primary impetus for a son to commit patricide. By eliminating his father the son gains possession of his mother.¹⁸ Three studies looked at sons who killed their fathers; 2 examined 10 perpetrators residing in a forensic hospital after the crimes^8,14 and the third was based on coroners’ reports.¹⁰ Although the sons’ personality traits were not described, the fathers were noted to be “domineering and aggressive,” and their relationships with their sons were “cruel and unusual.”⁸ In our review of these studies, >50% of sons were diagnosed with schizophrenia (weighted mean 60%, range 49% to 80%). Many perpetrators exhibited psychotic symptoms, including delusions and hallucinations. In 1 study, 40% of sons with psychotic symptoms perceived their fathers as posing “threats of physical or psychological annihilation.”¹⁴

In 2 of these studies all of the sons were single or separated from their spouses.^8,14 Most killed only their fathers at the time of the act. Immediately before the crime, one-half of the fathers were consuming alcohol and/or arguing with their sons. Ninety percent of the fathers were killed by excessive violence. Following the acts, the sons described feeling “relief rather than remorse or guilt…leading to a feeling of freedom from the abnormal relationship.”¹⁴ One study noted that, in the course of legal proceedings, one-fifth were deemed competent to stand trial and the others were found to be incompetent and hospitalized.¹⁴

Table 1

Sons who kill their parents: Schizophrenia is common

Daughters who commit parricide

d’Orban and O’Connor conducted the only major study examining women who commit parricide,⁹ a retrospective evaluation of 17 women who killed a parent and were housed in a prison or hospital. The authors highlight the importance of delusional beliefs as a motive for parricide (Table 2).⁹

In a 1970 Japanese study of 21 women who killed parents or in-laws, half of the victims were mothers-in-law, but none were biological mothers.¹⁹ According to the authors, this finding suggests that relationships between Japanese women and their mothers-in-law often are particularly contentious; however, no research has examined this theory in the United States.

Matricide by daughters. In the d’Orban and O’Connor study,⁹ >80% of women who committed parricide killed their mothers. In general, the daughters were described as being “in mid-life, living alone with an elderly, domineering mother in marked social isolation.” The parent-child relationship was “characterized by mutual hostility and dependence.” Seventy-five percent of the daughters suffered from psychotic illness. Extreme violence often was used.

Patricide by daughters. Of the 3 women who killed their fathers in d’Orban and O’Connor’s study,⁹ none were psychotic. Furthermore, 2 women had no psychiatric diagnosis—the third had antisocial personality disorder—and “killed tyrannical fathers in response to prolonged parental violence.” One woman reported that she was forced into a long-term incestuous relationship before killing her father. The women who killed their fathers were younger (mean age 21.3) than those who killed their mothers (mean age 39.5).

Table 2

Daughters who kill their parents: Strained relationships

Other perpetrators and victims

Patricide is most often committed by adults²⁰; however, some important conclusions can be drawn regarding juveniles who kill their parents (Table 3).^21-27 The most common scenario is of adolescent boys who have no history of psychosis and kill their fathers in a burst of rage brought on by ongoing abuse from parents. These murders typically are followed by feelings of relief rather than remorse.^21-27

Stepparents often have a more challenging relationship with children than biological parents.²⁸ Research indicates that stepparents are more likely than biological parents to be killed by juvenile offenders.²⁹ Also, stepparent victims tended to be younger than biological parent victims.²⁹

Table 3

Characteristics of juveniles who kill their parents or stepparents

Clinical applications

Ask adult schizophrenia patients living with a parent about the quality of the relationship. If the relationship is characterized by conflict or abuse or if psychotic symptoms are present, assess for violent thoughts toward the parent. For patients with uncontrolled psychosis coupled with a contentious parental relationship, in addition to aggressively treating psychotic symptoms, consider initiating family therapy, anger management classes, group home placement, or involuntary hospitalization to lower the risk of parricide.

Related resources

• Heide KM, Boots DP. A comparative analysis of media reports of U.S. parricide cases with officially reported national crime data and the psychiatric and psychological literature. Int J Offender Ther Comp Criminol. 2007;51(6):646-675.
• Jacobs A. On matricide: myth, psychoanalysis, and the law of the mother. New York, NY: Columbia University Press; 2007.

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/parricide-characteristics-of-sons-and.html#comments

Mr. B, age 37, is single and lives with his elderly mother. Since being diagnosed with schizophrenia in his early 20s, he has been intermittently compliant with antipsychotic therapy. When unmedicated, Mr. B develops paranoid delusions and becomes preoccupied with the idea that his mother is plotting to kill him. He has been hospitalized twice in the last 5 years for physical aggression toward his mother. In the last 10 years, Mr. B has been placed in several group homes, but when he takes his medications, he is able to convince his mother to allow him to live with her.

During his most recent stay in his mother’s home, Mr. B again stops taking his psychotropic medications and decompensates. His mother becomes concerned about her son’s paranoid behavior—such as trying to listen in on her telephone conversations and smelling his food before he eats it—and considers having her son involuntarily committed. One day, after she prepares Mr. B a sandwich, he decides the meat is poisoned. When his mother tries to convince him to eat the sandwich, Mr. B becomes enraged and stabs her 54 times with a kitchen knife.

Mr. B is arrested without resistance. He is adjudicated incompetent to stand trial and is restored to competency within 3 months. Mr. B is found not guilty by reason of insanity (NGRI) and is civilly committed to a state psychiatric facility.

Parricide—killing one’s parents—once was referred to as “the schizophrenic crime,”¹ but is now recognized as being more complex.² In the United States, parricides accounted for 2% of all homicides from 1976 to 1998,³ which is consistent with studies from France⁴ and the United Kingdom.⁵ Parricide’s scandalous nature has long attracted the public’s fascination (see this article at CurrentPsychiatry.com).

This article primarily focuses on the interplay of the diagnostic and demographic factors seen in adults who kill their biological parents but briefly notes differences seen in juvenile perpetrators and those who kill their stepparents. Knowledge of these characteristics can help clinicians identify and more safely manage patients who may be at risk of harming their parents.

Box

A limited evidence base

The common themes found in the literature on parricide should be interpreted cautiously because of the limitations of this research. The number of individuals assessed in these studies often is small, which limits the statistical power of the findings. Studies often are conducted in forensic hospitals, which excludes those who are imprisoned or commit suicide following the acts. Finally, most individuals studied were diagnosed with a psychiatric disorder after the crime, which makes it difficult to distinguish the primary illness from the crime’s effect on a person’s mental state. Additionally, some individuals may be tempted to exaggerate or feign psychiatric symptoms in an effort to be found NGRI or granted leniency during sentencing. Despite these limitations, several conclusions can be drawn from these investigations.

The sex of the victims and perpetrators needs to be carefully considered when reviewing characteristics of those who commit parricide. Killing a mother is matricide, and killing a father is patricide.

Sons who kill their parents

Men are more likely to kill their parents than women.^6-9 In a study of 5,488 cases of parricide in the United States, 4,738 (86%) of perpetrators were male.³ Common characteristics of men who commit parricide are listed in Table 1.^5,8,10-14

Matricide by sons. Although sons kill their fathers more often than their mothers,¹⁵ authors writing about parricide commonly focus on men who commit matricide. Wertham described sons who kill their mothers in terms of the “Orestes Complex,” which refers to ambivalent feelings toward the mother that ultimately manifest in homicidal rage. He noted that many matricides are committed with excessive force, occur in the bedroom, and are precipitated by trivial reasons. Wertham stated that these crimes represent the son’s unconscious hatred for his mother superimposed on sexual desire for her.¹⁶ Sigmund Freud argued that matricide served as a displacement defense against incestuous impulses.¹⁷

In 5 studies that looked at sons who killed their mothers (n=13 to 58),^5,10-13 most of which examined men residing in forensic hospitals after the crime, perpetrators were noted to be immature, dependent, and passive. In a study of 16 men with schizophrenia who committed matricide, subjects perceived themselves as “weak, small, inadequate, hopeless, doubtful about sexual identity, dependent, and unable to accept a separate, adult male role.”¹¹ Mothers generally were domineering, demanding, and possessive.

Based on our literature review, most men who committed matricide had a schizophrenia diagnosis (weighted mean 72%, range 50% to 100%); other diagnoses included depression and personality disorders. Many men were experiencing psychosis shortly before the crime, and their acts were influenced by persecutory delusions and/or auditory hallucinations. Approximately one-quarter of sons killed their mothers for altruistic reasons, such as to relieve actual or perceived suffering.

Nearly all men in these 5 studies were single and lived with their mothers before killing them, and many of the perpetrators’ fathers were absent. Mothers often were the only victims of their sons’ violent acts. In addition to delusional beliefs, sons were motivated to kill their mothers for various reasons, including threatened separation or minor arguments (eg, over food or money). Many of these homicides took place in the home. Sharp or blunt objects were the most common weapons, but guns and strangulation/asphyxiation also were used. Approximately one-half of the men used excessive violence; for example, 1 victim had 177 stab wounds. After the crimes, the perpetrators generally expressed remorse or relief.

Patricide by sons. Psychoanalysts may consider the Oedipal Complex to be the primary impetus for a son to commit patricide. By eliminating his father the son gains possession of his mother.¹⁸ Three studies looked at sons who killed their fathers; 2 examined 10 perpetrators residing in a forensic hospital after the crimes^8,14 and the third was based on coroners’ reports.¹⁰ Although the sons’ personality traits were not described, the fathers were noted to be “domineering and aggressive,” and their relationships with their sons were “cruel and unusual.”⁸ In our review of these studies, >50% of sons were diagnosed with schizophrenia (weighted mean 60%, range 49% to 80%). Many perpetrators exhibited psychotic symptoms, including delusions and hallucinations. In 1 study, 40% of sons with psychotic symptoms perceived their fathers as posing “threats of physical or psychological annihilation.”¹⁴

In 2 of these studies all of the sons were single or separated from their spouses.^8,14 Most killed only their fathers at the time of the act. Immediately before the crime, one-half of the fathers were consuming alcohol and/or arguing with their sons. Ninety percent of the fathers were killed by excessive violence. Following the acts, the sons described feeling “relief rather than remorse or guilt…leading to a feeling of freedom from the abnormal relationship.”¹⁴ One study noted that, in the course of legal proceedings, one-fifth were deemed competent to stand trial and the others were found to be incompetent and hospitalized.¹⁴

Table 1

Sons who kill their parents: Schizophrenia is common

Daughters who commit parricide

d’Orban and O’Connor conducted the only major study examining women who commit parricide,⁹ a retrospective evaluation of 17 women who killed a parent and were housed in a prison or hospital. The authors highlight the importance of delusional beliefs as a motive for parricide (Table 2).⁹

In a 1970 Japanese study of 21 women who killed parents or in-laws, half of the victims were mothers-in-law, but none were biological mothers.¹⁹ According to the authors, this finding suggests that relationships between Japanese women and their mothers-in-law often are particularly contentious; however, no research has examined this theory in the United States.

Matricide by daughters. In the d’Orban and O’Connor study,⁹ >80% of women who committed parricide killed their mothers. In general, the daughters were described as being “in mid-life, living alone with an elderly, domineering mother in marked social isolation.” The parent-child relationship was “characterized by mutual hostility and dependence.” Seventy-five percent of the daughters suffered from psychotic illness. Extreme violence often was used.

Patricide by daughters. Of the 3 women who killed their fathers in d’Orban and O’Connor’s study,⁹ none were psychotic. Furthermore, 2 women had no psychiatric diagnosis—the third had antisocial personality disorder—and “killed tyrannical fathers in response to prolonged parental violence.” One woman reported that she was forced into a long-term incestuous relationship before killing her father. The women who killed their fathers were younger (mean age 21.3) than those who killed their mothers (mean age 39.5).

Table 2

Daughters who kill their parents: Strained relationships

Other perpetrators and victims

Patricide is most often committed by adults²⁰; however, some important conclusions can be drawn regarding juveniles who kill their parents (Table 3).^21-27 The most common scenario is of adolescent boys who have no history of psychosis and kill their fathers in a burst of rage brought on by ongoing abuse from parents. These murders typically are followed by feelings of relief rather than remorse.^21-27

Stepparents often have a more challenging relationship with children than biological parents.²⁸ Research indicates that stepparents are more likely than biological parents to be killed by juvenile offenders.²⁹ Also, stepparent victims tended to be younger than biological parent victims.²⁹

Table 3

Characteristics of juveniles who kill their parents or stepparents

Clinical applications

Ask adult schizophrenia patients living with a parent about the quality of the relationship. If the relationship is characterized by conflict or abuse or if psychotic symptoms are present, assess for violent thoughts toward the parent. For patients with uncontrolled psychosis coupled with a contentious parental relationship, in addition to aggressively treating psychotic symptoms, consider initiating family therapy, anger management classes, group home placement, or involuntary hospitalization to lower the risk of parricide.

Related resources

• Heide KM, Boots DP. A comparative analysis of media reports of U.S. parricide cases with officially reported national crime data and the psychiatric and psychological literature. Int J Offender Ther Comp Criminol. 2007;51(6):646-675.
• Jacobs A. On matricide: myth, psychoanalysis, and the law of the mother. New York, NY: Columbia University Press; 2007.

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/parricide-characteristics-of-sons-and.html#comments

Mr. B, age 37, is single and lives with his elderly mother. Since being diagnosed with schizophrenia in his early 20s, he has been intermittently compliant with antipsychotic therapy. When unmedicated, Mr. B develops paranoid delusions and becomes preoccupied with the idea that his mother is plotting to kill him. He has been hospitalized twice in the last 5 years for physical aggression toward his mother. In the last 10 years, Mr. B has been placed in several group homes, but when he takes his medications, he is able to convince his mother to allow him to live with her.

During his most recent stay in his mother’s home, Mr. B again stops taking his psychotropic medications and decompensates. His mother becomes concerned about her son’s paranoid behavior—such as trying to listen in on her telephone conversations and smelling his food before he eats it—and considers having her son involuntarily committed. One day, after she prepares Mr. B a sandwich, he decides the meat is poisoned. When his mother tries to convince him to eat the sandwich, Mr. B becomes enraged and stabs her 54 times with a kitchen knife.

Mr. B is arrested without resistance. He is adjudicated incompetent to stand trial and is restored to competency within 3 months. Mr. B is found not guilty by reason of insanity (NGRI) and is civilly committed to a state psychiatric facility.

Parricide—killing one’s parents—once was referred to as “the schizophrenic crime,”¹ but is now recognized as being more complex.² In the United States, parricides accounted for 2% of all homicides from 1976 to 1998,³ which is consistent with studies from France⁴ and the United Kingdom.⁵ Parricide’s scandalous nature has long attracted the public’s fascination (see this article at CurrentPsychiatry.com).

This article primarily focuses on the interplay of the diagnostic and demographic factors seen in adults who kill their biological parents but briefly notes differences seen in juvenile perpetrators and those who kill their stepparents. Knowledge of these characteristics can help clinicians identify and more safely manage patients who may be at risk of harming their parents.

Box

A limited evidence base

The common themes found in the literature on parricide should be interpreted cautiously because of the limitations of this research. The number of individuals assessed in these studies often is small, which limits the statistical power of the findings. Studies often are conducted in forensic hospitals, which excludes those who are imprisoned or commit suicide following the acts. Finally, most individuals studied were diagnosed with a psychiatric disorder after the crime, which makes it difficult to distinguish the primary illness from the crime’s effect on a person’s mental state. Additionally, some individuals may be tempted to exaggerate or feign psychiatric symptoms in an effort to be found NGRI or granted leniency during sentencing. Despite these limitations, several conclusions can be drawn from these investigations.

The sex of the victims and perpetrators needs to be carefully considered when reviewing characteristics of those who commit parricide. Killing a mother is matricide, and killing a father is patricide.

Sons who kill their parents

Men are more likely to kill their parents than women.^6-9 In a study of 5,488 cases of parricide in the United States, 4,738 (86%) of perpetrators were male.³ Common characteristics of men who commit parricide are listed in Table 1.^5,8,10-14

Matricide by sons. Although sons kill their fathers more often than their mothers,¹⁵ authors writing about parricide commonly focus on men who commit matricide. Wertham described sons who kill their mothers in terms of the “Orestes Complex,” which refers to ambivalent feelings toward the mother that ultimately manifest in homicidal rage. He noted that many matricides are committed with excessive force, occur in the bedroom, and are precipitated by trivial reasons. Wertham stated that these crimes represent the son’s unconscious hatred for his mother superimposed on sexual desire for her.¹⁶ Sigmund Freud argued that matricide served as a displacement defense against incestuous impulses.¹⁷

In 5 studies that looked at sons who killed their mothers (n=13 to 58),^5,10-13 most of which examined men residing in forensic hospitals after the crime, perpetrators were noted to be immature, dependent, and passive. In a study of 16 men with schizophrenia who committed matricide, subjects perceived themselves as “weak, small, inadequate, hopeless, doubtful about sexual identity, dependent, and unable to accept a separate, adult male role.”¹¹ Mothers generally were domineering, demanding, and possessive.

Based on our literature review, most men who committed matricide had a schizophrenia diagnosis (weighted mean 72%, range 50% to 100%); other diagnoses included depression and personality disorders. Many men were experiencing psychosis shortly before the crime, and their acts were influenced by persecutory delusions and/or auditory hallucinations. Approximately one-quarter of sons killed their mothers for altruistic reasons, such as to relieve actual or perceived suffering.

Nearly all men in these 5 studies were single and lived with their mothers before killing them, and many of the perpetrators’ fathers were absent. Mothers often were the only victims of their sons’ violent acts. In addition to delusional beliefs, sons were motivated to kill their mothers for various reasons, including threatened separation or minor arguments (eg, over food or money). Many of these homicides took place in the home. Sharp or blunt objects were the most common weapons, but guns and strangulation/asphyxiation also were used. Approximately one-half of the men used excessive violence; for example, 1 victim had 177 stab wounds. After the crimes, the perpetrators generally expressed remorse or relief.

Patricide by sons. Psychoanalysts may consider the Oedipal Complex to be the primary impetus for a son to commit patricide. By eliminating his father the son gains possession of his mother.¹⁸ Three studies looked at sons who killed their fathers; 2 examined 10 perpetrators residing in a forensic hospital after the crimes^8,14 and the third was based on coroners’ reports.¹⁰ Although the sons’ personality traits were not described, the fathers were noted to be “domineering and aggressive,” and their relationships with their sons were “cruel and unusual.”⁸ In our review of these studies, >50% of sons were diagnosed with schizophrenia (weighted mean 60%, range 49% to 80%). Many perpetrators exhibited psychotic symptoms, including delusions and hallucinations. In 1 study, 40% of sons with psychotic symptoms perceived their fathers as posing “threats of physical or psychological annihilation.”¹⁴

In 2 of these studies all of the sons were single or separated from their spouses.^8,14 Most killed only their fathers at the time of the act. Immediately before the crime, one-half of the fathers were consuming alcohol and/or arguing with their sons. Ninety percent of the fathers were killed by excessive violence. Following the acts, the sons described feeling “relief rather than remorse or guilt…leading to a feeling of freedom from the abnormal relationship.”¹⁴ One study noted that, in the course of legal proceedings, one-fifth were deemed competent to stand trial and the others were found to be incompetent and hospitalized.¹⁴

Table 1

Sons who kill their parents: Schizophrenia is common

Daughters who commit parricide

d’Orban and O’Connor conducted the only major study examining women who commit parricide,⁹ a retrospective evaluation of 17 women who killed a parent and were housed in a prison or hospital. The authors highlight the importance of delusional beliefs as a motive for parricide (Table 2).⁹

In a 1970 Japanese study of 21 women who killed parents or in-laws, half of the victims were mothers-in-law, but none were biological mothers.¹⁹ According to the authors, this finding suggests that relationships between Japanese women and their mothers-in-law often are particularly contentious; however, no research has examined this theory in the United States.

Matricide by daughters. In the d’Orban and O’Connor study,⁹ >80% of women who committed parricide killed their mothers. In general, the daughters were described as being “in mid-life, living alone with an elderly, domineering mother in marked social isolation.” The parent-child relationship was “characterized by mutual hostility and dependence.” Seventy-five percent of the daughters suffered from psychotic illness. Extreme violence often was used.

Patricide by daughters. Of the 3 women who killed their fathers in d’Orban and O’Connor’s study,⁹ none were psychotic. Furthermore, 2 women had no psychiatric diagnosis—the third had antisocial personality disorder—and “killed tyrannical fathers in response to prolonged parental violence.” One woman reported that she was forced into a long-term incestuous relationship before killing her father. The women who killed their fathers were younger (mean age 21.3) than those who killed their mothers (mean age 39.5).

Table 2

Daughters who kill their parents: Strained relationships

Other perpetrators and victims

Patricide is most often committed by adults²⁰; however, some important conclusions can be drawn regarding juveniles who kill their parents (Table 3).^21-27 The most common scenario is of adolescent boys who have no history of psychosis and kill their fathers in a burst of rage brought on by ongoing abuse from parents. These murders typically are followed by feelings of relief rather than remorse.^21-27

Stepparents often have a more challenging relationship with children than biological parents.²⁸ Research indicates that stepparents are more likely than biological parents to be killed by juvenile offenders.²⁹ Also, stepparent victims tended to be younger than biological parent victims.²⁹

Table 3

Characteristics of juveniles who kill their parents or stepparents

Clinical applications

Ask adult schizophrenia patients living with a parent about the quality of the relationship. If the relationship is characterized by conflict or abuse or if psychotic symptoms are present, assess for violent thoughts toward the parent. For patients with uncontrolled psychosis coupled with a contentious parental relationship, in addition to aggressively treating psychotic symptoms, consider initiating family therapy, anger management classes, group home placement, or involuntary hospitalization to lower the risk of parricide.

Related resources

• Heide KM, Boots DP. A comparative analysis of media reports of U.S. parricide cases with officially reported national crime data and the psychiatric and psychological literature. Int J Offender Ther Comp Criminol. 2007;51(6):646-675.
• Jacobs A. On matricide: myth, psychoanalysis, and the law of the mother. New York, NY: Columbia University Press; 2007.

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/10/hallucinations-in-children-diagnostic.html#comments

Hallucinations in children are of grave concern to parents and clinicians, but aren’t necessarily a symptom of mental illness. In adults, hallucinations usually are linked to serious psychopathology; however, in children they are not uncommon and may be part of normal development (Box).

A hallucination is a false auditory, visual, gustatory, tactile, or olfactory perception not associated with real external stimuli.¹ It must be differentiated from similar phenomenon such as illusions (misperception of actual stimuli), elaborate fantasies, imaginary companions, and eidetic images (visual images stored in memory).

Box

Common, yet a cause for concern

Epidemiologic studies show 2.8% of adults report hallucinations before age 21.² Nonpsychotic children as young as age 5 have reported hallucinations.³ Hallucinatory phenomenon may be present in 8% to 21% of all 11-year-old children; two-thirds of these patients have no DSM-IV-TR diagnosis.^4,5 However, 1 evaluation of 62 nonpsychotic hallucinating children treated in a psychiatric emergency department (ED):

• 34% had depression
• 22% had attention-deficit/hyperactivity disorder (ADHD)
• 21% had disruptive behavior disorders
• 23% had other diagnoses.⁶

Studies suggest that children who have hallucinations but no other psychotic symptoms have a better long-term prognosis than those with additional psychotic symptoms.⁷ A 17-year longitudinal study of children with hallucinations and concurrent emotional and conduct problems found:

• up to 50% of patients still experience hallucinations at age 30
• hallucinations did not significantly predict clinical outcome at age 30
• childhood hallucinations did not increase the risk for psychosis, depression, organic brain disorder, or other psychiatric illnesses.⁷

In a study of children with psychosis and disruptive disorders, at 2- to 8-years follow-up 50% met criteria for major depressive disorder, bipolar disorder, or schizophreniform disorders.⁸ In a 15-year longitudinal study of 11-year-olds, self-reported psychotic symptoms—such as delusional beliefs and hallucinatory experiences—predicted a high risk of schizophreniform disorder at age 26.⁹ These studies suggest that experiencing significant disruptions in thoughts and perceptions during childhood may be related to later development of prominent mood and thought disorders.

Differential diagnosis

Table 1 lists possible causes of hallucination in children.^6,10-13 Hallucinations during childhood can occur in the context of several psychiatric disorders, including:

• schizophrenia
• schizophreniform disorders
• mood disorders with psychotic features (Table 2).¹⁴

They can also manifest as comorbid or associated symptoms of disorders not commonly associated with hallucinations, such as ADHD, disruptive disorders, anxiety disorders, and prodromal clinical states. Medications, substance use, and organic and metabolic disorders also must be considered in the differential diagnosis (Table 3).

Hallucinations may occur in low-functioning or anxious children, in the context of psychosocial adversity or abuse, and during bereavement of a deceased parent when the surviving parent is emotionally unavailable.^11-13,15-17 Rule out hypnagogic and hypnopompic hallucinations, which are predominantly visual hallucinations that occur immediately before falling asleep and during the transition from sleep to wakefulness, respectively.¹⁸ Rarely, a child who has had hallucinations for some time may learn to complain of them when he or she is not hallucinating in order to obtain a primary or secondary gain, such as getting attention from caregivers.

Little is known about psychosis and hallucinations in preschoolers (age ≤5); therefore, their language use may help assessment. Because of cognitive immaturity, children often use illogical thinking and loose association and may describe their thoughts as “voices.” This is common in children with language disorders—and sometimes in healthy patients—who may talk about voices because they cannot describe their own thoughts.

Children with ADHD and/or oppositional defiant disorder often are impulsive and show poor judgment and may blame voices for telling them to do bad things. These “hallucinations” may represent internal thoughts battling with the child’s conscience.⁶ Auditory and visual hallucinations have been reported in children with Tourette syndrome, especially when associated with ADHD or obsessive-compulsive disorder.¹⁹

Medical causes. Electrolyte disturbances, metabolic disorders, fever, and serious infections are common nonpsychiatric causes of hallucinations.²⁰ Brain neoplasm—particularly in visual association areas, the temporal lobe, or portions of the optic nerve or retina—also may produce hallucinations, which can be complex with full images.²¹

Medications such as steroids and anticholinergics may cause hallucinations. Case studies report visual and tactile hallucinations with methylphenidate therapy that resolve after discontinuing the medication.²² Illicit substances, including cannabis, lysergic acid diethylamide (LSD), cocaine, amphetamines, 3,4-methylenedioxymeth-amphetamine (ecstasy), opiates, and barbiturates, can induce hallucinations.

Suspect substance-induced hallucinations if your patient shows:

• acute onset of hallucinations
• dilated pupils
• extreme agitation or drowsiness
• other signs of intoxication.

Hallucinations caused by seizure disorders are rare but can be somatosensory, visual (occipital lobe focus), auditory, olfactory (uncinate, complex partial), or gustatory. The hallucinations may be unformed (flashing lights or rushing noises) or formed (images, spoken words, or music) and could be part of the aura arising from the temporal lobe (dreamlike, flashbacks). Command hallucinations are rare and adult and pediatric patients usually sense they are not real.²³

Migraines occur in approximately 5% of prepubertal children and often are comorbid with affective and anxiety disorders.²⁴ Hallucinations associated with migraine commonly are visual, but gustatory, olfactory, and auditory hallucinations also can occur, with or without headaches.³ Any hallucination associated with headaches should be investigated neurologically. Other diagnostic aspects of hallucinations to consider while interviewing children are listed in Table 4.^25-28

Table 1

Possible causes of hallucinations in children and adolescents

Table 2

Content of hallucinations may point to their cause

Table 3

Hallucinations in young patients: Differential diagnoses

Table 4

Diagnostic considerations when assessing a hallucinating child

Psychotic disorder not otherwise specified

(NOS) in children often is overused and misused. One reason could be that DSM-IV-TR does not have a category for hallucinations in nonpsychotic children or for children who are at risk for psychosis. However, recommendations regarding the diagnosis of psychotic disorder NOS note it:

• may be used if uncertainty persists after ruling out all other diagnoses
• should be avoided when hallucinations occur in nonpsychotic children
• should not be used longitudinally if a clinician later determines a specific disorder accounts for the hallucinations.²⁹

Treatment

Addressing underlying medical or psychiatric illness, including substance use, is primary. Some adolescents or children may think that cannabis use is relatively benign. Discuss the risks of cannabis use in an age-appropriate manner.

In the ED. Children or adolescents who present with hallucinations in the ED should undergo a thorough evaluation that explores the differential diagnoses. Suggestions for evaluating patients in this setting appear in Table 5.²¹

Prodromal or at-risk children. There is no consensus on how early to initiate treatment for children in the prodromal stages of psychosis. Early identification and treatment is imperative because duration of untreated psychosis (DUP) is a primary predictor of treatment response in first-admission patients, and longer DUP corresponds to poorer prognosis in children.³⁰

Assessment scales for early identification of psychosis have limitations because most are not standardized for use in children age <14. To assess symptoms and predict future psychosis in children consider using:

• Scale of Prodromal Symptoms
• Structured Interview for Prodromal Symptoms
• Comprehensive Assessment of At-Risk Mental States
• Bonn Scale for the Assessment of Basic Symptoms.

A hallucinating child may be considered prodromal if he or she has:

• 30% drop in Global Assessment Functioning score in the past month
• a first-degree relative with affective or nonaffective psychotic disorder or schizotypal personality disorder.³¹

Antipsychotics. When treating children, use antipsychotics with caution and consider short- and long-term risks and benefits. Early treatment is indicated when hallucinations are among a patient’s psychotic symptoms; however, antipsychotic use for children in the prodromal phase lacks consensus. McGlashan et al³² showed that in 60 high-risk patients (mean age 16), olanzapine, 5 to 15 mg/d, reduced conversion to psychosis by 50% over 6 months. McGorry et al³³ observed that in 59 ultra-high risk patients (mean age 20), adding low-dose risperidone (1 to 2 mg/d) and cognitive-behavioral therapy (CBT) was superior to case management and supportive psychotherapy in preventing psychosis after 6 months of treatment, but this difference was not maintained at 6 months of follow-up.

CBT slows progression to psychosis in ultra-high risk patients and reduces positive symptoms more specifically than it improves emotional dysfunction.³⁴ CBT for psychosis is based on the concept that auditory hallucinations have an underlying personalized meaning or cognitive schema.³⁵ The initial goal of treatment is to engage the child and understand:

• What do the hallucinations mean to the patient?
• How did they start?
• Can the child start or stop them?
• What does the patient think they are?

The clinician then strives to help the child identify alternative explanations for these hallucinations and develop coping strategies.³⁶ “Normalizing” the voices helps the child attribute these voices to a less anxiety-provoking cause.³⁷ Consider suggesting common reasons for the hallucinations, such as:

• lack of sleep
• isolation
• dehydration
• extreme stress
• strong thoughts (obsessions)
• fever and illness
• lack of food
• drugs and alcohol.

If your patient learns that any of these reasons could explain the hallucinations, he or she may start to have a less delusional understanding of them. Suggest that the voices are “real” only if your patient believes it.

Help children develop coping strategies to control auditory hallucinations such as:

• humming
• listening to music
• reading (forwards and backwards)
• talking to others
• exercising
• singing
• medication
• ignoring the voices.

With normalization and other coping strategies, children with visual hallucinations can learn to transform in their mind the frightful image to a funnier one, which is less anxiety-provoking and gives them a sense of control.

Table 5

Suggestions for evaluating hallucinating children in the ED

Related Resources

• Bartels-Velthuis AA, Jenner JA, van de Willige G, et al. Prevalence and correlates of auditory vocal hallucinations in middle childhood. Br J Psychiatry. 2010;196(1):41-46.
• Cepeda C. Psychotic symptoms in children and adolescents: assessment, differential diagnosis, and treatment. New York, NY: Routledge; 2007.

Drug Brand Names

• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Risperidone • Risperdal

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/10/hallucinations-in-children-diagnostic.html#comments

Hallucinations in children are of grave concern to parents and clinicians, but aren’t necessarily a symptom of mental illness. In adults, hallucinations usually are linked to serious psychopathology; however, in children they are not uncommon and may be part of normal development (Box).

A hallucination is a false auditory, visual, gustatory, tactile, or olfactory perception not associated with real external stimuli.¹ It must be differentiated from similar phenomenon such as illusions (misperception of actual stimuli), elaborate fantasies, imaginary companions, and eidetic images (visual images stored in memory).

Box

Common, yet a cause for concern

Epidemiologic studies show 2.8% of adults report hallucinations before age 21.² Nonpsychotic children as young as age 5 have reported hallucinations.³ Hallucinatory phenomenon may be present in 8% to 21% of all 11-year-old children; two-thirds of these patients have no DSM-IV-TR diagnosis.^4,5 However, 1 evaluation of 62 nonpsychotic hallucinating children treated in a psychiatric emergency department (ED):

• 34% had depression
• 22% had attention-deficit/hyperactivity disorder (ADHD)
• 21% had disruptive behavior disorders
• 23% had other diagnoses.⁶

Studies suggest that children who have hallucinations but no other psychotic symptoms have a better long-term prognosis than those with additional psychotic symptoms.⁷ A 17-year longitudinal study of children with hallucinations and concurrent emotional and conduct problems found:

• up to 50% of patients still experience hallucinations at age 30
• hallucinations did not significantly predict clinical outcome at age 30
• childhood hallucinations did not increase the risk for psychosis, depression, organic brain disorder, or other psychiatric illnesses.⁷

In a study of children with psychosis and disruptive disorders, at 2- to 8-years follow-up 50% met criteria for major depressive disorder, bipolar disorder, or schizophreniform disorders.⁸ In a 15-year longitudinal study of 11-year-olds, self-reported psychotic symptoms—such as delusional beliefs and hallucinatory experiences—predicted a high risk of schizophreniform disorder at age 26.⁹ These studies suggest that experiencing significant disruptions in thoughts and perceptions during childhood may be related to later development of prominent mood and thought disorders.

Differential diagnosis

Table 1 lists possible causes of hallucination in children.^6,10-13 Hallucinations during childhood can occur in the context of several psychiatric disorders, including:

• schizophrenia
• schizophreniform disorders
• mood disorders with psychotic features (Table 2).¹⁴

They can also manifest as comorbid or associated symptoms of disorders not commonly associated with hallucinations, such as ADHD, disruptive disorders, anxiety disorders, and prodromal clinical states. Medications, substance use, and organic and metabolic disorders also must be considered in the differential diagnosis (Table 3).

Hallucinations may occur in low-functioning or anxious children, in the context of psychosocial adversity or abuse, and during bereavement of a deceased parent when the surviving parent is emotionally unavailable.^11-13,15-17 Rule out hypnagogic and hypnopompic hallucinations, which are predominantly visual hallucinations that occur immediately before falling asleep and during the transition from sleep to wakefulness, respectively.¹⁸ Rarely, a child who has had hallucinations for some time may learn to complain of them when he or she is not hallucinating in order to obtain a primary or secondary gain, such as getting attention from caregivers.

Little is known about psychosis and hallucinations in preschoolers (age ≤5); therefore, their language use may help assessment. Because of cognitive immaturity, children often use illogical thinking and loose association and may describe their thoughts as “voices.” This is common in children with language disorders—and sometimes in healthy patients—who may talk about voices because they cannot describe their own thoughts.

Children with ADHD and/or oppositional defiant disorder often are impulsive and show poor judgment and may blame voices for telling them to do bad things. These “hallucinations” may represent internal thoughts battling with the child’s conscience.⁶ Auditory and visual hallucinations have been reported in children with Tourette syndrome, especially when associated with ADHD or obsessive-compulsive disorder.¹⁹

Medical causes. Electrolyte disturbances, metabolic disorders, fever, and serious infections are common nonpsychiatric causes of hallucinations.²⁰ Brain neoplasm—particularly in visual association areas, the temporal lobe, or portions of the optic nerve or retina—also may produce hallucinations, which can be complex with full images.²¹

Medications such as steroids and anticholinergics may cause hallucinations. Case studies report visual and tactile hallucinations with methylphenidate therapy that resolve after discontinuing the medication.²² Illicit substances, including cannabis, lysergic acid diethylamide (LSD), cocaine, amphetamines, 3,4-methylenedioxymeth-amphetamine (ecstasy), opiates, and barbiturates, can induce hallucinations.

Suspect substance-induced hallucinations if your patient shows:

• acute onset of hallucinations
• dilated pupils
• extreme agitation or drowsiness
• other signs of intoxication.

Hallucinations caused by seizure disorders are rare but can be somatosensory, visual (occipital lobe focus), auditory, olfactory (uncinate, complex partial), or gustatory. The hallucinations may be unformed (flashing lights or rushing noises) or formed (images, spoken words, or music) and could be part of the aura arising from the temporal lobe (dreamlike, flashbacks). Command hallucinations are rare and adult and pediatric patients usually sense they are not real.²³

Migraines occur in approximately 5% of prepubertal children and often are comorbid with affective and anxiety disorders.²⁴ Hallucinations associated with migraine commonly are visual, but gustatory, olfactory, and auditory hallucinations also can occur, with or without headaches.³ Any hallucination associated with headaches should be investigated neurologically. Other diagnostic aspects of hallucinations to consider while interviewing children are listed in Table 4.^25-28

Table 1

Possible causes of hallucinations in children and adolescents

Table 2

Content of hallucinations may point to their cause

Table 3

Hallucinations in young patients: Differential diagnoses

Table 4

Diagnostic considerations when assessing a hallucinating child

Psychotic disorder not otherwise specified

(NOS) in children often is overused and misused. One reason could be that DSM-IV-TR does not have a category for hallucinations in nonpsychotic children or for children who are at risk for psychosis. However, recommendations regarding the diagnosis of psychotic disorder NOS note it:

• may be used if uncertainty persists after ruling out all other diagnoses
• should be avoided when hallucinations occur in nonpsychotic children
• should not be used longitudinally if a clinician later determines a specific disorder accounts for the hallucinations.²⁹

Treatment

Addressing underlying medical or psychiatric illness, including substance use, is primary. Some adolescents or children may think that cannabis use is relatively benign. Discuss the risks of cannabis use in an age-appropriate manner.

In the ED. Children or adolescents who present with hallucinations in the ED should undergo a thorough evaluation that explores the differential diagnoses. Suggestions for evaluating patients in this setting appear in Table 5.²¹

Prodromal or at-risk children. There is no consensus on how early to initiate treatment for children in the prodromal stages of psychosis. Early identification and treatment is imperative because duration of untreated psychosis (DUP) is a primary predictor of treatment response in first-admission patients, and longer DUP corresponds to poorer prognosis in children.³⁰

Assessment scales for early identification of psychosis have limitations because most are not standardized for use in children age <14. To assess symptoms and predict future psychosis in children consider using:

• Scale of Prodromal Symptoms
• Structured Interview for Prodromal Symptoms
• Comprehensive Assessment of At-Risk Mental States
• Bonn Scale for the Assessment of Basic Symptoms.

A hallucinating child may be considered prodromal if he or she has:

• 30% drop in Global Assessment Functioning score in the past month
• a first-degree relative with affective or nonaffective psychotic disorder or schizotypal personality disorder.³¹

Antipsychotics. When treating children, use antipsychotics with caution and consider short- and long-term risks and benefits. Early treatment is indicated when hallucinations are among a patient’s psychotic symptoms; however, antipsychotic use for children in the prodromal phase lacks consensus. McGlashan et al³² showed that in 60 high-risk patients (mean age 16), olanzapine, 5 to 15 mg/d, reduced conversion to psychosis by 50% over 6 months. McGorry et al³³ observed that in 59 ultra-high risk patients (mean age 20), adding low-dose risperidone (1 to 2 mg/d) and cognitive-behavioral therapy (CBT) was superior to case management and supportive psychotherapy in preventing psychosis after 6 months of treatment, but this difference was not maintained at 6 months of follow-up.

CBT slows progression to psychosis in ultra-high risk patients and reduces positive symptoms more specifically than it improves emotional dysfunction.³⁴ CBT for psychosis is based on the concept that auditory hallucinations have an underlying personalized meaning or cognitive schema.³⁵ The initial goal of treatment is to engage the child and understand:

• What do the hallucinations mean to the patient?
• How did they start?
• Can the child start or stop them?
• What does the patient think they are?

The clinician then strives to help the child identify alternative explanations for these hallucinations and develop coping strategies.³⁶ “Normalizing” the voices helps the child attribute these voices to a less anxiety-provoking cause.³⁷ Consider suggesting common reasons for the hallucinations, such as:

• lack of sleep
• isolation
• dehydration
• extreme stress
• strong thoughts (obsessions)
• fever and illness
• lack of food
• drugs and alcohol.

If your patient learns that any of these reasons could explain the hallucinations, he or she may start to have a less delusional understanding of them. Suggest that the voices are “real” only if your patient believes it.

Help children develop coping strategies to control auditory hallucinations such as:

• humming
• listening to music
• reading (forwards and backwards)
• talking to others
• exercising
• singing
• medication
• ignoring the voices.

With normalization and other coping strategies, children with visual hallucinations can learn to transform in their mind the frightful image to a funnier one, which is less anxiety-provoking and gives them a sense of control.

Table 5

Suggestions for evaluating hallucinating children in the ED

Related Resources

• Bartels-Velthuis AA, Jenner JA, van de Willige G, et al. Prevalence and correlates of auditory vocal hallucinations in middle childhood. Br J Psychiatry. 2010;196(1):41-46.
• Cepeda C. Psychotic symptoms in children and adolescents: assessment, differential diagnosis, and treatment. New York, NY: Routledge; 2007.

Drug Brand Names

• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Risperidone • Risperdal

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/10/hallucinations-in-children-diagnostic.html#comments

Hallucinations in children are of grave concern to parents and clinicians, but aren’t necessarily a symptom of mental illness. In adults, hallucinations usually are linked to serious psychopathology; however, in children they are not uncommon and may be part of normal development (Box).

A hallucination is a false auditory, visual, gustatory, tactile, or olfactory perception not associated with real external stimuli.¹ It must be differentiated from similar phenomenon such as illusions (misperception of actual stimuli), elaborate fantasies, imaginary companions, and eidetic images (visual images stored in memory).

Box

Common, yet a cause for concern

Epidemiologic studies show 2.8% of adults report hallucinations before age 21.² Nonpsychotic children as young as age 5 have reported hallucinations.³ Hallucinatory phenomenon may be present in 8% to 21% of all 11-year-old children; two-thirds of these patients have no DSM-IV-TR diagnosis.^4,5 However, 1 evaluation of 62 nonpsychotic hallucinating children treated in a psychiatric emergency department (ED):

• 34% had depression
• 22% had attention-deficit/hyperactivity disorder (ADHD)
• 21% had disruptive behavior disorders
• 23% had other diagnoses.⁶

Studies suggest that children who have hallucinations but no other psychotic symptoms have a better long-term prognosis than those with additional psychotic symptoms.⁷ A 17-year longitudinal study of children with hallucinations and concurrent emotional and conduct problems found:

• up to 50% of patients still experience hallucinations at age 30
• hallucinations did not significantly predict clinical outcome at age 30
• childhood hallucinations did not increase the risk for psychosis, depression, organic brain disorder, or other psychiatric illnesses.⁷

In a study of children with psychosis and disruptive disorders, at 2- to 8-years follow-up 50% met criteria for major depressive disorder, bipolar disorder, or schizophreniform disorders.⁸ In a 15-year longitudinal study of 11-year-olds, self-reported psychotic symptoms—such as delusional beliefs and hallucinatory experiences—predicted a high risk of schizophreniform disorder at age 26.⁹ These studies suggest that experiencing significant disruptions in thoughts and perceptions during childhood may be related to later development of prominent mood and thought disorders.

Differential diagnosis

Table 1 lists possible causes of hallucination in children.^6,10-13 Hallucinations during childhood can occur in the context of several psychiatric disorders, including:

• schizophrenia
• schizophreniform disorders
• mood disorders with psychotic features (Table 2).¹⁴

They can also manifest as comorbid or associated symptoms of disorders not commonly associated with hallucinations, such as ADHD, disruptive disorders, anxiety disorders, and prodromal clinical states. Medications, substance use, and organic and metabolic disorders also must be considered in the differential diagnosis (Table 3).

Hallucinations may occur in low-functioning or anxious children, in the context of psychosocial adversity or abuse, and during bereavement of a deceased parent when the surviving parent is emotionally unavailable.^11-13,15-17 Rule out hypnagogic and hypnopompic hallucinations, which are predominantly visual hallucinations that occur immediately before falling asleep and during the transition from sleep to wakefulness, respectively.¹⁸ Rarely, a child who has had hallucinations for some time may learn to complain of them when he or she is not hallucinating in order to obtain a primary or secondary gain, such as getting attention from caregivers.

Little is known about psychosis and hallucinations in preschoolers (age ≤5); therefore, their language use may help assessment. Because of cognitive immaturity, children often use illogical thinking and loose association and may describe their thoughts as “voices.” This is common in children with language disorders—and sometimes in healthy patients—who may talk about voices because they cannot describe their own thoughts.

Children with ADHD and/or oppositional defiant disorder often are impulsive and show poor judgment and may blame voices for telling them to do bad things. These “hallucinations” may represent internal thoughts battling with the child’s conscience.⁶ Auditory and visual hallucinations have been reported in children with Tourette syndrome, especially when associated with ADHD or obsessive-compulsive disorder.¹⁹

Medical causes. Electrolyte disturbances, metabolic disorders, fever, and serious infections are common nonpsychiatric causes of hallucinations.²⁰ Brain neoplasm—particularly in visual association areas, the temporal lobe, or portions of the optic nerve or retina—also may produce hallucinations, which can be complex with full images.²¹

Medications such as steroids and anticholinergics may cause hallucinations. Case studies report visual and tactile hallucinations with methylphenidate therapy that resolve after discontinuing the medication.²² Illicit substances, including cannabis, lysergic acid diethylamide (LSD), cocaine, amphetamines, 3,4-methylenedioxymeth-amphetamine (ecstasy), opiates, and barbiturates, can induce hallucinations.

Suspect substance-induced hallucinations if your patient shows:

• acute onset of hallucinations
• dilated pupils
• extreme agitation or drowsiness
• other signs of intoxication.

Hallucinations caused by seizure disorders are rare but can be somatosensory, visual (occipital lobe focus), auditory, olfactory (uncinate, complex partial), or gustatory. The hallucinations may be unformed (flashing lights or rushing noises) or formed (images, spoken words, or music) and could be part of the aura arising from the temporal lobe (dreamlike, flashbacks). Command hallucinations are rare and adult and pediatric patients usually sense they are not real.²³

Migraines occur in approximately 5% of prepubertal children and often are comorbid with affective and anxiety disorders.²⁴ Hallucinations associated with migraine commonly are visual, but gustatory, olfactory, and auditory hallucinations also can occur, with or without headaches.³ Any hallucination associated with headaches should be investigated neurologically. Other diagnostic aspects of hallucinations to consider while interviewing children are listed in Table 4.^25-28

Table 1

Possible causes of hallucinations in children and adolescents

Table 2

Content of hallucinations may point to their cause

Table 3

Hallucinations in young patients: Differential diagnoses

Table 4

Diagnostic considerations when assessing a hallucinating child

Psychotic disorder not otherwise specified

(NOS) in children often is overused and misused. One reason could be that DSM-IV-TR does not have a category for hallucinations in nonpsychotic children or for children who are at risk for psychosis. However, recommendations regarding the diagnosis of psychotic disorder NOS note it:

• may be used if uncertainty persists after ruling out all other diagnoses
• should be avoided when hallucinations occur in nonpsychotic children
• should not be used longitudinally if a clinician later determines a specific disorder accounts for the hallucinations.²⁹

Treatment

Addressing underlying medical or psychiatric illness, including substance use, is primary. Some adolescents or children may think that cannabis use is relatively benign. Discuss the risks of cannabis use in an age-appropriate manner.

In the ED. Children or adolescents who present with hallucinations in the ED should undergo a thorough evaluation that explores the differential diagnoses. Suggestions for evaluating patients in this setting appear in Table 5.²¹

Prodromal or at-risk children. There is no consensus on how early to initiate treatment for children in the prodromal stages of psychosis. Early identification and treatment is imperative because duration of untreated psychosis (DUP) is a primary predictor of treatment response in first-admission patients, and longer DUP corresponds to poorer prognosis in children.³⁰

Assessment scales for early identification of psychosis have limitations because most are not standardized for use in children age <14. To assess symptoms and predict future psychosis in children consider using:

• Scale of Prodromal Symptoms
• Structured Interview for Prodromal Symptoms
• Comprehensive Assessment of At-Risk Mental States
• Bonn Scale for the Assessment of Basic Symptoms.

A hallucinating child may be considered prodromal if he or she has:

• 30% drop in Global Assessment Functioning score in the past month
• a first-degree relative with affective or nonaffective psychotic disorder or schizotypal personality disorder.³¹

Antipsychotics. When treating children, use antipsychotics with caution and consider short- and long-term risks and benefits. Early treatment is indicated when hallucinations are among a patient’s psychotic symptoms; however, antipsychotic use for children in the prodromal phase lacks consensus. McGlashan et al³² showed that in 60 high-risk patients (mean age 16), olanzapine, 5 to 15 mg/d, reduced conversion to psychosis by 50% over 6 months. McGorry et al³³ observed that in 59 ultra-high risk patients (mean age 20), adding low-dose risperidone (1 to 2 mg/d) and cognitive-behavioral therapy (CBT) was superior to case management and supportive psychotherapy in preventing psychosis after 6 months of treatment, but this difference was not maintained at 6 months of follow-up.

CBT slows progression to psychosis in ultra-high risk patients and reduces positive symptoms more specifically than it improves emotional dysfunction.³⁴ CBT for psychosis is based on the concept that auditory hallucinations have an underlying personalized meaning or cognitive schema.³⁵ The initial goal of treatment is to engage the child and understand:

• What do the hallucinations mean to the patient?
• How did they start?
• Can the child start or stop them?
• What does the patient think they are?

The clinician then strives to help the child identify alternative explanations for these hallucinations and develop coping strategies.³⁶ “Normalizing” the voices helps the child attribute these voices to a less anxiety-provoking cause.³⁷ Consider suggesting common reasons for the hallucinations, such as:

• lack of sleep
• isolation
• dehydration
• extreme stress
• strong thoughts (obsessions)
• fever and illness
• lack of food
• drugs and alcohol.

If your patient learns that any of these reasons could explain the hallucinations, he or she may start to have a less delusional understanding of them. Suggest that the voices are “real” only if your patient believes it.

Help children develop coping strategies to control auditory hallucinations such as:

• humming
• listening to music
• reading (forwards and backwards)
• talking to others
• exercising
• singing
• medication
• ignoring the voices.

With normalization and other coping strategies, children with visual hallucinations can learn to transform in their mind the frightful image to a funnier one, which is less anxiety-provoking and gives them a sense of control.

Table 5

Suggestions for evaluating hallucinating children in the ED

Related Resources

• Bartels-Velthuis AA, Jenner JA, van de Willige G, et al. Prevalence and correlates of auditory vocal hallucinations in middle childhood. Br J Psychiatry. 2010;196(1):41-46.
• Cepeda C. Psychotic symptoms in children and adolescents: assessment, differential diagnosis, and treatment. New York, NY: Routledge; 2007.

Drug Brand Names

• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Risperidone • Risperdal

Disclosure

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