Current Psychiatry

In the United States, >50% of psychiatric inpatients have vitamin D deficiency—<30 nmol/L (<12 ng/mL).¹ A growing body of literature has found associations between vitamin D deficiency and psychiatric illnesses, particularly depression. Several randomized controlled trials (RCTs) have demonstrated that vitamin D supplementation can benefit depression symptoms. In this article, we discuss the current literature on vitamin D and psychiatric illness, and provide practical information for clinicians on the use of vitamin D supplementation.

Biosynthesis of vitamin D

Biosynthesis of vitamin D begins with the sterol provitamin D₃ molecule 7-dehydrocholesterol (Figure).² When skin is exposed to sunlight, 7-dehydrocholesterol absorbs UV radiation and forms provitamin D₃, which undergoes rapid transformation to vitamin D₃.² Vitamin D₃ is released from the plasma membrane and enters systemic circulation in a protein-bound form that has a serum half-life of 36 to 78 hours.³ Vitamin D₃ can be taken up by adipocytes and stored in fat deposits, where it has a half-life of approximately 2 months.⁴

Figure: Biosynthesis of vitamin D
Provitamin D₃ (7-dehydrocholesterol) in the skin absorbs UV radiation and undergoes isomerization to form vitamin D₃. Endogenously produced vitamin D₃ along with dietary vitamin D₂ and vitamin D₃ absorbed in the gastrointestinal tract are metabolized in the liver to 25-hydroxyvitamin D (25[OH]D), which re-enters the circulation and is metabolized in the kidney and other tissues to the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D). Catabolism of 25(OH)D and 1,25(OH)2D into biologically-inactive molecules is primarily mediated by the cytochrome P450 (CYP) enzymes CYP24 and CYP3A4.
Source: Reference 2Circulating vitamin D₃ is metabolized in the liver by the enzyme vitamin D-25-hydroxylase to 25-hydroxyvitamin D (25[OH]D₃), which has a serum half-life of approximately 15 days.⁴ Circulating 25(OH)D₃ is not biologically active at the physiological level, and requires activation by conversion to 1,25-dihydroxyvitamin D (1,25[OH]2D₃) in the kidneys by the enzyme 25(OH)D-1α-hydroxylase. Production of 1,25(OH)2D₃ is regulated by serum phosphorus and parathyroid hormone levels and other factors.⁵ Catabolism of 1,25(OH)2D₃ is rapid, with a serum half-life of 3.5 to 21 hours.⁶ Vitamin D₂ is structurally similar to vitamin D₃, but occurs primarily in fungi, yeasts, and some invertebrates.

Risk factors for deficiency

A patient’s vitamin D status is determined by measuring 25(OH)D (Box 1). Risk factors for vitamin D deficiency include conditions that affect cutaneous production (insufficient sunlight exposure), obesity, gastrointestinal disorders, aging, renal disorders, and medications (Table 1). ^2,5,7,8 The link between sunscreen use, either alone or in cosmetics, and vitamin D deficiency continues to be debated. While controlled studies have found that application of sunscreen with high sun protection factor can significantly reduce vitamin D production, ⁹ studies in clinical populations have failed to confirm these findings. ^10,11 See Box 2 for a discussion of these risk factors and Box 3 for a discussion of acute and long-term medical manifestations of deficiency.

Box 1

Table 1

Risk factors associated with vitamin D deficiency

Box 2

Box 3

Vitamin D’s role in the brain

Vitamin D’s role in psychiatric illnesses is suggested by region-specific expression of vitamin D receptors (VDR) in the cingulate cortex, thalamus, cerebellum, amygdala, and hippocampus.¹² Most of these regions also express 1α-hydroxylase enzymes capable of metabolizing 25(OH)D to 1,25(OH)2D₃, which suggests that vitamin D may have an autocrine or paracrine function in brain.¹³

Vitamin D regulates expression of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, norepinephrine, and epinephrine.¹⁴ Vitamin D also promotes survival of monoaminergic neurons through upregulation of glial cell line-derived neurotrophic factor, which supports survival of midbrain dopaminergic neurons and confers resistance to neurotoxins that deplete dopaminergic neurons in Parkinson’s disease.¹⁵ Vitamin D also promotes neuronal survival by inhibiting oxidative pathways in the brain through inhibition of inducible nitric oxide synthase (reducing free radical formation)¹⁶ and upregulation of γ-glutamyl transpeptidase (increasing antioxidant production).¹⁷ Vitamin D may play a neuroprotective role through regulation of calcium channels. In vitro studies have shown that vitamin D downregulates expression of L-type calcium channels, conferring protection against excitatory neurotoxins in cultured neurons.¹⁸ Proteomic analysis of brain tissue in a rat model of developmental vitamin D revealed dysregulation of 36 brain proteins involved in many biologic pathways involved in calcium homeostasis, synaptic plasticity, and neurotransmission.¹⁹ Taken together, these findings suggest vitamin D has a neurosteroid-like role in the CNS.

Psychotic disorders

Several epidemiologic studies have linked low vitamin D levels to schizophrenia and other psychotic disorders. Researchers in Norway who used a structured clinical interview to identify psychosis consistently found low levels of 25(OH)D among immigrants and native Norwegians with psychotic symptoms.²⁰ A study of 8,411 Swedish women found low vitamin D levels were associated with psychotic symptoms.²¹ The Finnish birth cohort study found that use of vitamin D supplementation during the first year of life reduced the incidence of schizophrenia.²² In another pilot study, researchers measured third-trimester serum 25(OH)D levels and found that low levels of maternal vitamin D may be associated with an increased risk of schizophrenia.²³ These studies suggest that low prenatal vitamin D levels may adversely impact the developing brain, increasing the risk for adult-onset schizophrenia.

Cognitive dysfunction

Low vitamin D concentrations have been associated with impairments in cognitive functions such as memory and orientation,²⁴ executive function impairments,²⁵ and Alzheimer’s disease (AD).²⁶ A large study conducted from 1998 to 2006 in Italy concluded that persons with severe vitamin D deficiency (<25 nmol/L) had a higher risk of substantial decline on Mini-Mental State Examination than those with sufficient levels (≥75 nmol/L).²⁷ Other studies have linked low vitamin D levels to poor cognitive performance in depressed older adults.²⁸ Low vitamin D levels in older women have been associated with risk of AD, but not with other dementias.²⁹ Polymorphisms of VDR have been associated with depression and poor cognitive performance.³⁰

Depression

Epidemiologic studies evaluating vitamin D deficiency have had conflicting results. The Third National Health and Nutrition Examination Survey, which used a sample of 7,970 non-institutionalized U.S. residents age 15 to 39, demonstrated that individuals with serum vitamin D ≤50 nmol/L are at a significantly higher risk of developing depression than those with vitamin D ≥75 nmol/L.³¹ A study of 1,282 adults age 65 to 95 in the Netherlands found that 25(OH)D levels were 14% lower in depressed patients compared with controls.³² However, a large epidemiologic study in China did not detect a relationship between vitamin D and depression in 3,262 men and women age 50 to 70.³³ After researchers adjusted for geography, body mass index, physical activity, and smoking, 25(OH)D levels did not correlate significantly with the presence or severity of depression. In a case series,³⁴ after 48 vitamin D-deficient depressed adolescents were given vitamin D₃ over 3 months, there was a significant improvement in well-being, depressive symptoms, irritability, and fatigue.³⁴ Other small, cross-sectional studies have examined associations between vitamin D status and depression with divergent results, which may reflect differences in population and methodology.

Prospective interventional studies. Although direct causal relationships are difficult to establish, several prospective studies have tested the hypothesis that treating vitamin D deficiency can improve depressive symptoms.

In a double-blind, controlled trial, Jorde et al³⁵ randomized 441 individuals age 21 to 70 to vitamin D, 20,000 IU per week; vitamin D, 40,000 IU per week; or placebo for 1 year. Individuals with serum 25(OH)D levels <40 nmol/L scored significantly higher on depression rating scales than those with serum 25(OH)D levels ≥40 nmol/L at the end of the study. There was no significant improvement in depression ratings in the placebo group (Table 2).³⁵ These results must be interpreted with care because depressive symptoms were secondary endpoints in this study.

Table 2

Effect of vitamin D supplementation on depressive symptoms in a controlled trial

Kjærgaard et al³⁶ systematically examined vitamin D levels in a case-control study followed by a randomized controlled trial (RCT) of vitamin D supplementation. In the case-control phase, participants with low 25(OH)D levels at baseline were significantly more depressed than participants with high 25(OH)D levels. Participants with low 25(OH)D levels were randomized to placebo or 40,000 IU vitamin D₃ per week for 6 months. Low levels of vitamin D were strongly associated with depressive symptoms, but vitamin D supplementation did not have a significant effect on depressive symptom scores.

Seasonal affective disorder (SAD). Seasonal variation in vitamin D levels suggests that supplementation may help patients who have seasonal mood disturbances. In a randomized, double-blind study, 44 healthy individuals received vitamin D₃, 400 IU/d, 800 IU/d, or no vitamin D₃ for 5 days during late winter. Based on self-reports, vitamin D₃ significantly enhanced positive affect and there was some evidence it reduced negative affect.³⁷ In a pilot study of 9 women with serum vitamin D levels <40 ng/ml, vitamin D supplementation during winter was associated with an average 10-point decline in Beck Depression Inventory-II scores.³⁸ In a prospective RCT of 15 individuals with SAD, all patients who received vitamin D improved in all outcome measures.³⁹ Vieth⁴⁰ randomized 82 adults with vitamin D deficiency to 600 IU/d or 4,000 IU/d of vitamin D₃ for 3 months over 2 consecutive winters. Patients taking the higher dose showed some evidence of improved well-being compared with those taking the lower dose, although results were not significant for all comparisons. Two other trials did not observe any improvement in SAD symptoms with vitamin D treatment.^41,42

Treating vitamin D deficiency

The Endocrine Society recently developed consensus guidelines for diagnosing and managing vitamin D deficiency.⁴³ In addition, the Institute of Medicine of the National Academies recommends daily vitamin D supplementation to prevent deficiency:

• age <70: 400 IU/d
• age >70: 800 IU/d
• pregnant or lactating women: 600 IU/d
• upper limit: 4,000 IU/d.⁷

Higher doses may be used for patients deprived of sun exposure.⁸ A typical replacement regimen consists of oral ergocalciferol, 50,000 IU per week for 8 weeks.⁴⁴ The optimal time for rechecking serum levels after repletion has not been clearly defined, but serum 25(OH)D levels should be measured again after therapy is completed. If values have not reached or exceeded 20 ng/mL, consider a second 8-week course of ergocalciferol (see the Box 1 for a discussion of measuring vitamin D levels). If serum 25(OH)D levels have not increased, the most likely cause is nonadherence or malabsorption.

Contraindications and toxicity. Contraindications to vitamin D supplementation include granulomatous diseases, sarcoidosis, metastatic bone disease, and Williams syndrome.⁴⁵Table 3⁴⁵ lists signs of vitamin D toxicity. There is little risk of toxicity at dosages of up to 2,000 IU/d.⁴⁶

Table 3

Signs of vitamin D toxicity

Related Resources

• LaFerney MC. Vitamin D deficiency in older adults. Current Psychiatry. 2012;11(11):63.
• National Institutes of Health Office of Dietary Supplements. Dietary supplement fact sheet: vitamin D. http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional.

Drug Brand Names

• Cholestyramine • Questran
• Ergocalciferol • Calciferol, Drisdol

Disclosures

Dr. Harris is an employee of Rho, Chapel Hill, NC.

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

Dr. Holmes receives research support from Bristol-Myers Squibb, Elan, Merck, Otsuka, Shire, Takeda, and Theravance, and is on the speaker’s bureau for Forest Pharmaceuticals and PamLab.

Dr. Patkar is a consultant for Dey Pharmaceuticals, Forest, Gilead, and TTK Pharma and is on the speaker’s bureau and received honoraria from Alkermes, Bristol-Myers Squibb, Dey Pharmaceuticals, Pfizer, and Sunovion; and has received grant support from the Duke Endowment, Dey Pharmaceuticals, Envivo, Forest, Janssen, Lundbeck, The National Institutes of Health, the National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, Pfizer Inc., Shire, Sunovion, and Titan.

Dr. Weisler has been a consultant to, on the speaker’s bureaus of, and/or received research support from Abbott, Agency for Toxic Substances and Disease Registry, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cenerx, Centers for Disease Control and Prevention, Cephalon, Ciba Geigy, CoMentis, Corcept, Cortex, Dainippon Sumitomo Pharma America, Eisai, Elan, Eli Lilly and Company, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil Pharmaceuticals, Medicinova, Medscape Advisory Board, Merck, National Institute of Mental Health, Neurochem, New River Pharmaceuticals, Novartis, Organon, Otsuka America Pharma, Pfizer Inc., Pharmacia, Repligen, Saegis, Sandoz, Sanofi, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, Solvay, Sunovion, Synaptic, Takeda, TAP, Theravance, Transcept Pharma, TransTech, UCB Pharma, Validus, Vela, and Wyeth.

In the United States, >50% of psychiatric inpatients have vitamin D deficiency—<30 nmol/L (<12 ng/mL).¹ A growing body of literature has found associations between vitamin D deficiency and psychiatric illnesses, particularly depression. Several randomized controlled trials (RCTs) have demonstrated that vitamin D supplementation can benefit depression symptoms. In this article, we discuss the current literature on vitamin D and psychiatric illness, and provide practical information for clinicians on the use of vitamin D supplementation.

Biosynthesis of vitamin D

Biosynthesis of vitamin D begins with the sterol provitamin D₃ molecule 7-dehydrocholesterol (Figure).² When skin is exposed to sunlight, 7-dehydrocholesterol absorbs UV radiation and forms provitamin D₃, which undergoes rapid transformation to vitamin D₃.² Vitamin D₃ is released from the plasma membrane and enters systemic circulation in a protein-bound form that has a serum half-life of 36 to 78 hours.³ Vitamin D₃ can be taken up by adipocytes and stored in fat deposits, where it has a half-life of approximately 2 months.⁴

Figure: Biosynthesis of vitamin D
Provitamin D₃ (7-dehydrocholesterol) in the skin absorbs UV radiation and undergoes isomerization to form vitamin D₃. Endogenously produced vitamin D₃ along with dietary vitamin D₂ and vitamin D₃ absorbed in the gastrointestinal tract are metabolized in the liver to 25-hydroxyvitamin D (25[OH]D), which re-enters the circulation and is metabolized in the kidney and other tissues to the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D). Catabolism of 25(OH)D and 1,25(OH)2D into biologically-inactive molecules is primarily mediated by the cytochrome P450 (CYP) enzymes CYP24 and CYP3A4.
Source: Reference 2Circulating vitamin D₃ is metabolized in the liver by the enzyme vitamin D-25-hydroxylase to 25-hydroxyvitamin D (25[OH]D₃), which has a serum half-life of approximately 15 days.⁴ Circulating 25(OH)D₃ is not biologically active at the physiological level, and requires activation by conversion to 1,25-dihydroxyvitamin D (1,25[OH]2D₃) in the kidneys by the enzyme 25(OH)D-1α-hydroxylase. Production of 1,25(OH)2D₃ is regulated by serum phosphorus and parathyroid hormone levels and other factors.⁵ Catabolism of 1,25(OH)2D₃ is rapid, with a serum half-life of 3.5 to 21 hours.⁶ Vitamin D₂ is structurally similar to vitamin D₃, but occurs primarily in fungi, yeasts, and some invertebrates.

Risk factors for deficiency

A patient’s vitamin D status is determined by measuring 25(OH)D (Box 1). Risk factors for vitamin D deficiency include conditions that affect cutaneous production (insufficient sunlight exposure), obesity, gastrointestinal disorders, aging, renal disorders, and medications (Table 1). ^2,5,7,8 The link between sunscreen use, either alone or in cosmetics, and vitamin D deficiency continues to be debated. While controlled studies have found that application of sunscreen with high sun protection factor can significantly reduce vitamin D production, ⁹ studies in clinical populations have failed to confirm these findings. ^10,11 See Box 2 for a discussion of these risk factors and Box 3 for a discussion of acute and long-term medical manifestations of deficiency.

Box 1

Table 1

Risk factors associated with vitamin D deficiency

Box 2

Box 3

Vitamin D’s role in the brain

Vitamin D’s role in psychiatric illnesses is suggested by region-specific expression of vitamin D receptors (VDR) in the cingulate cortex, thalamus, cerebellum, amygdala, and hippocampus.¹² Most of these regions also express 1α-hydroxylase enzymes capable of metabolizing 25(OH)D to 1,25(OH)2D₃, which suggests that vitamin D may have an autocrine or paracrine function in brain.¹³

Vitamin D regulates expression of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, norepinephrine, and epinephrine.¹⁴ Vitamin D also promotes survival of monoaminergic neurons through upregulation of glial cell line-derived neurotrophic factor, which supports survival of midbrain dopaminergic neurons and confers resistance to neurotoxins that deplete dopaminergic neurons in Parkinson’s disease.¹⁵ Vitamin D also promotes neuronal survival by inhibiting oxidative pathways in the brain through inhibition of inducible nitric oxide synthase (reducing free radical formation)¹⁶ and upregulation of γ-glutamyl transpeptidase (increasing antioxidant production).¹⁷ Vitamin D may play a neuroprotective role through regulation of calcium channels. In vitro studies have shown that vitamin D downregulates expression of L-type calcium channels, conferring protection against excitatory neurotoxins in cultured neurons.¹⁸ Proteomic analysis of brain tissue in a rat model of developmental vitamin D revealed dysregulation of 36 brain proteins involved in many biologic pathways involved in calcium homeostasis, synaptic plasticity, and neurotransmission.¹⁹ Taken together, these findings suggest vitamin D has a neurosteroid-like role in the CNS.

Psychotic disorders

Several epidemiologic studies have linked low vitamin D levels to schizophrenia and other psychotic disorders. Researchers in Norway who used a structured clinical interview to identify psychosis consistently found low levels of 25(OH)D among immigrants and native Norwegians with psychotic symptoms.²⁰ A study of 8,411 Swedish women found low vitamin D levels were associated with psychotic symptoms.²¹ The Finnish birth cohort study found that use of vitamin D supplementation during the first year of life reduced the incidence of schizophrenia.²² In another pilot study, researchers measured third-trimester serum 25(OH)D levels and found that low levels of maternal vitamin D may be associated with an increased risk of schizophrenia.²³ These studies suggest that low prenatal vitamin D levels may adversely impact the developing brain, increasing the risk for adult-onset schizophrenia.

Cognitive dysfunction

Low vitamin D concentrations have been associated with impairments in cognitive functions such as memory and orientation,²⁴ executive function impairments,²⁵ and Alzheimer’s disease (AD).²⁶ A large study conducted from 1998 to 2006 in Italy concluded that persons with severe vitamin D deficiency (<25 nmol/L) had a higher risk of substantial decline on Mini-Mental State Examination than those with sufficient levels (≥75 nmol/L).²⁷ Other studies have linked low vitamin D levels to poor cognitive performance in depressed older adults.²⁸ Low vitamin D levels in older women have been associated with risk of AD, but not with other dementias.²⁹ Polymorphisms of VDR have been associated with depression and poor cognitive performance.³⁰

Depression

Epidemiologic studies evaluating vitamin D deficiency have had conflicting results. The Third National Health and Nutrition Examination Survey, which used a sample of 7,970 non-institutionalized U.S. residents age 15 to 39, demonstrated that individuals with serum vitamin D ≤50 nmol/L are at a significantly higher risk of developing depression than those with vitamin D ≥75 nmol/L.³¹ A study of 1,282 adults age 65 to 95 in the Netherlands found that 25(OH)D levels were 14% lower in depressed patients compared with controls.³² However, a large epidemiologic study in China did not detect a relationship between vitamin D and depression in 3,262 men and women age 50 to 70.³³ After researchers adjusted for geography, body mass index, physical activity, and smoking, 25(OH)D levels did not correlate significantly with the presence or severity of depression. In a case series,³⁴ after 48 vitamin D-deficient depressed adolescents were given vitamin D₃ over 3 months, there was a significant improvement in well-being, depressive symptoms, irritability, and fatigue.³⁴ Other small, cross-sectional studies have examined associations between vitamin D status and depression with divergent results, which may reflect differences in population and methodology.

Prospective interventional studies. Although direct causal relationships are difficult to establish, several prospective studies have tested the hypothesis that treating vitamin D deficiency can improve depressive symptoms.

In a double-blind, controlled trial, Jorde et al³⁵ randomized 441 individuals age 21 to 70 to vitamin D, 20,000 IU per week; vitamin D, 40,000 IU per week; or placebo for 1 year. Individuals with serum 25(OH)D levels <40 nmol/L scored significantly higher on depression rating scales than those with serum 25(OH)D levels ≥40 nmol/L at the end of the study. There was no significant improvement in depression ratings in the placebo group (Table 2).³⁵ These results must be interpreted with care because depressive symptoms were secondary endpoints in this study.

Table 2

Effect of vitamin D supplementation on depressive symptoms in a controlled trial

Kjærgaard et al³⁶ systematically examined vitamin D levels in a case-control study followed by a randomized controlled trial (RCT) of vitamin D supplementation. In the case-control phase, participants with low 25(OH)D levels at baseline were significantly more depressed than participants with high 25(OH)D levels. Participants with low 25(OH)D levels were randomized to placebo or 40,000 IU vitamin D₃ per week for 6 months. Low levels of vitamin D were strongly associated with depressive symptoms, but vitamin D supplementation did not have a significant effect on depressive symptom scores.

Seasonal affective disorder (SAD). Seasonal variation in vitamin D levels suggests that supplementation may help patients who have seasonal mood disturbances. In a randomized, double-blind study, 44 healthy individuals received vitamin D₃, 400 IU/d, 800 IU/d, or no vitamin D₃ for 5 days during late winter. Based on self-reports, vitamin D₃ significantly enhanced positive affect and there was some evidence it reduced negative affect.³⁷ In a pilot study of 9 women with serum vitamin D levels <40 ng/ml, vitamin D supplementation during winter was associated with an average 10-point decline in Beck Depression Inventory-II scores.³⁸ In a prospective RCT of 15 individuals with SAD, all patients who received vitamin D improved in all outcome measures.³⁹ Vieth⁴⁰ randomized 82 adults with vitamin D deficiency to 600 IU/d or 4,000 IU/d of vitamin D₃ for 3 months over 2 consecutive winters. Patients taking the higher dose showed some evidence of improved well-being compared with those taking the lower dose, although results were not significant for all comparisons. Two other trials did not observe any improvement in SAD symptoms with vitamin D treatment.^41,42

Treating vitamin D deficiency

The Endocrine Society recently developed consensus guidelines for diagnosing and managing vitamin D deficiency.⁴³ In addition, the Institute of Medicine of the National Academies recommends daily vitamin D supplementation to prevent deficiency:

• age <70: 400 IU/d
• age >70: 800 IU/d
• pregnant or lactating women: 600 IU/d
• upper limit: 4,000 IU/d.⁷

Higher doses may be used for patients deprived of sun exposure.⁸ A typical replacement regimen consists of oral ergocalciferol, 50,000 IU per week for 8 weeks.⁴⁴ The optimal time for rechecking serum levels after repletion has not been clearly defined, but serum 25(OH)D levels should be measured again after therapy is completed. If values have not reached or exceeded 20 ng/mL, consider a second 8-week course of ergocalciferol (see the Box 1 for a discussion of measuring vitamin D levels). If serum 25(OH)D levels have not increased, the most likely cause is nonadherence or malabsorption.

Contraindications and toxicity. Contraindications to vitamin D supplementation include granulomatous diseases, sarcoidosis, metastatic bone disease, and Williams syndrome.⁴⁵Table 3⁴⁵ lists signs of vitamin D toxicity. There is little risk of toxicity at dosages of up to 2,000 IU/d.⁴⁶

Table 3

Signs of vitamin D toxicity

Related Resources

• LaFerney MC. Vitamin D deficiency in older adults. Current Psychiatry. 2012;11(11):63.
• National Institutes of Health Office of Dietary Supplements. Dietary supplement fact sheet: vitamin D. http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional.

Drug Brand Names

• Cholestyramine • Questran
• Ergocalciferol • Calciferol, Drisdol

Disclosures

Dr. Harris is an employee of Rho, Chapel Hill, NC.

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

Dr. Holmes receives research support from Bristol-Myers Squibb, Elan, Merck, Otsuka, Shire, Takeda, and Theravance, and is on the speaker’s bureau for Forest Pharmaceuticals and PamLab.

Dr. Patkar is a consultant for Dey Pharmaceuticals, Forest, Gilead, and TTK Pharma and is on the speaker’s bureau and received honoraria from Alkermes, Bristol-Myers Squibb, Dey Pharmaceuticals, Pfizer, and Sunovion; and has received grant support from the Duke Endowment, Dey Pharmaceuticals, Envivo, Forest, Janssen, Lundbeck, The National Institutes of Health, the National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, Pfizer Inc., Shire, Sunovion, and Titan.

Dr. Weisler has been a consultant to, on the speaker’s bureaus of, and/or received research support from Abbott, Agency for Toxic Substances and Disease Registry, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cenerx, Centers for Disease Control and Prevention, Cephalon, Ciba Geigy, CoMentis, Corcept, Cortex, Dainippon Sumitomo Pharma America, Eisai, Elan, Eli Lilly and Company, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil Pharmaceuticals, Medicinova, Medscape Advisory Board, Merck, National Institute of Mental Health, Neurochem, New River Pharmaceuticals, Novartis, Organon, Otsuka America Pharma, Pfizer Inc., Pharmacia, Repligen, Saegis, Sandoz, Sanofi, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, Solvay, Sunovion, Synaptic, Takeda, TAP, Theravance, Transcept Pharma, TransTech, UCB Pharma, Validus, Vela, and Wyeth.

In the United States, >50% of psychiatric inpatients have vitamin D deficiency—<30 nmol/L (<12 ng/mL).¹ A growing body of literature has found associations between vitamin D deficiency and psychiatric illnesses, particularly depression. Several randomized controlled trials (RCTs) have demonstrated that vitamin D supplementation can benefit depression symptoms. In this article, we discuss the current literature on vitamin D and psychiatric illness, and provide practical information for clinicians on the use of vitamin D supplementation.

Biosynthesis of vitamin D

Biosynthesis of vitamin D begins with the sterol provitamin D₃ molecule 7-dehydrocholesterol (Figure).² When skin is exposed to sunlight, 7-dehydrocholesterol absorbs UV radiation and forms provitamin D₃, which undergoes rapid transformation to vitamin D₃.² Vitamin D₃ is released from the plasma membrane and enters systemic circulation in a protein-bound form that has a serum half-life of 36 to 78 hours.³ Vitamin D₃ can be taken up by adipocytes and stored in fat deposits, where it has a half-life of approximately 2 months.⁴

Figure: Biosynthesis of vitamin D
Provitamin D₃ (7-dehydrocholesterol) in the skin absorbs UV radiation and undergoes isomerization to form vitamin D₃. Endogenously produced vitamin D₃ along with dietary vitamin D₂ and vitamin D₃ absorbed in the gastrointestinal tract are metabolized in the liver to 25-hydroxyvitamin D (25[OH]D), which re-enters the circulation and is metabolized in the kidney and other tissues to the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D). Catabolism of 25(OH)D and 1,25(OH)2D into biologically-inactive molecules is primarily mediated by the cytochrome P450 (CYP) enzymes CYP24 and CYP3A4.
Source: Reference 2Circulating vitamin D₃ is metabolized in the liver by the enzyme vitamin D-25-hydroxylase to 25-hydroxyvitamin D (25[OH]D₃), which has a serum half-life of approximately 15 days.⁴ Circulating 25(OH)D₃ is not biologically active at the physiological level, and requires activation by conversion to 1,25-dihydroxyvitamin D (1,25[OH]2D₃) in the kidneys by the enzyme 25(OH)D-1α-hydroxylase. Production of 1,25(OH)2D₃ is regulated by serum phosphorus and parathyroid hormone levels and other factors.⁵ Catabolism of 1,25(OH)2D₃ is rapid, with a serum half-life of 3.5 to 21 hours.⁶ Vitamin D₂ is structurally similar to vitamin D₃, but occurs primarily in fungi, yeasts, and some invertebrates.

Risk factors for deficiency

A patient’s vitamin D status is determined by measuring 25(OH)D (Box 1). Risk factors for vitamin D deficiency include conditions that affect cutaneous production (insufficient sunlight exposure), obesity, gastrointestinal disorders, aging, renal disorders, and medications (Table 1). ^2,5,7,8 The link between sunscreen use, either alone or in cosmetics, and vitamin D deficiency continues to be debated. While controlled studies have found that application of sunscreen with high sun protection factor can significantly reduce vitamin D production, ⁹ studies in clinical populations have failed to confirm these findings. ^10,11 See Box 2 for a discussion of these risk factors and Box 3 for a discussion of acute and long-term medical manifestations of deficiency.

Box 1

Table 1

Risk factors associated with vitamin D deficiency

Box 2

Box 3

Vitamin D’s role in the brain

Vitamin D’s role in psychiatric illnesses is suggested by region-specific expression of vitamin D receptors (VDR) in the cingulate cortex, thalamus, cerebellum, amygdala, and hippocampus.¹² Most of these regions also express 1α-hydroxylase enzymes capable of metabolizing 25(OH)D to 1,25(OH)2D₃, which suggests that vitamin D may have an autocrine or paracrine function in brain.¹³

Vitamin D regulates expression of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, norepinephrine, and epinephrine.¹⁴ Vitamin D also promotes survival of monoaminergic neurons through upregulation of glial cell line-derived neurotrophic factor, which supports survival of midbrain dopaminergic neurons and confers resistance to neurotoxins that deplete dopaminergic neurons in Parkinson’s disease.¹⁵ Vitamin D also promotes neuronal survival by inhibiting oxidative pathways in the brain through inhibition of inducible nitric oxide synthase (reducing free radical formation)¹⁶ and upregulation of γ-glutamyl transpeptidase (increasing antioxidant production).¹⁷ Vitamin D may play a neuroprotective role through regulation of calcium channels. In vitro studies have shown that vitamin D downregulates expression of L-type calcium channels, conferring protection against excitatory neurotoxins in cultured neurons.¹⁸ Proteomic analysis of brain tissue in a rat model of developmental vitamin D revealed dysregulation of 36 brain proteins involved in many biologic pathways involved in calcium homeostasis, synaptic plasticity, and neurotransmission.¹⁹ Taken together, these findings suggest vitamin D has a neurosteroid-like role in the CNS.

Psychotic disorders

Several epidemiologic studies have linked low vitamin D levels to schizophrenia and other psychotic disorders. Researchers in Norway who used a structured clinical interview to identify psychosis consistently found low levels of 25(OH)D among immigrants and native Norwegians with psychotic symptoms.²⁰ A study of 8,411 Swedish women found low vitamin D levels were associated with psychotic symptoms.²¹ The Finnish birth cohort study found that use of vitamin D supplementation during the first year of life reduced the incidence of schizophrenia.²² In another pilot study, researchers measured third-trimester serum 25(OH)D levels and found that low levels of maternal vitamin D may be associated with an increased risk of schizophrenia.²³ These studies suggest that low prenatal vitamin D levels may adversely impact the developing brain, increasing the risk for adult-onset schizophrenia.

Cognitive dysfunction

Low vitamin D concentrations have been associated with impairments in cognitive functions such as memory and orientation,²⁴ executive function impairments,²⁵ and Alzheimer’s disease (AD).²⁶ A large study conducted from 1998 to 2006 in Italy concluded that persons with severe vitamin D deficiency (<25 nmol/L) had a higher risk of substantial decline on Mini-Mental State Examination than those with sufficient levels (≥75 nmol/L).²⁷ Other studies have linked low vitamin D levels to poor cognitive performance in depressed older adults.²⁸ Low vitamin D levels in older women have been associated with risk of AD, but not with other dementias.²⁹ Polymorphisms of VDR have been associated with depression and poor cognitive performance.³⁰

Depression

Epidemiologic studies evaluating vitamin D deficiency have had conflicting results. The Third National Health and Nutrition Examination Survey, which used a sample of 7,970 non-institutionalized U.S. residents age 15 to 39, demonstrated that individuals with serum vitamin D ≤50 nmol/L are at a significantly higher risk of developing depression than those with vitamin D ≥75 nmol/L.³¹ A study of 1,282 adults age 65 to 95 in the Netherlands found that 25(OH)D levels were 14% lower in depressed patients compared with controls.³² However, a large epidemiologic study in China did not detect a relationship between vitamin D and depression in 3,262 men and women age 50 to 70.³³ After researchers adjusted for geography, body mass index, physical activity, and smoking, 25(OH)D levels did not correlate significantly with the presence or severity of depression. In a case series,³⁴ after 48 vitamin D-deficient depressed adolescents were given vitamin D₃ over 3 months, there was a significant improvement in well-being, depressive symptoms, irritability, and fatigue.³⁴ Other small, cross-sectional studies have examined associations between vitamin D status and depression with divergent results, which may reflect differences in population and methodology.

Prospective interventional studies. Although direct causal relationships are difficult to establish, several prospective studies have tested the hypothesis that treating vitamin D deficiency can improve depressive symptoms.

In a double-blind, controlled trial, Jorde et al³⁵ randomized 441 individuals age 21 to 70 to vitamin D, 20,000 IU per week; vitamin D, 40,000 IU per week; or placebo for 1 year. Individuals with serum 25(OH)D levels <40 nmol/L scored significantly higher on depression rating scales than those with serum 25(OH)D levels ≥40 nmol/L at the end of the study. There was no significant improvement in depression ratings in the placebo group (Table 2).³⁵ These results must be interpreted with care because depressive symptoms were secondary endpoints in this study.

Table 2

Effect of vitamin D supplementation on depressive symptoms in a controlled trial

Kjærgaard et al³⁶ systematically examined vitamin D levels in a case-control study followed by a randomized controlled trial (RCT) of vitamin D supplementation. In the case-control phase, participants with low 25(OH)D levels at baseline were significantly more depressed than participants with high 25(OH)D levels. Participants with low 25(OH)D levels were randomized to placebo or 40,000 IU vitamin D₃ per week for 6 months. Low levels of vitamin D were strongly associated with depressive symptoms, but vitamin D supplementation did not have a significant effect on depressive symptom scores.

Seasonal affective disorder (SAD). Seasonal variation in vitamin D levels suggests that supplementation may help patients who have seasonal mood disturbances. In a randomized, double-blind study, 44 healthy individuals received vitamin D₃, 400 IU/d, 800 IU/d, or no vitamin D₃ for 5 days during late winter. Based on self-reports, vitamin D₃ significantly enhanced positive affect and there was some evidence it reduced negative affect.³⁷ In a pilot study of 9 women with serum vitamin D levels <40 ng/ml, vitamin D supplementation during winter was associated with an average 10-point decline in Beck Depression Inventory-II scores.³⁸ In a prospective RCT of 15 individuals with SAD, all patients who received vitamin D improved in all outcome measures.³⁹ Vieth⁴⁰ randomized 82 adults with vitamin D deficiency to 600 IU/d or 4,000 IU/d of vitamin D₃ for 3 months over 2 consecutive winters. Patients taking the higher dose showed some evidence of improved well-being compared with those taking the lower dose, although results were not significant for all comparisons. Two other trials did not observe any improvement in SAD symptoms with vitamin D treatment.^41,42

Treating vitamin D deficiency

The Endocrine Society recently developed consensus guidelines for diagnosing and managing vitamin D deficiency.⁴³ In addition, the Institute of Medicine of the National Academies recommends daily vitamin D supplementation to prevent deficiency:

• age <70: 400 IU/d
• age >70: 800 IU/d
• pregnant or lactating women: 600 IU/d
• upper limit: 4,000 IU/d.⁷

Higher doses may be used for patients deprived of sun exposure.⁸ A typical replacement regimen consists of oral ergocalciferol, 50,000 IU per week for 8 weeks.⁴⁴ The optimal time for rechecking serum levels after repletion has not been clearly defined, but serum 25(OH)D levels should be measured again after therapy is completed. If values have not reached or exceeded 20 ng/mL, consider a second 8-week course of ergocalciferol (see the Box 1 for a discussion of measuring vitamin D levels). If serum 25(OH)D levels have not increased, the most likely cause is nonadherence or malabsorption.

Contraindications and toxicity. Contraindications to vitamin D supplementation include granulomatous diseases, sarcoidosis, metastatic bone disease, and Williams syndrome.⁴⁵Table 3⁴⁵ lists signs of vitamin D toxicity. There is little risk of toxicity at dosages of up to 2,000 IU/d.⁴⁶

Table 3

Signs of vitamin D toxicity

Related Resources

• LaFerney MC. Vitamin D deficiency in older adults. Current Psychiatry. 2012;11(11):63.
• National Institutes of Health Office of Dietary Supplements. Dietary supplement fact sheet: vitamin D. http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional.

Drug Brand Names

• Cholestyramine • Questran
• Ergocalciferol • Calciferol, Drisdol

Disclosures

Dr. Harris is an employee of Rho, Chapel Hill, NC.

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

Dr. Holmes receives research support from Bristol-Myers Squibb, Elan, Merck, Otsuka, Shire, Takeda, and Theravance, and is on the speaker’s bureau for Forest Pharmaceuticals and PamLab.

Dr. Patkar is a consultant for Dey Pharmaceuticals, Forest, Gilead, and TTK Pharma and is on the speaker’s bureau and received honoraria from Alkermes, Bristol-Myers Squibb, Dey Pharmaceuticals, Pfizer, and Sunovion; and has received grant support from the Duke Endowment, Dey Pharmaceuticals, Envivo, Forest, Janssen, Lundbeck, The National Institutes of Health, the National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, Pfizer Inc., Shire, Sunovion, and Titan.

Dr. Weisler has been a consultant to, on the speaker’s bureaus of, and/or received research support from Abbott, Agency for Toxic Substances and Disease Registry, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cenerx, Centers for Disease Control and Prevention, Cephalon, Ciba Geigy, CoMentis, Corcept, Cortex, Dainippon Sumitomo Pharma America, Eisai, Elan, Eli Lilly and Company, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil Pharmaceuticals, Medicinova, Medscape Advisory Board, Merck, National Institute of Mental Health, Neurochem, New River Pharmaceuticals, Novartis, Organon, Otsuka America Pharma, Pfizer Inc., Pharmacia, Repligen, Saegis, Sandoz, Sanofi, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, Solvay, Sunovion, Synaptic, Takeda, TAP, Theravance, Transcept Pharma, TransTech, UCB Pharma, Validus, Vela, and Wyeth.

Mr. P, age 31, has been using heroin intravenously for 9 years. He smokes 1 pack of cigarettes daily, but denies using other substances, including alcohol. After an unintentional heroin overdose, Mr. P enrolls in a methadone maintenance treatment program (MMTP) that includes primary medical care and addiction medicine and psychiatric specialists, where he undergoes medical evaluation and screening for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Laboratory data reveal that although Mr. P is HIV negative, he has been exposed to HCV and treatment is indicated.

Among the approximately 3 million people in the United States with chronic HCV—an enveloped, single-stranded RNA virus—there’s a high prevalence of premorbid psychopathology and substance abuse, as well as neuropsychiatric effects caused by HCV treatment.^1-3 Because underdiagnosing and undertreating psychiatric disorders contributes to morbidity and mortality in HCV patients, early identification and prompt treatment is critical.

IV drug use is the most common route for HCV infection, accounting for 65% to 70% of infections.¹ The prevalence of HCV among IV drug users is 28% to 90%.¹ Once exposed to HCV, 75% to 85% of patients do not clear the initial infection and become chronically infected.

This article reviews the pathophysiology, identification, and management of psychiatric manifestations found among HCV patients and provides an understanding of how psychiatric symptoms manifest in HCV patients. This article also discusses HCV treatment and its neuropsychiatric side effects.

Testing for HCV

Chronically infected HCV patients may have few, if any, specific physical complaints, and often are diagnosed during screenings or other routine laboratory evaluations. The presence of risk factors, such as a history of injection drug use or receiving a blood transfusion before 1992,¹ guides the decision to screen for HCV. Normal liver function test results should not preclude testing because many HCV-positive patients have transaminases within the normal range.⁴ Initial screening is via an antibody-mediated immunoassay that is highly specific and sensitive for past exposure to HCV (Table 1).⁴ However, a positive screen does not indicate the presence of active infection. Evidence of the virus via a viral assay will identify active HCV, but does not indicate need for treatment. Liver biopsy confirms the presence of liver injury and quantifies its extent. The severity of liver damage will determine whether treatment is needed. HCV genotyping determines the appropriate duration and dosage of pharmacotherapy.

Table 1

Tests to diagnose and evaluate HCV

CASE CONTINUED: Mood improves, but fatigue persists

As part of pre-HCV treatment evaluation, Mr. P undergoes a psychiatric evaluation. He describes periods of low mood while actively engaged in drug use but has never received psychiatric treatment, experienced suicidal ideation, or attempted suicide. Since starting opioid agonist therapy, he reports improved mood but endorses continued mild fatigue and difficulty falling sleep. The psychiatrist determines Mr. P does not meet criteria for an axis I diagnosis other than a substance use disorder.

Although most HCV patients have few, if any, nonspecific physical symptoms, many have psychiatric symptoms or disorders before the HCV diagnosis is made or treatment is initiated; substance use disorders are most common. Batki et al¹ found that 56% of HCV patients in an MMTP met criteria for a nonsubstance axis I disorder and 82% met criteria for such a disorder during their lifetime. Additionally, 66% of patients were taking psychiatric medications. Table 2^1,5,6 lists the rates of other psychiatric disorders found in patients with untreated HCV.

Table 2

Rates of psychiatric disorders in patients with untreated hepatitis C virus

Many patients with chronic HCV complain of chronic fatigue and deficiencies in attention, concentration, higher executive functions, learning ability, and memory that result in significant reduction in quality of life (Box 1).^7-9 These findings have been found to be independent of the degree of liver disease and are seen in HCV patients with normal liver function.^7,8

Box 1

CASE CONTINUED: Motivated and compliant

Since joining the MMTP 6 months ago, Mr. P has been motivated and compliant with all appointments and treatments. Routine urine toxicology screening supports his claim of abstinence. Mr. P begins HCV treatment while continuing follow-up with addiction medicine and psychiatric clinicians and maintains open communication with all treatment providers.

For many years the standard HCV treatment was pegylated interferon-α (IFN-α) and ribavirin. IFN-α is a proinflammatory cytokine with antiproliferative, antiviral, and immunoregulatory properties. The half-life of IFN-α significantly increases with pegylation, which allows for weekly injections.^10,11 IFN-α usually is combined with ribavirin, which increases its efficacy as measured by the sustained virological response (SVR) compared with IFN-α alone. Depending on the virus genotype, treatment lasts 24 to 48 weeks; SVR rates range from 40% to 82%.^11-13 In 2011, the FDA approved 2 agents—telaprevir and boceprevir—for adjunctive treatment of HCV genotype 1 infection. These 2 agents are protease inhibitors that when added to IFN-α and ribavirin increase the SVR rate in genotype 1 infection from 40% to 50% to approximately 75%.^14,15

Although the neuropsychiatric side effects of telaprevir and boceprevir have not been determined, treating chronic HCV with IFN-α and ribavirin has been associated with multiple psychiatric symptoms, including depression, mania, suicidality, anxiety, and psychosis.^11-14 Psychiatric symptoms are a common reason for discontinuing or reducing HCV treatment. Because of the high frequency of neuropsychiatric complications, some clinicians believe HCV patients with preexisting affective, psychotic, or substance use disorders should be excluded from HCV treatment. This has led to many HCV patients being untreated despite a lack of prospective, controlled data to support this opinion.¹² To improve outcomes and decrease morbidity, providing appropriate psychiatric services appears to be more important than attempting to select lower-risk patients for antiviral therapy.^1,12,16 The goals of psychiatric treatment should be to alleviate symptoms and allow patients to complete IFN-α therapy without interruption.^16,17

Studies of high-risk patients who attend multidisciplinary treatment programs that can monitor adherence and efficacy and control side effects before and during HCV treatment have found psychiatric patients have similar adherence, compliance, and SVR rates and were not at increased risk of worsening depressive or psychotic symptoms compared with patients without a psychiatric history.^12,18 Additionally, HCV patients with a psychiatric history are not at an increased risk of suicide.^13,16 Similar findings have been observed in patients with active IV drug use or those receiving opioid agonist therapy. When HCV and substance use are treated simultaneously, patients can successfully complete HCV treatment with SVR rates comparable to those of patients not receiving opioid agonist therapy.^19-21

CASE CONTINUED: Worsening symptoms

During a psychiatric follow-up 12 weeks after starting HCV treatment, Mr. P reports worsening depressive symptoms with low mood, decreased enjoyment of activities, poor sleep, low appetite, and fatigue. He shows no evidence of psychosis and denies suicidal ideation. We continue his HCV treatment, schedule more frequent psychiatric visits, and initiate citalopram, titrated to 40 mg/d.

Depressive symptoms, the most common neuropsychiatric manifestation of HCV, typically begin early in treatment, usually within the first 12 weeks. Two distinct symptom clusters are noted. A neurovegetative cluster characterized by reduced energy, anorexia, and psychomotor retardation typically begins within the first few months of treatment. Months later, a depression-specific syndrome appears that includes depressed mood, anxiety, and cognitive impairment.²²

Depressive symptoms may occur in up to 60% of patients treated with IFN-α.¹¹ When more rigorous depression measures are used, rates decrease to approximately 20% to 30%.^11,13 Accurate diagnosis and treatment of emerging depressive symptoms is essential because untreated depression can lead to postponing or excluding patients from antiviral treatment.² Screening instruments such as the Beck Depression Inventory-Second Edition (BDI-II) can be used to measure depressive symptoms in HCV patients with high sensitivity. However, because specificity has been low and somatic symptoms of chronic illness and depression often overlap, the BDI-II and other inventories may overestimate depression. Some researchers have suggested that focusing on questions targeting cognitive and affective symptoms rather than somatic ones may be a more valid measure of depression in patients undergoing immunotherapy for HCV.²

The immune system is implicated in IFN-α-induced depression because depressive symptoms share many features with a constellation of somatic and behavioral symptoms termed “sickness behavior.”¹¹ These behaviors can occur when patients are exposed to cytokines that lead to a depressed level of functioning, which may allow the body to devote more energy to fighting illness. IFN-α, a cytokine, stimulates the immune system, which can lead to increases of interleukin (IL)-2, IL-6, and IL-10. Increased circulating levels of these ILs have been correlated with higher depression scores. Additionally, studies have found that patients who develop depression during IFN-α treatment have higher SVR rates, suggesting a more robust immune response.^11,22 For a discussion of how serotonin metabolism and genetic polymorphisms also may help explain the prevalence of depression in patients with HCV, see Box 2.

Box 2

Treating depressed HCV patients

Antidepressants are the treatment of choice for IFN-α-induced depression. Most currently used antidepressants are effective²² and selective serotonin reuptake inhibitors are considered first choice.¹⁶ Antidepressant choice should be guided by principles similar to those used for patients without HCV: using side effects profiles to target specific symptoms and being mindful of pharmacokinetic properties.

Two treatment approaches have been investigated: prophylactic and symptomatic. A 2012 study²³ of 181 HCV patients with no history of mental illness determined escitalopram, 10 mg/d, effectively reduced the incidence and severity of interferon-associated depression. Other studies examining prophylactic treatment of all patients who were to undergo interferon treatment found this approach did not prevent depressive episodes.^24,25 However, antidepressants have been beneficial for patients with subsyndromal depressive symptoms at baseline²⁶ and after clinically significant depressive symptoms emerge.²⁷ Electroconvulsive therapy also has been reported to effectively treat depression in HCV patients undergoing antiviral therapy.²⁸

CASE CONTINUED: Lingering symptoms

Mr. P responds to citalopram with an improvement in mood, anhedonia, and appetite, but he continues to complain of low energy and poor concentration. In an effort to target these symptoms, methylphenidate, titrated to 30 mg/d in divided doses, is added to his regimen, which rapidly improves his symptoms. Insomnia is treated successfully with trazodone, 50 mg/d. Mr. P frequently visits his psychiatrist, who monitors his depressive symptoms using the BDI-II. Mr. P completes HCV treatment without recurrence of depressive symptoms or relapse to heroin use.

Although antidepressants are effective for treating affective and cognitive symptoms, they are not as effective for fatigue and other neurovegetative symptoms.^16,29 The psychostimulants methylphenidate and dextroamphetamine and the nonstimulant modafinil have been studied for treating depressive symptoms in medically ill patients and can be used to treat IFN-α-induced fatigue.^16,22,29

IFN-α’s effect on serotonin metabolism leads to a tryptophan-deficient state because of increased catabolism as a result of activation of indoleamine-2,3-dioxygenase (IDO). This has led to use of tryptophan supplementation, either as augmentation or monotherapy, for managing depressive symptoms in patients treated with IFN-α. Schaefer et al³⁰ reported 3 cases where tryptophan supplementation significantly decreased depressive symptoms. Other researchers have argued that supplementing tryptophan in the context of IDO activation can lead to greater production of kynurenine and quinolinic acid, which have been linked to increased depressive symptoms in patients receiving IFN-α.³¹ They argue that supplementation of 5-HTP, which is available as a dietary supplement without a prescription, can lead to increased serotonin levels and improvement in depressive symptoms.³¹

IFN-α treatment also is associated with mania and psychosis. The incidence, pathophysiology, and management of these treatment-emergent symptoms are not as well studied as IFN-α-induced depression. Mania and hypomania have been reported with interferon treatment, discontinuation of interferon, and use of antidepressants for interferon-induced depression.^29,32 Psychosis, in association with mood symptoms or alone, has been reported to occur in <1% of treated patients.³³ Treatment for mania and psychosis consists of decreasing or discontinuing immunotherapy and adding mood stabilizers and antipsychotics. Once immunotherapy is discontinued, mania and psychosis usually resolve, but prolonged duration of symptoms has been reported.^29,32,33

Related Resources

• Centers for Disease Control and Prevention. Hepatitis C information for health professionals. www.cdc.gov/hepatitis/hcv/index.htm.
• Hep C Connection. www.hepc-connection.org.
• United States Department of Veterans Affairs. Hepatitis C. www.hepatitis.va.gov.

Drug Brand Names

• Boceprevir • Victrelis
• Citalopram • Celexa
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Interferon-α • Intron
• Methadone • Dolophine, Methadose
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Ondansetron • Zofran
• Ribavirin • Copegus, Rebetol, others
• Telaprevir • Incivek
• Trazodone • Desyrel, Oleptro

Disclosure

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

Mr. P, age 31, has been using heroin intravenously for 9 years. He smokes 1 pack of cigarettes daily, but denies using other substances, including alcohol. After an unintentional heroin overdose, Mr. P enrolls in a methadone maintenance treatment program (MMTP) that includes primary medical care and addiction medicine and psychiatric specialists, where he undergoes medical evaluation and screening for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Laboratory data reveal that although Mr. P is HIV negative, he has been exposed to HCV and treatment is indicated.

Among the approximately 3 million people in the United States with chronic HCV—an enveloped, single-stranded RNA virus—there’s a high prevalence of premorbid psychopathology and substance abuse, as well as neuropsychiatric effects caused by HCV treatment.^1-3 Because underdiagnosing and undertreating psychiatric disorders contributes to morbidity and mortality in HCV patients, early identification and prompt treatment is critical.

IV drug use is the most common route for HCV infection, accounting for 65% to 70% of infections.¹ The prevalence of HCV among IV drug users is 28% to 90%.¹ Once exposed to HCV, 75% to 85% of patients do not clear the initial infection and become chronically infected.

This article reviews the pathophysiology, identification, and management of psychiatric manifestations found among HCV patients and provides an understanding of how psychiatric symptoms manifest in HCV patients. This article also discusses HCV treatment and its neuropsychiatric side effects.

Testing for HCV

Chronically infected HCV patients may have few, if any, specific physical complaints, and often are diagnosed during screenings or other routine laboratory evaluations. The presence of risk factors, such as a history of injection drug use or receiving a blood transfusion before 1992,¹ guides the decision to screen for HCV. Normal liver function test results should not preclude testing because many HCV-positive patients have transaminases within the normal range.⁴ Initial screening is via an antibody-mediated immunoassay that is highly specific and sensitive for past exposure to HCV (Table 1).⁴ However, a positive screen does not indicate the presence of active infection. Evidence of the virus via a viral assay will identify active HCV, but does not indicate need for treatment. Liver biopsy confirms the presence of liver injury and quantifies its extent. The severity of liver damage will determine whether treatment is needed. HCV genotyping determines the appropriate duration and dosage of pharmacotherapy.

Table 1

Tests to diagnose and evaluate HCV

CASE CONTINUED: Mood improves, but fatigue persists

As part of pre-HCV treatment evaluation, Mr. P undergoes a psychiatric evaluation. He describes periods of low mood while actively engaged in drug use but has never received psychiatric treatment, experienced suicidal ideation, or attempted suicide. Since starting opioid agonist therapy, he reports improved mood but endorses continued mild fatigue and difficulty falling sleep. The psychiatrist determines Mr. P does not meet criteria for an axis I diagnosis other than a substance use disorder.

Although most HCV patients have few, if any, nonspecific physical symptoms, many have psychiatric symptoms or disorders before the HCV diagnosis is made or treatment is initiated; substance use disorders are most common. Batki et al¹ found that 56% of HCV patients in an MMTP met criteria for a nonsubstance axis I disorder and 82% met criteria for such a disorder during their lifetime. Additionally, 66% of patients were taking psychiatric medications. Table 2^1,5,6 lists the rates of other psychiatric disorders found in patients with untreated HCV.

Table 2

Rates of psychiatric disorders in patients with untreated hepatitis C virus

Many patients with chronic HCV complain of chronic fatigue and deficiencies in attention, concentration, higher executive functions, learning ability, and memory that result in significant reduction in quality of life (Box 1).^7-9 These findings have been found to be independent of the degree of liver disease and are seen in HCV patients with normal liver function.^7,8

Box 1

CASE CONTINUED: Motivated and compliant

Since joining the MMTP 6 months ago, Mr. P has been motivated and compliant with all appointments and treatments. Routine urine toxicology screening supports his claim of abstinence. Mr. P begins HCV treatment while continuing follow-up with addiction medicine and psychiatric clinicians and maintains open communication with all treatment providers.

For many years the standard HCV treatment was pegylated interferon-α (IFN-α) and ribavirin. IFN-α is a proinflammatory cytokine with antiproliferative, antiviral, and immunoregulatory properties. The half-life of IFN-α significantly increases with pegylation, which allows for weekly injections.^10,11 IFN-α usually is combined with ribavirin, which increases its efficacy as measured by the sustained virological response (SVR) compared with IFN-α alone. Depending on the virus genotype, treatment lasts 24 to 48 weeks; SVR rates range from 40% to 82%.^11-13 In 2011, the FDA approved 2 agents—telaprevir and boceprevir—for adjunctive treatment of HCV genotype 1 infection. These 2 agents are protease inhibitors that when added to IFN-α and ribavirin increase the SVR rate in genotype 1 infection from 40% to 50% to approximately 75%.^14,15

Although the neuropsychiatric side effects of telaprevir and boceprevir have not been determined, treating chronic HCV with IFN-α and ribavirin has been associated with multiple psychiatric symptoms, including depression, mania, suicidality, anxiety, and psychosis.^11-14 Psychiatric symptoms are a common reason for discontinuing or reducing HCV treatment. Because of the high frequency of neuropsychiatric complications, some clinicians believe HCV patients with preexisting affective, psychotic, or substance use disorders should be excluded from HCV treatment. This has led to many HCV patients being untreated despite a lack of prospective, controlled data to support this opinion.¹² To improve outcomes and decrease morbidity, providing appropriate psychiatric services appears to be more important than attempting to select lower-risk patients for antiviral therapy.^1,12,16 The goals of psychiatric treatment should be to alleviate symptoms and allow patients to complete IFN-α therapy without interruption.^16,17

Studies of high-risk patients who attend multidisciplinary treatment programs that can monitor adherence and efficacy and control side effects before and during HCV treatment have found psychiatric patients have similar adherence, compliance, and SVR rates and were not at increased risk of worsening depressive or psychotic symptoms compared with patients without a psychiatric history.^12,18 Additionally, HCV patients with a psychiatric history are not at an increased risk of suicide.^13,16 Similar findings have been observed in patients with active IV drug use or those receiving opioid agonist therapy. When HCV and substance use are treated simultaneously, patients can successfully complete HCV treatment with SVR rates comparable to those of patients not receiving opioid agonist therapy.^19-21

CASE CONTINUED: Worsening symptoms

During a psychiatric follow-up 12 weeks after starting HCV treatment, Mr. P reports worsening depressive symptoms with low mood, decreased enjoyment of activities, poor sleep, low appetite, and fatigue. He shows no evidence of psychosis and denies suicidal ideation. We continue his HCV treatment, schedule more frequent psychiatric visits, and initiate citalopram, titrated to 40 mg/d.

Depressive symptoms, the most common neuropsychiatric manifestation of HCV, typically begin early in treatment, usually within the first 12 weeks. Two distinct symptom clusters are noted. A neurovegetative cluster characterized by reduced energy, anorexia, and psychomotor retardation typically begins within the first few months of treatment. Months later, a depression-specific syndrome appears that includes depressed mood, anxiety, and cognitive impairment.²²

Depressive symptoms may occur in up to 60% of patients treated with IFN-α.¹¹ When more rigorous depression measures are used, rates decrease to approximately 20% to 30%.^11,13 Accurate diagnosis and treatment of emerging depressive symptoms is essential because untreated depression can lead to postponing or excluding patients from antiviral treatment.² Screening instruments such as the Beck Depression Inventory-Second Edition (BDI-II) can be used to measure depressive symptoms in HCV patients with high sensitivity. However, because specificity has been low and somatic symptoms of chronic illness and depression often overlap, the BDI-II and other inventories may overestimate depression. Some researchers have suggested that focusing on questions targeting cognitive and affective symptoms rather than somatic ones may be a more valid measure of depression in patients undergoing immunotherapy for HCV.²

The immune system is implicated in IFN-α-induced depression because depressive symptoms share many features with a constellation of somatic and behavioral symptoms termed “sickness behavior.”¹¹ These behaviors can occur when patients are exposed to cytokines that lead to a depressed level of functioning, which may allow the body to devote more energy to fighting illness. IFN-α, a cytokine, stimulates the immune system, which can lead to increases of interleukin (IL)-2, IL-6, and IL-10. Increased circulating levels of these ILs have been correlated with higher depression scores. Additionally, studies have found that patients who develop depression during IFN-α treatment have higher SVR rates, suggesting a more robust immune response.^11,22 For a discussion of how serotonin metabolism and genetic polymorphisms also may help explain the prevalence of depression in patients with HCV, see Box 2.

Box 2

Treating depressed HCV patients

Antidepressants are the treatment of choice for IFN-α-induced depression. Most currently used antidepressants are effective²² and selective serotonin reuptake inhibitors are considered first choice.¹⁶ Antidepressant choice should be guided by principles similar to those used for patients without HCV: using side effects profiles to target specific symptoms and being mindful of pharmacokinetic properties.

Two treatment approaches have been investigated: prophylactic and symptomatic. A 2012 study²³ of 181 HCV patients with no history of mental illness determined escitalopram, 10 mg/d, effectively reduced the incidence and severity of interferon-associated depression. Other studies examining prophylactic treatment of all patients who were to undergo interferon treatment found this approach did not prevent depressive episodes.^24,25 However, antidepressants have been beneficial for patients with subsyndromal depressive symptoms at baseline²⁶ and after clinically significant depressive symptoms emerge.²⁷ Electroconvulsive therapy also has been reported to effectively treat depression in HCV patients undergoing antiviral therapy.²⁸

CASE CONTINUED: Lingering symptoms

Mr. P responds to citalopram with an improvement in mood, anhedonia, and appetite, but he continues to complain of low energy and poor concentration. In an effort to target these symptoms, methylphenidate, titrated to 30 mg/d in divided doses, is added to his regimen, which rapidly improves his symptoms. Insomnia is treated successfully with trazodone, 50 mg/d. Mr. P frequently visits his psychiatrist, who monitors his depressive symptoms using the BDI-II. Mr. P completes HCV treatment without recurrence of depressive symptoms or relapse to heroin use.

Although antidepressants are effective for treating affective and cognitive symptoms, they are not as effective for fatigue and other neurovegetative symptoms.^16,29 The psychostimulants methylphenidate and dextroamphetamine and the nonstimulant modafinil have been studied for treating depressive symptoms in medically ill patients and can be used to treat IFN-α-induced fatigue.^16,22,29

IFN-α’s effect on serotonin metabolism leads to a tryptophan-deficient state because of increased catabolism as a result of activation of indoleamine-2,3-dioxygenase (IDO). This has led to use of tryptophan supplementation, either as augmentation or monotherapy, for managing depressive symptoms in patients treated with IFN-α. Schaefer et al³⁰ reported 3 cases where tryptophan supplementation significantly decreased depressive symptoms. Other researchers have argued that supplementing tryptophan in the context of IDO activation can lead to greater production of kynurenine and quinolinic acid, which have been linked to increased depressive symptoms in patients receiving IFN-α.³¹ They argue that supplementation of 5-HTP, which is available as a dietary supplement without a prescription, can lead to increased serotonin levels and improvement in depressive symptoms.³¹

IFN-α treatment also is associated with mania and psychosis. The incidence, pathophysiology, and management of these treatment-emergent symptoms are not as well studied as IFN-α-induced depression. Mania and hypomania have been reported with interferon treatment, discontinuation of interferon, and use of antidepressants for interferon-induced depression.^29,32 Psychosis, in association with mood symptoms or alone, has been reported to occur in <1% of treated patients.³³ Treatment for mania and psychosis consists of decreasing or discontinuing immunotherapy and adding mood stabilizers and antipsychotics. Once immunotherapy is discontinued, mania and psychosis usually resolve, but prolonged duration of symptoms has been reported.^29,32,33

Related Resources

• Centers for Disease Control and Prevention. Hepatitis C information for health professionals. www.cdc.gov/hepatitis/hcv/index.htm.
• Hep C Connection. www.hepc-connection.org.
• United States Department of Veterans Affairs. Hepatitis C. www.hepatitis.va.gov.

Drug Brand Names

• Boceprevir • Victrelis
• Citalopram • Celexa
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Interferon-α • Intron
• Methadone • Dolophine, Methadose
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Ondansetron • Zofran
• Ribavirin • Copegus, Rebetol, others
• Telaprevir • Incivek
• Trazodone • Desyrel, Oleptro

Disclosure

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

Mr. P, age 31, has been using heroin intravenously for 9 years. He smokes 1 pack of cigarettes daily, but denies using other substances, including alcohol. After an unintentional heroin overdose, Mr. P enrolls in a methadone maintenance treatment program (MMTP) that includes primary medical care and addiction medicine and psychiatric specialists, where he undergoes medical evaluation and screening for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Laboratory data reveal that although Mr. P is HIV negative, he has been exposed to HCV and treatment is indicated.

Among the approximately 3 million people in the United States with chronic HCV—an enveloped, single-stranded RNA virus—there’s a high prevalence of premorbid psychopathology and substance abuse, as well as neuropsychiatric effects caused by HCV treatment.^1-3 Because underdiagnosing and undertreating psychiatric disorders contributes to morbidity and mortality in HCV patients, early identification and prompt treatment is critical.

IV drug use is the most common route for HCV infection, accounting for 65% to 70% of infections.¹ The prevalence of HCV among IV drug users is 28% to 90%.¹ Once exposed to HCV, 75% to 85% of patients do not clear the initial infection and become chronically infected.

This article reviews the pathophysiology, identification, and management of psychiatric manifestations found among HCV patients and provides an understanding of how psychiatric symptoms manifest in HCV patients. This article also discusses HCV treatment and its neuropsychiatric side effects.

Testing for HCV

Chronically infected HCV patients may have few, if any, specific physical complaints, and often are diagnosed during screenings or other routine laboratory evaluations. The presence of risk factors, such as a history of injection drug use or receiving a blood transfusion before 1992,¹ guides the decision to screen for HCV. Normal liver function test results should not preclude testing because many HCV-positive patients have transaminases within the normal range.⁴ Initial screening is via an antibody-mediated immunoassay that is highly specific and sensitive for past exposure to HCV (Table 1).⁴ However, a positive screen does not indicate the presence of active infection. Evidence of the virus via a viral assay will identify active HCV, but does not indicate need for treatment. Liver biopsy confirms the presence of liver injury and quantifies its extent. The severity of liver damage will determine whether treatment is needed. HCV genotyping determines the appropriate duration and dosage of pharmacotherapy.

Table 1

Tests to diagnose and evaluate HCV

CASE CONTINUED: Mood improves, but fatigue persists

As part of pre-HCV treatment evaluation, Mr. P undergoes a psychiatric evaluation. He describes periods of low mood while actively engaged in drug use but has never received psychiatric treatment, experienced suicidal ideation, or attempted suicide. Since starting opioid agonist therapy, he reports improved mood but endorses continued mild fatigue and difficulty falling sleep. The psychiatrist determines Mr. P does not meet criteria for an axis I diagnosis other than a substance use disorder.

Although most HCV patients have few, if any, nonspecific physical symptoms, many have psychiatric symptoms or disorders before the HCV diagnosis is made or treatment is initiated; substance use disorders are most common. Batki et al¹ found that 56% of HCV patients in an MMTP met criteria for a nonsubstance axis I disorder and 82% met criteria for such a disorder during their lifetime. Additionally, 66% of patients were taking psychiatric medications. Table 2^1,5,6 lists the rates of other psychiatric disorders found in patients with untreated HCV.

Table 2

Rates of psychiatric disorders in patients with untreated hepatitis C virus

Many patients with chronic HCV complain of chronic fatigue and deficiencies in attention, concentration, higher executive functions, learning ability, and memory that result in significant reduction in quality of life (Box 1).^7-9 These findings have been found to be independent of the degree of liver disease and are seen in HCV patients with normal liver function.^7,8

Box 1

CASE CONTINUED: Motivated and compliant

Since joining the MMTP 6 months ago, Mr. P has been motivated and compliant with all appointments and treatments. Routine urine toxicology screening supports his claim of abstinence. Mr. P begins HCV treatment while continuing follow-up with addiction medicine and psychiatric clinicians and maintains open communication with all treatment providers.

For many years the standard HCV treatment was pegylated interferon-α (IFN-α) and ribavirin. IFN-α is a proinflammatory cytokine with antiproliferative, antiviral, and immunoregulatory properties. The half-life of IFN-α significantly increases with pegylation, which allows for weekly injections.^10,11 IFN-α usually is combined with ribavirin, which increases its efficacy as measured by the sustained virological response (SVR) compared with IFN-α alone. Depending on the virus genotype, treatment lasts 24 to 48 weeks; SVR rates range from 40% to 82%.^11-13 In 2011, the FDA approved 2 agents—telaprevir and boceprevir—for adjunctive treatment of HCV genotype 1 infection. These 2 agents are protease inhibitors that when added to IFN-α and ribavirin increase the SVR rate in genotype 1 infection from 40% to 50% to approximately 75%.^14,15

Although the neuropsychiatric side effects of telaprevir and boceprevir have not been determined, treating chronic HCV with IFN-α and ribavirin has been associated with multiple psychiatric symptoms, including depression, mania, suicidality, anxiety, and psychosis.^11-14 Psychiatric symptoms are a common reason for discontinuing or reducing HCV treatment. Because of the high frequency of neuropsychiatric complications, some clinicians believe HCV patients with preexisting affective, psychotic, or substance use disorders should be excluded from HCV treatment. This has led to many HCV patients being untreated despite a lack of prospective, controlled data to support this opinion.¹² To improve outcomes and decrease morbidity, providing appropriate psychiatric services appears to be more important than attempting to select lower-risk patients for antiviral therapy.^1,12,16 The goals of psychiatric treatment should be to alleviate symptoms and allow patients to complete IFN-α therapy without interruption.^16,17

Studies of high-risk patients who attend multidisciplinary treatment programs that can monitor adherence and efficacy and control side effects before and during HCV treatment have found psychiatric patients have similar adherence, compliance, and SVR rates and were not at increased risk of worsening depressive or psychotic symptoms compared with patients without a psychiatric history.^12,18 Additionally, HCV patients with a psychiatric history are not at an increased risk of suicide.^13,16 Similar findings have been observed in patients with active IV drug use or those receiving opioid agonist therapy. When HCV and substance use are treated simultaneously, patients can successfully complete HCV treatment with SVR rates comparable to those of patients not receiving opioid agonist therapy.^19-21

CASE CONTINUED: Worsening symptoms

During a psychiatric follow-up 12 weeks after starting HCV treatment, Mr. P reports worsening depressive symptoms with low mood, decreased enjoyment of activities, poor sleep, low appetite, and fatigue. He shows no evidence of psychosis and denies suicidal ideation. We continue his HCV treatment, schedule more frequent psychiatric visits, and initiate citalopram, titrated to 40 mg/d.

Depressive symptoms, the most common neuropsychiatric manifestation of HCV, typically begin early in treatment, usually within the first 12 weeks. Two distinct symptom clusters are noted. A neurovegetative cluster characterized by reduced energy, anorexia, and psychomotor retardation typically begins within the first few months of treatment. Months later, a depression-specific syndrome appears that includes depressed mood, anxiety, and cognitive impairment.²²

Depressive symptoms may occur in up to 60% of patients treated with IFN-α.¹¹ When more rigorous depression measures are used, rates decrease to approximately 20% to 30%.^11,13 Accurate diagnosis and treatment of emerging depressive symptoms is essential because untreated depression can lead to postponing or excluding patients from antiviral treatment.² Screening instruments such as the Beck Depression Inventory-Second Edition (BDI-II) can be used to measure depressive symptoms in HCV patients with high sensitivity. However, because specificity has been low and somatic symptoms of chronic illness and depression often overlap, the BDI-II and other inventories may overestimate depression. Some researchers have suggested that focusing on questions targeting cognitive and affective symptoms rather than somatic ones may be a more valid measure of depression in patients undergoing immunotherapy for HCV.²

The immune system is implicated in IFN-α-induced depression because depressive symptoms share many features with a constellation of somatic and behavioral symptoms termed “sickness behavior.”¹¹ These behaviors can occur when patients are exposed to cytokines that lead to a depressed level of functioning, which may allow the body to devote more energy to fighting illness. IFN-α, a cytokine, stimulates the immune system, which can lead to increases of interleukin (IL)-2, IL-6, and IL-10. Increased circulating levels of these ILs have been correlated with higher depression scores. Additionally, studies have found that patients who develop depression during IFN-α treatment have higher SVR rates, suggesting a more robust immune response.^11,22 For a discussion of how serotonin metabolism and genetic polymorphisms also may help explain the prevalence of depression in patients with HCV, see Box 2.

Box 2

Treating depressed HCV patients

Antidepressants are the treatment of choice for IFN-α-induced depression. Most currently used antidepressants are effective²² and selective serotonin reuptake inhibitors are considered first choice.¹⁶ Antidepressant choice should be guided by principles similar to those used for patients without HCV: using side effects profiles to target specific symptoms and being mindful of pharmacokinetic properties.

Two treatment approaches have been investigated: prophylactic and symptomatic. A 2012 study²³ of 181 HCV patients with no history of mental illness determined escitalopram, 10 mg/d, effectively reduced the incidence and severity of interferon-associated depression. Other studies examining prophylactic treatment of all patients who were to undergo interferon treatment found this approach did not prevent depressive episodes.^24,25 However, antidepressants have been beneficial for patients with subsyndromal depressive symptoms at baseline²⁶ and after clinically significant depressive symptoms emerge.²⁷ Electroconvulsive therapy also has been reported to effectively treat depression in HCV patients undergoing antiviral therapy.²⁸

CASE CONTINUED: Lingering symptoms

Mr. P responds to citalopram with an improvement in mood, anhedonia, and appetite, but he continues to complain of low energy and poor concentration. In an effort to target these symptoms, methylphenidate, titrated to 30 mg/d in divided doses, is added to his regimen, which rapidly improves his symptoms. Insomnia is treated successfully with trazodone, 50 mg/d. Mr. P frequently visits his psychiatrist, who monitors his depressive symptoms using the BDI-II. Mr. P completes HCV treatment without recurrence of depressive symptoms or relapse to heroin use.

Although antidepressants are effective for treating affective and cognitive symptoms, they are not as effective for fatigue and other neurovegetative symptoms.^16,29 The psychostimulants methylphenidate and dextroamphetamine and the nonstimulant modafinil have been studied for treating depressive symptoms in medically ill patients and can be used to treat IFN-α-induced fatigue.^16,22,29

IFN-α’s effect on serotonin metabolism leads to a tryptophan-deficient state because of increased catabolism as a result of activation of indoleamine-2,3-dioxygenase (IDO). This has led to use of tryptophan supplementation, either as augmentation or monotherapy, for managing depressive symptoms in patients treated with IFN-α. Schaefer et al³⁰ reported 3 cases where tryptophan supplementation significantly decreased depressive symptoms. Other researchers have argued that supplementing tryptophan in the context of IDO activation can lead to greater production of kynurenine and quinolinic acid, which have been linked to increased depressive symptoms in patients receiving IFN-α.³¹ They argue that supplementation of 5-HTP, which is available as a dietary supplement without a prescription, can lead to increased serotonin levels and improvement in depressive symptoms.³¹

IFN-α treatment also is associated with mania and psychosis. The incidence, pathophysiology, and management of these treatment-emergent symptoms are not as well studied as IFN-α-induced depression. Mania and hypomania have been reported with interferon treatment, discontinuation of interferon, and use of antidepressants for interferon-induced depression.^29,32 Psychosis, in association with mood symptoms or alone, has been reported to occur in <1% of treated patients.³³ Treatment for mania and psychosis consists of decreasing or discontinuing immunotherapy and adding mood stabilizers and antipsychotics. Once immunotherapy is discontinued, mania and psychosis usually resolve, but prolonged duration of symptoms has been reported.^29,32,33

Related Resources

• Centers for Disease Control and Prevention. Hepatitis C information for health professionals. www.cdc.gov/hepatitis/hcv/index.htm.
• Hep C Connection. www.hepc-connection.org.
• United States Department of Veterans Affairs. Hepatitis C. www.hepatitis.va.gov.

Drug Brand Names

• Boceprevir • Victrelis
• Citalopram • Celexa
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Interferon-α • Intron
• Methadone • Dolophine, Methadose
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Ondansetron • Zofran
• Ribavirin • Copegus, Rebetol, others
• Telaprevir • Incivek
• Trazodone • Desyrel, Oleptro

Disclosure

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

In “Pharmacotherapy for comorbid depression and alcohol dependence” (Current Psychiatry, January 2013, p. 24-32; http://bit.ly/1dBavVI), Drs. Gianoli and Petrakis report that the potential benefits of mixing antidepressants and alcohol dependence medications is extremely limited. Their article confirms the general wisdom in addiction psychiatry and is distressing in the short shrift given to the primary avenue physicians have for treating this dual condition—encouraging abstinence.

McLellan et al¹ found that treating alcohol addiction produces outcomes comparable to treating hypertension and diabetes. However, if psychiatry were to bring its current overemphasis on pharmacology and underappreciation of psychotherapy to treating alcohol addiction, it would not produce the effectiveness of current multimodal, multidisciplinary approaches. Under the Affordable Care Act, primary care physicians will be expected to identify high-risk alcohol consumption and encourage reduction of risk, including treatment and recovery. What the authors allude to as “encouraging abstinence” is a complex art and craft that all physicians will need to attend to more than in the past. Drs. Gianoli and Petrakis’ work tells us why this is so: pharmacology does not rule in the treatment of mixed depression and alcohol dependence.

Timmen L. Cermak, MD
Immediate Past President
California Society of Addiction Medicine
Mill Valley, CA

The authors respond

We thank Dr. Cermak for his comments on our article. We wrote a review of the literature on the efficacy of various pharmacologic treatments to treat patients with comorbid depression and alcohol dependence. The purpose of our review was to remind practitioners that efficacy of antidepressants or medications to treat alcohol use disorders may be different in individuals with a comorbid disorder. Studies determining efficacy have been conducted primarily in noncomorbid groups and the results may not be generalizable. Emerging literature is trying to address this shortcoming. This is an important point that we hope we adequately conveyed to Current Psychiatry’s readers.

Our article was not a comprehensive review of all possible treatment options; we mentioned that a review of nonpharmacologic treatments was beyond the scope of our review. This does not mean that psychosocial treatments are not valued or important; they are an important part of any comprehensive treatment plan.

Mayumi Okada Gianoli, PhD
Postdoctoral Fellow
Department of Psychiatry
Yale University School of Medicine

Ismene L. Petrakis, MD
Professor of Psychiatry
Yale University School of Medicine
Chief of Psychiatry Service
Veterans Affairs Connecticut Healthcare Systems
New Haven, CT

In “Pharmacotherapy for comorbid depression and alcohol dependence” (Current Psychiatry, January 2013, p. 24-32; http://bit.ly/1dBavVI), Drs. Gianoli and Petrakis report that the potential benefits of mixing antidepressants and alcohol dependence medications is extremely limited. Their article confirms the general wisdom in addiction psychiatry and is distressing in the short shrift given to the primary avenue physicians have for treating this dual condition—encouraging abstinence.

McLellan et al¹ found that treating alcohol addiction produces outcomes comparable to treating hypertension and diabetes. However, if psychiatry were to bring its current overemphasis on pharmacology and underappreciation of psychotherapy to treating alcohol addiction, it would not produce the effectiveness of current multimodal, multidisciplinary approaches. Under the Affordable Care Act, primary care physicians will be expected to identify high-risk alcohol consumption and encourage reduction of risk, including treatment and recovery. What the authors allude to as “encouraging abstinence” is a complex art and craft that all physicians will need to attend to more than in the past. Drs. Gianoli and Petrakis’ work tells us why this is so: pharmacology does not rule in the treatment of mixed depression and alcohol dependence.

Timmen L. Cermak, MD
Immediate Past President
California Society of Addiction Medicine
Mill Valley, CA

The authors respond

We thank Dr. Cermak for his comments on our article. We wrote a review of the literature on the efficacy of various pharmacologic treatments to treat patients with comorbid depression and alcohol dependence. The purpose of our review was to remind practitioners that efficacy of antidepressants or medications to treat alcohol use disorders may be different in individuals with a comorbid disorder. Studies determining efficacy have been conducted primarily in noncomorbid groups and the results may not be generalizable. Emerging literature is trying to address this shortcoming. This is an important point that we hope we adequately conveyed to Current Psychiatry’s readers.

Our article was not a comprehensive review of all possible treatment options; we mentioned that a review of nonpharmacologic treatments was beyond the scope of our review. This does not mean that psychosocial treatments are not valued or important; they are an important part of any comprehensive treatment plan.

Mayumi Okada Gianoli, PhD
Postdoctoral Fellow
Department of Psychiatry
Yale University School of Medicine

Ismene L. Petrakis, MD
Professor of Psychiatry
Yale University School of Medicine
Chief of Psychiatry Service
Veterans Affairs Connecticut Healthcare Systems
New Haven, CT

In “Pharmacotherapy for comorbid depression and alcohol dependence” (Current Psychiatry, January 2013, p. 24-32; http://bit.ly/1dBavVI), Drs. Gianoli and Petrakis report that the potential benefits of mixing antidepressants and alcohol dependence medications is extremely limited. Their article confirms the general wisdom in addiction psychiatry and is distressing in the short shrift given to the primary avenue physicians have for treating this dual condition—encouraging abstinence.

McLellan et al¹ found that treating alcohol addiction produces outcomes comparable to treating hypertension and diabetes. However, if psychiatry were to bring its current overemphasis on pharmacology and underappreciation of psychotherapy to treating alcohol addiction, it would not produce the effectiveness of current multimodal, multidisciplinary approaches. Under the Affordable Care Act, primary care physicians will be expected to identify high-risk alcohol consumption and encourage reduction of risk, including treatment and recovery. What the authors allude to as “encouraging abstinence” is a complex art and craft that all physicians will need to attend to more than in the past. Drs. Gianoli and Petrakis’ work tells us why this is so: pharmacology does not rule in the treatment of mixed depression and alcohol dependence.

Timmen L. Cermak, MD
Immediate Past President
California Society of Addiction Medicine
Mill Valley, CA

The authors respond

We thank Dr. Cermak for his comments on our article. We wrote a review of the literature on the efficacy of various pharmacologic treatments to treat patients with comorbid depression and alcohol dependence. The purpose of our review was to remind practitioners that efficacy of antidepressants or medications to treat alcohol use disorders may be different in individuals with a comorbid disorder. Studies determining efficacy have been conducted primarily in noncomorbid groups and the results may not be generalizable. Emerging literature is trying to address this shortcoming. This is an important point that we hope we adequately conveyed to Current Psychiatry’s readers.

Our article was not a comprehensive review of all possible treatment options; we mentioned that a review of nonpharmacologic treatments was beyond the scope of our review. This does not mean that psychosocial treatments are not valued or important; they are an important part of any comprehensive treatment plan.

Mayumi Okada Gianoli, PhD
Postdoctoral Fellow
Department of Psychiatry
Yale University School of Medicine

Ismene L. Petrakis, MD
Professor of Psychiatry
Yale University School of Medicine
Chief of Psychiatry Service
Veterans Affairs Connecticut Healthcare Systems
New Haven, CT

The demand for “legal highs”— intoxicating natural or synthetic substances that are not prohibited by law—continues to increase. Young adults may use these substances, which are widely available on the internet, at “head shops,” and at gas stations. Such substances frequently cause adverse medical and psychiatric effects, exemplified by recent reports concerning the dangers of using synthetic cannabinoids (eg, “Spice,” “K2”) and synthetic cathinones (“bath salts”). Although these 2 substances now are illegal in many jurisdictions, other novel substances of misuse remain legal and widely available, including Kratom and methoxetamine.

Because these substances usually are not detectable on standard urine toxicology screens, clinicians need to be aware of them to be able to take an accurate substance use history, consider possible dangerous interactions with prescribed psychotropics, and address medical and psychiatric complications.

Kratom is an herbal product derived from Mitragyna speciosa, a plant native to Southeast Asia. Traditionally used as a medicinal herb, it increasingly is being used for recreational purposes and remains legal and widely available in the United States. Kratom’s leaves contain multiple alkaloids, including mitragynine and 7-hydroxymitragynine, which are believed to act as agonists at the μ-opioid receptor. Mitragynine also may have agonist activity at post-synaptic α2-adrenergic receptors, as well as antagonist activity at 5-HT2A receptors.¹ Mitragynine is 13 times more potent than morphine, and 7-hydroxymitragynine is 4 times more potent than mitragynine.²

Kratom is available as leaves, powdered leaves, or gum. It can be smoked, brewed into tea, or mixed with liquid and ingested. Effects are dose-dependent; lower doses tend to produce a stimulant effect and higher doses produce an opioid effect. A typical dose is 1 to 8 g.³ Users may take Kratom to experience euphoria or analgesia, or to self-treat opioid withdrawal symptoms.³ Kratom withdrawal syndrome shares many features of classic opioid withdrawal—diarrhea, rhinorrhea, cravings, anxiety, tremor, myalgia, sweating, and irritability—but has been reported to be less severe and shorter-lasting.¹ Kratom withdrawal, like opioid withdrawal, may respond to supportive care in combination with opioid-replacement therapy. Airway management and naloxone treatment may be needed on an emergent basis if a user develops respiratory depression.² There have been case reports of seizures occurring following Kratom use.²

Methoxetamine is a ketamine analog originally developed as an alternative to ketamine. It isn’t classified as a controlled substance in the United States and is available on the internet.² Methoxetamine is a white powder typically snorted or taken sublingually, although it can be injected intramuscularly. Because methoxetamine’s structure is similar to ketamine, its mechanism of action is assumed to involve glutamate N-methyl-D-aspartate receptor antagonism and dopamine reuptake inhibition. Doses range from 20 to 100 mg orally and 10 to 50 mg when injected. Effects may not be apparent for 30 to 90 minutes after the drug is snorted, which may cause users to take another dose or ingest a different substance, possibly leading to synergistic adverse effects. Effects may emerge within 5 minutes when injected. The duration of effect generally is 5 to 7 hours—notably longer than ketamine—but as little as 1 hour when injected.

No clinical human or animal studies have been conducted on methoxetamine, which makes it difficult to ascertain the drug’s true clinical and toxic effects; instead, these effects must be surmised from user reports and case studies. Desired effects described by users are similar to those of ketamine: dissociation, short-term mood elevation, visual hallucinations, and alteration of sensory experiences. Reported adverse effects include catatonia, confusion, agitation, and depression.⁴ In addition, methoxetamine may induce sympathomimetic toxicity as evidenced by tachycardia and hypertension. Researchers have suggested that patients who experience methoxetamine toxicity and require emergency treatment be managed with supportive care and benzodiazepines.⁵

Staying current is key

A paucity of clinical research on these substances means their effects are poorly understood, which creates a dangerous situation for users and physicians. In addition, many users assume these substances are safer than illegal substances. New and potentially dangerous substances are being produced so quickly distributors are able to stay ahead of regulatory efforts. When one substance is declared illegal, another related substance quickly is available to take its place. To provide the best care for our patients, it is essential for psychiatrists to stay up-to-date about these novel substances.

Disclosure

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

The demand for “legal highs”— intoxicating natural or synthetic substances that are not prohibited by law—continues to increase. Young adults may use these substances, which are widely available on the internet, at “head shops,” and at gas stations. Such substances frequently cause adverse medical and psychiatric effects, exemplified by recent reports concerning the dangers of using synthetic cannabinoids (eg, “Spice,” “K2”) and synthetic cathinones (“bath salts”). Although these 2 substances now are illegal in many jurisdictions, other novel substances of misuse remain legal and widely available, including Kratom and methoxetamine.

Because these substances usually are not detectable on standard urine toxicology screens, clinicians need to be aware of them to be able to take an accurate substance use history, consider possible dangerous interactions with prescribed psychotropics, and address medical and psychiatric complications.

Kratom is an herbal product derived from Mitragyna speciosa, a plant native to Southeast Asia. Traditionally used as a medicinal herb, it increasingly is being used for recreational purposes and remains legal and widely available in the United States. Kratom’s leaves contain multiple alkaloids, including mitragynine and 7-hydroxymitragynine, which are believed to act as agonists at the μ-opioid receptor. Mitragynine also may have agonist activity at post-synaptic α2-adrenergic receptors, as well as antagonist activity at 5-HT2A receptors.¹ Mitragynine is 13 times more potent than morphine, and 7-hydroxymitragynine is 4 times more potent than mitragynine.²

Kratom is available as leaves, powdered leaves, or gum. It can be smoked, brewed into tea, or mixed with liquid and ingested. Effects are dose-dependent; lower doses tend to produce a stimulant effect and higher doses produce an opioid effect. A typical dose is 1 to 8 g.³ Users may take Kratom to experience euphoria or analgesia, or to self-treat opioid withdrawal symptoms.³ Kratom withdrawal syndrome shares many features of classic opioid withdrawal—diarrhea, rhinorrhea, cravings, anxiety, tremor, myalgia, sweating, and irritability—but has been reported to be less severe and shorter-lasting.¹ Kratom withdrawal, like opioid withdrawal, may respond to supportive care in combination with opioid-replacement therapy. Airway management and naloxone treatment may be needed on an emergent basis if a user develops respiratory depression.² There have been case reports of seizures occurring following Kratom use.²

Methoxetamine is a ketamine analog originally developed as an alternative to ketamine. It isn’t classified as a controlled substance in the United States and is available on the internet.² Methoxetamine is a white powder typically snorted or taken sublingually, although it can be injected intramuscularly. Because methoxetamine’s structure is similar to ketamine, its mechanism of action is assumed to involve glutamate N-methyl-D-aspartate receptor antagonism and dopamine reuptake inhibition. Doses range from 20 to 100 mg orally and 10 to 50 mg when injected. Effects may not be apparent for 30 to 90 minutes after the drug is snorted, which may cause users to take another dose or ingest a different substance, possibly leading to synergistic adverse effects. Effects may emerge within 5 minutes when injected. The duration of effect generally is 5 to 7 hours—notably longer than ketamine—but as little as 1 hour when injected.

No clinical human or animal studies have been conducted on methoxetamine, which makes it difficult to ascertain the drug’s true clinical and toxic effects; instead, these effects must be surmised from user reports and case studies. Desired effects described by users are similar to those of ketamine: dissociation, short-term mood elevation, visual hallucinations, and alteration of sensory experiences. Reported adverse effects include catatonia, confusion, agitation, and depression.⁴ In addition, methoxetamine may induce sympathomimetic toxicity as evidenced by tachycardia and hypertension. Researchers have suggested that patients who experience methoxetamine toxicity and require emergency treatment be managed with supportive care and benzodiazepines.⁵

Staying current is key

A paucity of clinical research on these substances means their effects are poorly understood, which creates a dangerous situation for users and physicians. In addition, many users assume these substances are safer than illegal substances. New and potentially dangerous substances are being produced so quickly distributors are able to stay ahead of regulatory efforts. When one substance is declared illegal, another related substance quickly is available to take its place. To provide the best care for our patients, it is essential for psychiatrists to stay up-to-date about these novel substances.

Disclosure

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

The demand for “legal highs”— intoxicating natural or synthetic substances that are not prohibited by law—continues to increase. Young adults may use these substances, which are widely available on the internet, at “head shops,” and at gas stations. Such substances frequently cause adverse medical and psychiatric effects, exemplified by recent reports concerning the dangers of using synthetic cannabinoids (eg, “Spice,” “K2”) and synthetic cathinones (“bath salts”). Although these 2 substances now are illegal in many jurisdictions, other novel substances of misuse remain legal and widely available, including Kratom and methoxetamine.

Because these substances usually are not detectable on standard urine toxicology screens, clinicians need to be aware of them to be able to take an accurate substance use history, consider possible dangerous interactions with prescribed psychotropics, and address medical and psychiatric complications.

Kratom is an herbal product derived from Mitragyna speciosa, a plant native to Southeast Asia. Traditionally used as a medicinal herb, it increasingly is being used for recreational purposes and remains legal and widely available in the United States. Kratom’s leaves contain multiple alkaloids, including mitragynine and 7-hydroxymitragynine, which are believed to act as agonists at the μ-opioid receptor. Mitragynine also may have agonist activity at post-synaptic α2-adrenergic receptors, as well as antagonist activity at 5-HT2A receptors.¹ Mitragynine is 13 times more potent than morphine, and 7-hydroxymitragynine is 4 times more potent than mitragynine.²

Kratom is available as leaves, powdered leaves, or gum. It can be smoked, brewed into tea, or mixed with liquid and ingested. Effects are dose-dependent; lower doses tend to produce a stimulant effect and higher doses produce an opioid effect. A typical dose is 1 to 8 g.³ Users may take Kratom to experience euphoria or analgesia, or to self-treat opioid withdrawal symptoms.³ Kratom withdrawal syndrome shares many features of classic opioid withdrawal—diarrhea, rhinorrhea, cravings, anxiety, tremor, myalgia, sweating, and irritability—but has been reported to be less severe and shorter-lasting.¹ Kratom withdrawal, like opioid withdrawal, may respond to supportive care in combination with opioid-replacement therapy. Airway management and naloxone treatment may be needed on an emergent basis if a user develops respiratory depression.² There have been case reports of seizures occurring following Kratom use.²

Methoxetamine is a ketamine analog originally developed as an alternative to ketamine. It isn’t classified as a controlled substance in the United States and is available on the internet.² Methoxetamine is a white powder typically snorted or taken sublingually, although it can be injected intramuscularly. Because methoxetamine’s structure is similar to ketamine, its mechanism of action is assumed to involve glutamate N-methyl-D-aspartate receptor antagonism and dopamine reuptake inhibition. Doses range from 20 to 100 mg orally and 10 to 50 mg when injected. Effects may not be apparent for 30 to 90 minutes after the drug is snorted, which may cause users to take another dose or ingest a different substance, possibly leading to synergistic adverse effects. Effects may emerge within 5 minutes when injected. The duration of effect generally is 5 to 7 hours—notably longer than ketamine—but as little as 1 hour when injected.

No clinical human or animal studies have been conducted on methoxetamine, which makes it difficult to ascertain the drug’s true clinical and toxic effects; instead, these effects must be surmised from user reports and case studies. Desired effects described by users are similar to those of ketamine: dissociation, short-term mood elevation, visual hallucinations, and alteration of sensory experiences. Reported adverse effects include catatonia, confusion, agitation, and depression.⁴ In addition, methoxetamine may induce sympathomimetic toxicity as evidenced by tachycardia and hypertension. Researchers have suggested that patients who experience methoxetamine toxicity and require emergency treatment be managed with supportive care and benzodiazepines.⁵

Staying current is key

A paucity of clinical research on these substances means their effects are poorly understood, which creates a dangerous situation for users and physicians. In addition, many users assume these substances are safer than illegal substances. New and potentially dangerous substances are being produced so quickly distributors are able to stay ahead of regulatory efforts. When one substance is declared illegal, another related substance quickly is available to take its place. To provide the best care for our patients, it is essential for psychiatrists to stay up-to-date about these novel substances.

Disclosure

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

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.