Sneezing, coughing, and a sore throat are hallmark symptoms of a common cold, but what keeps you in bed are the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain, and apathetic withdrawal. This “sickness behavior” is induced by inflammatory markers released in response to illness.^1,2 These symptoms are similar to the constellation of symptoms that define depression. Within the inflammatory response to illness, we see the shadow of depression, but the precise relationship remains murky.

Is depression part of a normal somatic inflammatory response run amok? Some researchers have argued that “sickness behavior” is adaptive, forcing the body into a constricted pattern in order to funnel energy into healing.^1,3 If depression and inflammation are related, depression pushes past these adaptive roots and is less a forced pause than a debilitating withdrawal. Perhaps depression, or a subtype, is a sign of inflammation along with heat, pain, redness, and swelling. In some instances, depression may be a sign of an underlying inflammatory process.⁴

In our progression toward understanding depression’s pathophysiology, we see factors that point to a relationship between depression and inflammation:

• depression frequently is comorbid with many inflammatory illnesses

• increased inflammatory biomarkers are associated with major depressive disorder (MDD) 

• exposure to immunomodulating agents may increase the risk of developing depression 

• stress can activate proinflammatory pathways

• antidepressants can decrease inflammatory response

• inhibition of inflammatory pathways can improve mood. 

Exploring these factors and a possible pathway linking inflammation and neurobiologic changes found in depression allows us to look closer at the possible integration of the inflammatory process and depressive symptoms.

Illness and depression rates

Individuals with inflammatory illnesses—autoimmune diseases, cardiovascular disease, diabetes, and cancer—often struggle with depression. Nearly 1 in 5 persons with cardiovascular disease experiences MDD.⁵ A diabetes diagnosis doubles the odds of having depression.⁶ Up to 70% of patients with autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus, experience depression.^7,8 In a large-scale longitudinal study, having a prior autoimmune disease increased the risk of depression by 45% and history of hospitalization with infection increased a patient’s risk by 62%; the risk more than doubled in individuals with both.⁹ Several studies show that 15% to 25% of cancer patients experience depression,¹⁰ compared with 9% in the general population.¹¹

Role of inflammatory markers

During an inflammatory episode the body releases cytokines, which are small, cell-signaling protein molecules. These inflammatory markers launch signaling cascades that incite the immune system into action. Type 1 cytokines (interferon-ã, tumor necrosis factor-á [TNF-á], interleukin [IL]-1) enhance cellular immune responses, and type 2 cytokines (IL-6, IL-10, IL-13) engage antibody responses. These cytokines also induce acute phase proteins, such as C-reactive protein (CRP), which can activate the immune system. Significantly higher levels of inflammatory markers are associated with a range of depressive symptoms, which grants insight into disease severity and treatment response.^3,12,13

Multiple studies have explored the link between depression and inflammatory markers (Table).^14-21 Peripheral inflammatory markers such as IL-6, IL-1â, CRP, and TNF-á are elevated in inflammatory diseases and in otherwise healthy individuals with MDD.¹² In a meta-analysis of 24 studies measuring cytokines in depressed patients, Dowlati et al¹⁴ found individuals with MDD had significantly higher concentrations of TNF-á and IL-6 compared with controls. Increased peripheral inflammatory markers were found among antidepressant nonresponders more often than those who responded to treatment.^15,22 

Cytokines and depression risk

Administering immunomodulating agents has been shown to increase the risk of developing depression. Injecting animals with IL-1â or TNF-á causes sickness behavior in a dose- and time-related manner.¹ As these inflammatory signaling proteins increase, sickness behaviors become more pronounced.

In humans, a natural model arises in the use of the cytokine interferon-á (INF-á) for treating hepatitis C, multiple sclerosis, malignant melanoma, and some blood cancers. Patients receiving INF-á have higher rates of depression than those not administered interferon.¹⁶ Patients receiving chronic immunotherapy treatment show long-term changes in monoamine neurotransmitters and along the HPA axis; these changes mimic those seen in depressed individuals.^17,23 Acutely administered immunotherapeutic agents, such as the typhoid vaccine, have led to depressive symptoms with brain changes similar to those seen in MDD.¹⁸ Low levels of IL-6 and CRP independently predicted development of depression over several years.¹⁹

Immunotherapy-induced depression looks similar to any other major depressive episode through our current diagnostic framework and at the molecular and anatomical level.

Stress and inflammation

Depression can develop in the absence of inflammatory illness. Knowing that depressive symptoms may be associated with increased peripheral inflammatory markers, what induces the inflammatory process in some persons who are depressed but medically healthy? One theory is that psychological stress can activate inflammation.

Acute and chronic stress is associated with increased availability of proinflammatory cytokines and decreases in anti-inflammatory cytokines.^3,24 One theory looks to glucocorticoid response to stress as an explanation. Miller et al²⁵ found glucocorticoid sensitivity decreased among depressed women after exposure to a mock job interview stressor and increased among nondepressed controls. Because glucocorticoids normally stop the inflammatory cascade, this finding suggests depressed individuals may not be able to control inflammation during stress.²⁶ At the level of genetic expression, there is increased transcription of proinflammatory genes in response to stress as a result of increased activation of nuclear factor kappa B.^3,27

Shared pathways

If there is a relationship between inflammation and depression, what is the possible shared pathway?

There are 4 pathways by which cytokines effect changes in the CNS:¹²

• cytokines can activate primary afferent neurons (eg, vagal nerve)

• cytokines, released by macrophage-like cells in response to pathogens, diffuse through the brain’s circumventricular organs 

• cytokine transporters saturate the blood-brain barrier 

• cytokine IL-1 activates receptors on perivascular macrophages and endothelial cells of brain venules, causing local release of prostaglandin E2.

Through these pathways, cytokines initiate a cascade of reactions that lower serotonin levels and boost glutamatergic actions, possibly contributing to development of depressive symptoms. Depression correlates with a deficiency in serotonergic neurotransmission and increased glutamate receptor N-methyl-d-aspartate (NMDA) activation.²⁸

Proinflammatory cytokines activate theextrahepatic enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan, a precursor to serotonin (Figure 1). Tryptophan is channeled increasingly toward production of kynurenine via IDO degradation, competing with the serotonin pathway. Within the microglia, which are preferentially activated over astrocytes during inflammatory states, kynurenine is metabolized into quinolinic acid, which is an agonist of glutamatergic NMDA receptors.²⁸ Therefore, there is a serotonergic deficiency and glutamatergic overdrive in proinflammatory states that paves the way toward a likely depressive syndrome (Figure 2).

Antidepressants’ effects

The symptoms of cytokine-induced depression are no different from MDD with unknown etiology²⁹ and both are effectively treated with antidepressants. Even sickness behavior can be improved with antidepressant treatment.³⁰

Antidepressants not only decrease immunotherapy-induced depressive symptoms but have been shown to decrease inflammatory response and lower proinflammatory factors (IL-2, IL-6, TNF-á, and INF-ã).^31-33 Electroconvulsive therapy has been shown to normalize elevated TNF-á levels.³⁴

Enhancing depression treatment

Researchers are investigating whether treatment with anti-inflammatory agents can ease depressive symptoms. In animal studies, normal behavioral reactions to a stressor—similar to sickness behavior and overlapping with several features of depression—were reduced with administration of cytokine antagonists or anti-inflammatory cytokines directly into the brain.³⁵ However, there have been few successful trials in humans. Both anti-inflammatory agents such as cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid (aspirin), and TNF receptor antagonists can enhance depression treatments. Persoons et al³⁶ found that Crohn’s disease patients who had higher pretreatment CRP levels and MDD had greater remission of depressive symptoms after treatment with the TNF-á antagonist infliximab. In studies, depression within the context of other autoimmune disorders or any condition with increased inflammation has responded to treatment with TNF-á antagonists.^37,38 COX-2 inhibitors added to a standard antidepressant regimen improved depressive symptoms in medically healthy individuals during an acute depressive episode.³⁹ Aspirin has shown some benefits as an adjuvant agent in persons who have failed selective serotonin reuptake inhibitor monotherapy.^40,41

These anti-inflammatory agents have shown benefits in treating depression in some persons, but not in all. The key difference between those subsets of patients is elusive, mired in the complex interactions of the many systems that contribute to the symptoms we label as depression.

Future clinical applications

The association between depression and inflammation raises the possibility of a tantalizing line of future theories and treatment options. However, when considered individually, these pieces are limited in defining the precise relationship - a task nearly impossible for such a diffuse symptom as inflammation and such a complex disease as depression.

It is evident that inflammation and depression form a strong relationship to each other in individuals, which suggests the possibility of an inflammatory subtype of depression. At least within that limited group, there is the possibility of successful intervention and treatment of depression by directly treating inflammation with anti-inflammatory agents.

Perhaps once the relationship between depression and inflammation is further defined and a high-risk population identified—maybe even by genotype—depressive symptoms might be used to flag a provider’s attention to a possible disease process and serve as a new tool for identifying dangerous inflammatory activity at an early stage. Managing stress and depression may become the next tool to prevent inflammatory diseases.

Given our current knowledge, clinicians treating patients with inflammatory conditions should be aware of the increased risk of depression and ensure that depression screening is routinely completed and treatment is initiated or referrals made as needed. Ensuring appropriate depression treatment may help improve patients’ quality of life and ease the inflammatory response itself. 

For psychiatrists seeing patients with an inflammatory condition, brief explanations of the known links between depression and inflammation can provide patients—particularly those ambivalent about seeking mental health care—support for engaging in treatment and adhering to medication. Describing the links between inflammation and depression also can help encourage regular exercise and healthy diets rich in fruits, vegetables, and omega-3 fatty acids. In cases of treatment-resistant depression, particularly in those with known high inflammatory factors, it may be worthwhile to consider anti-inflammatory agents, such as infliximab, as an adjuvant treatment. 

The relationship between inflammation and depression is rapidly unfolding, but the full intricacies have not yet described. However, this beginning awareness of the interplay among stress, inflammation, and depression can broaden our approach to care and treatment.

Bottom Line

Depression and inflammation are linked in many ways, although neither appears to be wholly necessary or sufficient for the other. Most likely there exists a particular subset of patients for whom inflammation will precipitate and perpetuate depression.

Related Resources

• The Emory University Mind-Body Program. www.
  psychiatry.emory.edu/PROGRAMS/mindbody/index.html.
• Gabriel B. The evolutionary advantage of depression. The Atlantic. October 2, 2012. www.theatlantic.com/health/archive/2012/10/the-evolutionary-advantage-of-depression/263124.

Drug Brand Names

Infliximab • Remicade     Ribavirin • Rebetol, Virazole
Interferon-α • Intron

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

References

1. Dantzer R, O’Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.

2. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988;12(2):123-137.

3. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24-31.

4. Lamers F, Vogelzangs N, Merikangas KR, et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression [published online October 23, 2012]. Mol Psychiatry. doi: 10.1038/mp.2012.144.

5. Hoen P, Kupper N, de Jonge P. Depression and cardiovascular disease progression: epidemiology, mechanisms and treatment. In: Hjemdahl P, Rosengren A, Steptoe A, eds. Stress and cardiovascular disease. London, United Kingdom: Springer; 2012:211-233.

6. Anderson RJ, Freedland KE, Clouse RE, et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24(6):1069-1078.

7. Bachen EA, Chesney MA, Criswell LA. Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus. Arthritis Rheum. 2009;61(6):822-829.

8. Dickens C, McGowan L, Clark-Carter D, et al. Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis. Psychosom Med. 2002;64(1):52-60.

9. Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmunity and infections as risk factors for depression and other severe mental illnesses. Neurology, Psychiatry and Brain Research. 2012;18(2):40-41.

10. National Cancer Institute. Depression (PDQ). http://www.cancer.gov/cancertopics/pdq/supportivecare/depression/HealthProfessional/page1. Updated January 9, 2013. Accessed April 23, 2013.

11. Centers for Disease Control and Prevention. Current depression among adults—United States, 2006 and 2008. Morb Mortal Wkly Rep. 2010;59(38):1229-1235.

12. Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry. 2012;83(5):495-502.

13. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741.

14. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-457.

15. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9(11):853-858.

16. Raison CL, Borisov AS, Broadwell SD, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry. 2005;66(1):41-48.

17. Capuron L, Raison CL, Musselman DL, et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003;160(7):1342-1345.

18. Eisenberger NI, Berkman ET, Inagaki TK, et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68(8):748-754.

19. Pasco JA, Nicholson GC, Williams LJ, et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197(5):372-377.

20. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41.

21. Martinez JM, Garakani A, Yehuda R, et al. Proinflammatory and “resiliency” proteins in the CSF of patients with major depression. Depress Anxiety. 2012;29(1):32-38.

22. Lanquillon S, Krieg JC, Bening-Abu-Shach U, et al. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22(4):370-379.

23. Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry Rep. 2011;13(6):467-775.

24. Maes M, Song C, Lin A, et al. The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and Th1-like response in stress-induced anxiety. Cytokine. 1998;10(4):313-318.

25. Miller GE, Rohleder N, Stetler C, et al. Clinical depression and regulation of the inflammatory response during acute stress. Psychosom Med. 2005;67(5):679-687.

26. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160(9):1554-1565.

27. Tak PP, Firestein GS. NF-êB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7-12.

28. Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12(11):988-1000.

29. Capuron L, Fornwalt FB, Knight BT, et al. Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord. 2009;119(1-3):181-185.

30. Yirmiya R, Pollak Y, Morag M, et al. Illness, cytokines, and depression. Ann N Y Acad Sci. 2000;917(1):478-487.

31. Maes M. The immunoregulatory effects of antidepressants. Hum Psychopharmacol. 2001;16(1):95-103.

32. Szuster-Ciesielska A, Tustanowska-Stachura A, Słotwin`ska M, et al. In vitro immunoregulatory effects of antidepressants in healthy volunteers. Pol J Pharmacol. 2003;55(3):353-362.

33. Maes M, Berk M, Goehler L, et al. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med. 2012;10(1):66.

34. Hestad KA, Tønseth S, Støen CD, et al. Raised plasma levels of tumor necrosis factor [alpha] in patients with depression: normalization during electroconvulsive therapy. J ECT. 2003;19(4):183-188.

35. Maier SF, Watkins LR. Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock. Brain Res. 1995;695(2):279-282.

36. Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol Ther. 2005;22(2):101-110.

37. Mathias SD, Colwell HH, Miller DP, et al. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther. 2000;22(1):128-139.

38. Raison C, Rutherford RE, Woolwine B, et al. The tumor necrosis factor-alpha antagonist infliximab reduces depressive symptoms in patients with treatment resistant depression and high inflammation. Brain, Behavior, and Immunity. 2012;26(suppl 1):S49.

39. Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11(7):680-684.

40. Mendlewicz J, Kriwin P, Oswald P, et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21(4):227-231.

41. Brunello N, Alboni S, Capone G, et al. Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21(4):219-225.

Sneezing, coughing, and a sore throat are hallmark symptoms of a common cold, but what keeps you in bed are the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain, and apathetic withdrawal. This “sickness behavior” is induced by inflammatory markers released in response to illness.^1,2 These symptoms are similar to the constellation of symptoms that define depression. Within the inflammatory response to illness, we see the shadow of depression, but the precise relationship remains murky.

Is depression part of a normal somatic inflammatory response run amok? Some researchers have argued that “sickness behavior” is adaptive, forcing the body into a constricted pattern in order to funnel energy into healing.^1,3 If depression and inflammation are related, depression pushes past these adaptive roots and is less a forced pause than a debilitating withdrawal. Perhaps depression, or a subtype, is a sign of inflammation along with heat, pain, redness, and swelling. In some instances, depression may be a sign of an underlying inflammatory process.⁴

In our progression toward understanding depression’s pathophysiology, we see factors that point to a relationship between depression and inflammation:

• depression frequently is comorbid with many inflammatory illnesses

• increased inflammatory biomarkers are associated with major depressive disorder (MDD) 

• exposure to immunomodulating agents may increase the risk of developing depression 

• stress can activate proinflammatory pathways

• antidepressants can decrease inflammatory response

• inhibition of inflammatory pathways can improve mood. 

Exploring these factors and a possible pathway linking inflammation and neurobiologic changes found in depression allows us to look closer at the possible integration of the inflammatory process and depressive symptoms.

Illness and depression rates

Individuals with inflammatory illnesses—autoimmune diseases, cardiovascular disease, diabetes, and cancer—often struggle with depression. Nearly 1 in 5 persons with cardiovascular disease experiences MDD.⁵ A diabetes diagnosis doubles the odds of having depression.⁶ Up to 70% of patients with autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus, experience depression.^7,8 In a large-scale longitudinal study, having a prior autoimmune disease increased the risk of depression by 45% and history of hospitalization with infection increased a patient’s risk by 62%; the risk more than doubled in individuals with both.⁹ Several studies show that 15% to 25% of cancer patients experience depression,¹⁰ compared with 9% in the general population.¹¹

Role of inflammatory markers

During an inflammatory episode the body releases cytokines, which are small, cell-signaling protein molecules. These inflammatory markers launch signaling cascades that incite the immune system into action. Type 1 cytokines (interferon-ã, tumor necrosis factor-á [TNF-á], interleukin [IL]-1) enhance cellular immune responses, and type 2 cytokines (IL-6, IL-10, IL-13) engage antibody responses. These cytokines also induce acute phase proteins, such as C-reactive protein (CRP), which can activate the immune system. Significantly higher levels of inflammatory markers are associated with a range of depressive symptoms, which grants insight into disease severity and treatment response.^3,12,13

Multiple studies have explored the link between depression and inflammatory markers (Table).^14-21 Peripheral inflammatory markers such as IL-6, IL-1â, CRP, and TNF-á are elevated in inflammatory diseases and in otherwise healthy individuals with MDD.¹² In a meta-analysis of 24 studies measuring cytokines in depressed patients, Dowlati et al¹⁴ found individuals with MDD had significantly higher concentrations of TNF-á and IL-6 compared with controls. Increased peripheral inflammatory markers were found among antidepressant nonresponders more often than those who responded to treatment.^15,22 

Cytokines and depression risk

Administering immunomodulating agents has been shown to increase the risk of developing depression. Injecting animals with IL-1â or TNF-á causes sickness behavior in a dose- and time-related manner.¹ As these inflammatory signaling proteins increase, sickness behaviors become more pronounced.

In humans, a natural model arises in the use of the cytokine interferon-á (INF-á) for treating hepatitis C, multiple sclerosis, malignant melanoma, and some blood cancers. Patients receiving INF-á have higher rates of depression than those not administered interferon.¹⁶ Patients receiving chronic immunotherapy treatment show long-term changes in monoamine neurotransmitters and along the HPA axis; these changes mimic those seen in depressed individuals.^17,23 Acutely administered immunotherapeutic agents, such as the typhoid vaccine, have led to depressive symptoms with brain changes similar to those seen in MDD.¹⁸ Low levels of IL-6 and CRP independently predicted development of depression over several years.¹⁹

Immunotherapy-induced depression looks similar to any other major depressive episode through our current diagnostic framework and at the molecular and anatomical level.

Stress and inflammation

Depression can develop in the absence of inflammatory illness. Knowing that depressive symptoms may be associated with increased peripheral inflammatory markers, what induces the inflammatory process in some persons who are depressed but medically healthy? One theory is that psychological stress can activate inflammation.

Acute and chronic stress is associated with increased availability of proinflammatory cytokines and decreases in anti-inflammatory cytokines.^3,24 One theory looks to glucocorticoid response to stress as an explanation. Miller et al²⁵ found glucocorticoid sensitivity decreased among depressed women after exposure to a mock job interview stressor and increased among nondepressed controls. Because glucocorticoids normally stop the inflammatory cascade, this finding suggests depressed individuals may not be able to control inflammation during stress.²⁶ At the level of genetic expression, there is increased transcription of proinflammatory genes in response to stress as a result of increased activation of nuclear factor kappa B.^3,27

Shared pathways

If there is a relationship between inflammation and depression, what is the possible shared pathway?

There are 4 pathways by which cytokines effect changes in the CNS:¹²

• cytokines can activate primary afferent neurons (eg, vagal nerve)

• cytokines, released by macrophage-like cells in response to pathogens, diffuse through the brain’s circumventricular organs 

• cytokine transporters saturate the blood-brain barrier 

• cytokine IL-1 activates receptors on perivascular macrophages and endothelial cells of brain venules, causing local release of prostaglandin E2.

Through these pathways, cytokines initiate a cascade of reactions that lower serotonin levels and boost glutamatergic actions, possibly contributing to development of depressive symptoms. Depression correlates with a deficiency in serotonergic neurotransmission and increased glutamate receptor N-methyl-d-aspartate (NMDA) activation.²⁸

Proinflammatory cytokines activate theextrahepatic enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan, a precursor to serotonin (Figure 1). Tryptophan is channeled increasingly toward production of kynurenine via IDO degradation, competing with the serotonin pathway. Within the microglia, which are preferentially activated over astrocytes during inflammatory states, kynurenine is metabolized into quinolinic acid, which is an agonist of glutamatergic NMDA receptors.²⁸ Therefore, there is a serotonergic deficiency and glutamatergic overdrive in proinflammatory states that paves the way toward a likely depressive syndrome (Figure 2).

Antidepressants’ effects

The symptoms of cytokine-induced depression are no different from MDD with unknown etiology²⁹ and both are effectively treated with antidepressants. Even sickness behavior can be improved with antidepressant treatment.³⁰

Antidepressants not only decrease immunotherapy-induced depressive symptoms but have been shown to decrease inflammatory response and lower proinflammatory factors (IL-2, IL-6, TNF-á, and INF-ã).^31-33 Electroconvulsive therapy has been shown to normalize elevated TNF-á levels.³⁴

Enhancing depression treatment

Researchers are investigating whether treatment with anti-inflammatory agents can ease depressive symptoms. In animal studies, normal behavioral reactions to a stressor—similar to sickness behavior and overlapping with several features of depression—were reduced with administration of cytokine antagonists or anti-inflammatory cytokines directly into the brain.³⁵ However, there have been few successful trials in humans. Both anti-inflammatory agents such as cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid (aspirin), and TNF receptor antagonists can enhance depression treatments. Persoons et al³⁶ found that Crohn’s disease patients who had higher pretreatment CRP levels and MDD had greater remission of depressive symptoms after treatment with the TNF-á antagonist infliximab. In studies, depression within the context of other autoimmune disorders or any condition with increased inflammation has responded to treatment with TNF-á antagonists.^37,38 COX-2 inhibitors added to a standard antidepressant regimen improved depressive symptoms in medically healthy individuals during an acute depressive episode.³⁹ Aspirin has shown some benefits as an adjuvant agent in persons who have failed selective serotonin reuptake inhibitor monotherapy.^40,41

These anti-inflammatory agents have shown benefits in treating depression in some persons, but not in all. The key difference between those subsets of patients is elusive, mired in the complex interactions of the many systems that contribute to the symptoms we label as depression.

Future clinical applications

The association between depression and inflammation raises the possibility of a tantalizing line of future theories and treatment options. However, when considered individually, these pieces are limited in defining the precise relationship - a task nearly impossible for such a diffuse symptom as inflammation and such a complex disease as depression.

It is evident that inflammation and depression form a strong relationship to each other in individuals, which suggests the possibility of an inflammatory subtype of depression. At least within that limited group, there is the possibility of successful intervention and treatment of depression by directly treating inflammation with anti-inflammatory agents.

Perhaps once the relationship between depression and inflammation is further defined and a high-risk population identified—maybe even by genotype—depressive symptoms might be used to flag a provider’s attention to a possible disease process and serve as a new tool for identifying dangerous inflammatory activity at an early stage. Managing stress and depression may become the next tool to prevent inflammatory diseases.

Given our current knowledge, clinicians treating patients with inflammatory conditions should be aware of the increased risk of depression and ensure that depression screening is routinely completed and treatment is initiated or referrals made as needed. Ensuring appropriate depression treatment may help improve patients’ quality of life and ease the inflammatory response itself. 

For psychiatrists seeing patients with an inflammatory condition, brief explanations of the known links between depression and inflammation can provide patients—particularly those ambivalent about seeking mental health care—support for engaging in treatment and adhering to medication. Describing the links between inflammation and depression also can help encourage regular exercise and healthy diets rich in fruits, vegetables, and omega-3 fatty acids. In cases of treatment-resistant depression, particularly in those with known high inflammatory factors, it may be worthwhile to consider anti-inflammatory agents, such as infliximab, as an adjuvant treatment. 

The relationship between inflammation and depression is rapidly unfolding, but the full intricacies have not yet described. However, this beginning awareness of the interplay among stress, inflammation, and depression can broaden our approach to care and treatment.

Bottom Line

Depression and inflammation are linked in many ways, although neither appears to be wholly necessary or sufficient for the other. Most likely there exists a particular subset of patients for whom inflammation will precipitate and perpetuate depression.

Related Resources

• The Emory University Mind-Body Program. www.
  psychiatry.emory.edu/PROGRAMS/mindbody/index.html.
• Gabriel B. The evolutionary advantage of depression. The Atlantic. October 2, 2012. www.theatlantic.com/health/archive/2012/10/the-evolutionary-advantage-of-depression/263124.

Drug Brand Names

Infliximab • Remicade     Ribavirin • Rebetol, Virazole
Interferon-α • Intron

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

References

1. Dantzer R, O’Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.

2. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988;12(2):123-137.

3. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24-31.

4. Lamers F, Vogelzangs N, Merikangas KR, et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression [published online October 23, 2012]. Mol Psychiatry. doi: 10.1038/mp.2012.144.

5. Hoen P, Kupper N, de Jonge P. Depression and cardiovascular disease progression: epidemiology, mechanisms and treatment. In: Hjemdahl P, Rosengren A, Steptoe A, eds. Stress and cardiovascular disease. London, United Kingdom: Springer; 2012:211-233.

6. Anderson RJ, Freedland KE, Clouse RE, et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24(6):1069-1078.

7. Bachen EA, Chesney MA, Criswell LA. Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus. Arthritis Rheum. 2009;61(6):822-829.

8. Dickens C, McGowan L, Clark-Carter D, et al. Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis. Psychosom Med. 2002;64(1):52-60.

9. Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmunity and infections as risk factors for depression and other severe mental illnesses. Neurology, Psychiatry and Brain Research. 2012;18(2):40-41.

10. National Cancer Institute. Depression (PDQ). http://www.cancer.gov/cancertopics/pdq/supportivecare/depression/HealthProfessional/page1. Updated January 9, 2013. Accessed April 23, 2013.

11. Centers for Disease Control and Prevention. Current depression among adults—United States, 2006 and 2008. Morb Mortal Wkly Rep. 2010;59(38):1229-1235.

12. Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry. 2012;83(5):495-502.

13. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741.

14. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-457.

15. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9(11):853-858.

16. Raison CL, Borisov AS, Broadwell SD, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry. 2005;66(1):41-48.

17. Capuron L, Raison CL, Musselman DL, et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003;160(7):1342-1345.

18. Eisenberger NI, Berkman ET, Inagaki TK, et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68(8):748-754.

19. Pasco JA, Nicholson GC, Williams LJ, et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197(5):372-377.

20. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41.

21. Martinez JM, Garakani A, Yehuda R, et al. Proinflammatory and “resiliency” proteins in the CSF of patients with major depression. Depress Anxiety. 2012;29(1):32-38.

22. Lanquillon S, Krieg JC, Bening-Abu-Shach U, et al. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22(4):370-379.

23. Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry Rep. 2011;13(6):467-775.

24. Maes M, Song C, Lin A, et al. The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and Th1-like response in stress-induced anxiety. Cytokine. 1998;10(4):313-318.

25. Miller GE, Rohleder N, Stetler C, et al. Clinical depression and regulation of the inflammatory response during acute stress. Psychosom Med. 2005;67(5):679-687.

26. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160(9):1554-1565.

27. Tak PP, Firestein GS. NF-êB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7-12.

28. Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12(11):988-1000.

29. Capuron L, Fornwalt FB, Knight BT, et al. Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord. 2009;119(1-3):181-185.

30. Yirmiya R, Pollak Y, Morag M, et al. Illness, cytokines, and depression. Ann N Y Acad Sci. 2000;917(1):478-487.

31. Maes M. The immunoregulatory effects of antidepressants. Hum Psychopharmacol. 2001;16(1):95-103.

32. Szuster-Ciesielska A, Tustanowska-Stachura A, Słotwin`ska M, et al. In vitro immunoregulatory effects of antidepressants in healthy volunteers. Pol J Pharmacol. 2003;55(3):353-362.

33. Maes M, Berk M, Goehler L, et al. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med. 2012;10(1):66.

34. Hestad KA, Tønseth S, Støen CD, et al. Raised plasma levels of tumor necrosis factor [alpha] in patients with depression: normalization during electroconvulsive therapy. J ECT. 2003;19(4):183-188.

35. Maier SF, Watkins LR. Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock. Brain Res. 1995;695(2):279-282.

36. Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol Ther. 2005;22(2):101-110.

37. Mathias SD, Colwell HH, Miller DP, et al. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther. 2000;22(1):128-139.

38. Raison C, Rutherford RE, Woolwine B, et al. The tumor necrosis factor-alpha antagonist infliximab reduces depressive symptoms in patients with treatment resistant depression and high inflammation. Brain, Behavior, and Immunity. 2012;26(suppl 1):S49.

39. Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11(7):680-684.

40. Mendlewicz J, Kriwin P, Oswald P, et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21(4):227-231.

41. Brunello N, Alboni S, Capone G, et al. Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21(4):219-225.

Sneezing, coughing, and a sore throat are hallmark symptoms of a common cold, but what keeps you in bed are the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain, and apathetic withdrawal. This “sickness behavior” is induced by inflammatory markers released in response to illness.^1,2 These symptoms are similar to the constellation of symptoms that define depression. Within the inflammatory response to illness, we see the shadow of depression, but the precise relationship remains murky.

Is depression part of a normal somatic inflammatory response run amok? Some researchers have argued that “sickness behavior” is adaptive, forcing the body into a constricted pattern in order to funnel energy into healing.^1,3 If depression and inflammation are related, depression pushes past these adaptive roots and is less a forced pause than a debilitating withdrawal. Perhaps depression, or a subtype, is a sign of inflammation along with heat, pain, redness, and swelling. In some instances, depression may be a sign of an underlying inflammatory process.⁴

In our progression toward understanding depression’s pathophysiology, we see factors that point to a relationship between depression and inflammation:

• depression frequently is comorbid with many inflammatory illnesses

• increased inflammatory biomarkers are associated with major depressive disorder (MDD) 

• exposure to immunomodulating agents may increase the risk of developing depression 

• stress can activate proinflammatory pathways

• antidepressants can decrease inflammatory response

• inhibition of inflammatory pathways can improve mood. 

Exploring these factors and a possible pathway linking inflammation and neurobiologic changes found in depression allows us to look closer at the possible integration of the inflammatory process and depressive symptoms.

Illness and depression rates

Individuals with inflammatory illnesses—autoimmune diseases, cardiovascular disease, diabetes, and cancer—often struggle with depression. Nearly 1 in 5 persons with cardiovascular disease experiences MDD.⁵ A diabetes diagnosis doubles the odds of having depression.⁶ Up to 70% of patients with autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus, experience depression.^7,8 In a large-scale longitudinal study, having a prior autoimmune disease increased the risk of depression by 45% and history of hospitalization with infection increased a patient’s risk by 62%; the risk more than doubled in individuals with both.⁹ Several studies show that 15% to 25% of cancer patients experience depression,¹⁰ compared with 9% in the general population.¹¹

Role of inflammatory markers

During an inflammatory episode the body releases cytokines, which are small, cell-signaling protein molecules. These inflammatory markers launch signaling cascades that incite the immune system into action. Type 1 cytokines (interferon-ã, tumor necrosis factor-á [TNF-á], interleukin [IL]-1) enhance cellular immune responses, and type 2 cytokines (IL-6, IL-10, IL-13) engage antibody responses. These cytokines also induce acute phase proteins, such as C-reactive protein (CRP), which can activate the immune system. Significantly higher levels of inflammatory markers are associated with a range of depressive symptoms, which grants insight into disease severity and treatment response.^3,12,13

Multiple studies have explored the link between depression and inflammatory markers (Table).^14-21 Peripheral inflammatory markers such as IL-6, IL-1â, CRP, and TNF-á are elevated in inflammatory diseases and in otherwise healthy individuals with MDD.¹² In a meta-analysis of 24 studies measuring cytokines in depressed patients, Dowlati et al¹⁴ found individuals with MDD had significantly higher concentrations of TNF-á and IL-6 compared with controls. Increased peripheral inflammatory markers were found among antidepressant nonresponders more often than those who responded to treatment.^15,22 

Cytokines and depression risk

Administering immunomodulating agents has been shown to increase the risk of developing depression. Injecting animals with IL-1â or TNF-á causes sickness behavior in a dose- and time-related manner.¹ As these inflammatory signaling proteins increase, sickness behaviors become more pronounced.

In humans, a natural model arises in the use of the cytokine interferon-á (INF-á) for treating hepatitis C, multiple sclerosis, malignant melanoma, and some blood cancers. Patients receiving INF-á have higher rates of depression than those not administered interferon.¹⁶ Patients receiving chronic immunotherapy treatment show long-term changes in monoamine neurotransmitters and along the HPA axis; these changes mimic those seen in depressed individuals.^17,23 Acutely administered immunotherapeutic agents, such as the typhoid vaccine, have led to depressive symptoms with brain changes similar to those seen in MDD.¹⁸ Low levels of IL-6 and CRP independently predicted development of depression over several years.¹⁹

Immunotherapy-induced depression looks similar to any other major depressive episode through our current diagnostic framework and at the molecular and anatomical level.

Stress and inflammation

Depression can develop in the absence of inflammatory illness. Knowing that depressive symptoms may be associated with increased peripheral inflammatory markers, what induces the inflammatory process in some persons who are depressed but medically healthy? One theory is that psychological stress can activate inflammation.

Acute and chronic stress is associated with increased availability of proinflammatory cytokines and decreases in anti-inflammatory cytokines.^3,24 One theory looks to glucocorticoid response to stress as an explanation. Miller et al²⁵ found glucocorticoid sensitivity decreased among depressed women after exposure to a mock job interview stressor and increased among nondepressed controls. Because glucocorticoids normally stop the inflammatory cascade, this finding suggests depressed individuals may not be able to control inflammation during stress.²⁶ At the level of genetic expression, there is increased transcription of proinflammatory genes in response to stress as a result of increased activation of nuclear factor kappa B.^3,27

Shared pathways

If there is a relationship between inflammation and depression, what is the possible shared pathway?

There are 4 pathways by which cytokines effect changes in the CNS:¹²

• cytokines can activate primary afferent neurons (eg, vagal nerve)

• cytokines, released by macrophage-like cells in response to pathogens, diffuse through the brain’s circumventricular organs 

• cytokine transporters saturate the blood-brain barrier 

• cytokine IL-1 activates receptors on perivascular macrophages and endothelial cells of brain venules, causing local release of prostaglandin E2.

Through these pathways, cytokines initiate a cascade of reactions that lower serotonin levels and boost glutamatergic actions, possibly contributing to development of depressive symptoms. Depression correlates with a deficiency in serotonergic neurotransmission and increased glutamate receptor N-methyl-d-aspartate (NMDA) activation.²⁸

Proinflammatory cytokines activate theextrahepatic enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan, a precursor to serotonin (Figure 1). Tryptophan is channeled increasingly toward production of kynurenine via IDO degradation, competing with the serotonin pathway. Within the microglia, which are preferentially activated over astrocytes during inflammatory states, kynurenine is metabolized into quinolinic acid, which is an agonist of glutamatergic NMDA receptors.²⁸ Therefore, there is a serotonergic deficiency and glutamatergic overdrive in proinflammatory states that paves the way toward a likely depressive syndrome (Figure 2).

Antidepressants’ effects

The symptoms of cytokine-induced depression are no different from MDD with unknown etiology²⁹ and both are effectively treated with antidepressants. Even sickness behavior can be improved with antidepressant treatment.³⁰

Antidepressants not only decrease immunotherapy-induced depressive symptoms but have been shown to decrease inflammatory response and lower proinflammatory factors (IL-2, IL-6, TNF-á, and INF-ã).^31-33 Electroconvulsive therapy has been shown to normalize elevated TNF-á levels.³⁴

Enhancing depression treatment

Researchers are investigating whether treatment with anti-inflammatory agents can ease depressive symptoms. In animal studies, normal behavioral reactions to a stressor—similar to sickness behavior and overlapping with several features of depression—were reduced with administration of cytokine antagonists or anti-inflammatory cytokines directly into the brain.³⁵ However, there have been few successful trials in humans. Both anti-inflammatory agents such as cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid (aspirin), and TNF receptor antagonists can enhance depression treatments. Persoons et al³⁶ found that Crohn’s disease patients who had higher pretreatment CRP levels and MDD had greater remission of depressive symptoms after treatment with the TNF-á antagonist infliximab. In studies, depression within the context of other autoimmune disorders or any condition with increased inflammation has responded to treatment with TNF-á antagonists.^37,38 COX-2 inhibitors added to a standard antidepressant regimen improved depressive symptoms in medically healthy individuals during an acute depressive episode.³⁹ Aspirin has shown some benefits as an adjuvant agent in persons who have failed selective serotonin reuptake inhibitor monotherapy.^40,41

These anti-inflammatory agents have shown benefits in treating depression in some persons, but not in all. The key difference between those subsets of patients is elusive, mired in the complex interactions of the many systems that contribute to the symptoms we label as depression.

Future clinical applications

The association between depression and inflammation raises the possibility of a tantalizing line of future theories and treatment options. However, when considered individually, these pieces are limited in defining the precise relationship - a task nearly impossible for such a diffuse symptom as inflammation and such a complex disease as depression.

It is evident that inflammation and depression form a strong relationship to each other in individuals, which suggests the possibility of an inflammatory subtype of depression. At least within that limited group, there is the possibility of successful intervention and treatment of depression by directly treating inflammation with anti-inflammatory agents.

Perhaps once the relationship between depression and inflammation is further defined and a high-risk population identified—maybe even by genotype—depressive symptoms might be used to flag a provider’s attention to a possible disease process and serve as a new tool for identifying dangerous inflammatory activity at an early stage. Managing stress and depression may become the next tool to prevent inflammatory diseases.

Given our current knowledge, clinicians treating patients with inflammatory conditions should be aware of the increased risk of depression and ensure that depression screening is routinely completed and treatment is initiated or referrals made as needed. Ensuring appropriate depression treatment may help improve patients’ quality of life and ease the inflammatory response itself. 

For psychiatrists seeing patients with an inflammatory condition, brief explanations of the known links between depression and inflammation can provide patients—particularly those ambivalent about seeking mental health care—support for engaging in treatment and adhering to medication. Describing the links between inflammation and depression also can help encourage regular exercise and healthy diets rich in fruits, vegetables, and omega-3 fatty acids. In cases of treatment-resistant depression, particularly in those with known high inflammatory factors, it may be worthwhile to consider anti-inflammatory agents, such as infliximab, as an adjuvant treatment. 

The relationship between inflammation and depression is rapidly unfolding, but the full intricacies have not yet described. However, this beginning awareness of the interplay among stress, inflammation, and depression can broaden our approach to care and treatment.

Bottom Line

Depression and inflammation are linked in many ways, although neither appears to be wholly necessary or sufficient for the other. Most likely there exists a particular subset of patients for whom inflammation will precipitate and perpetuate depression.

Related Resources

• The Emory University Mind-Body Program. www.
  psychiatry.emory.edu/PROGRAMS/mindbody/index.html.
• Gabriel B. The evolutionary advantage of depression. The Atlantic. October 2, 2012. www.theatlantic.com/health/archive/2012/10/the-evolutionary-advantage-of-depression/263124.

Drug Brand Names

Infliximab • Remicade     Ribavirin • Rebetol, Virazole
Interferon-α • Intron

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

References

1. Dantzer R, O’Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.

2. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988;12(2):123-137.

3. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24-31.

4. Lamers F, Vogelzangs N, Merikangas KR, et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression [published online October 23, 2012]. Mol Psychiatry. doi: 10.1038/mp.2012.144.

5. Hoen P, Kupper N, de Jonge P. Depression and cardiovascular disease progression: epidemiology, mechanisms and treatment. In: Hjemdahl P, Rosengren A, Steptoe A, eds. Stress and cardiovascular disease. London, United Kingdom: Springer; 2012:211-233.

6. Anderson RJ, Freedland KE, Clouse RE, et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24(6):1069-1078.

7. Bachen EA, Chesney MA, Criswell LA. Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus. Arthritis Rheum. 2009;61(6):822-829.

8. Dickens C, McGowan L, Clark-Carter D, et al. Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis. Psychosom Med. 2002;64(1):52-60.

9. Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmunity and infections as risk factors for depression and other severe mental illnesses. Neurology, Psychiatry and Brain Research. 2012;18(2):40-41.

10. National Cancer Institute. Depression (PDQ). http://www.cancer.gov/cancertopics/pdq/supportivecare/depression/HealthProfessional/page1. Updated January 9, 2013. Accessed April 23, 2013.

11. Centers for Disease Control and Prevention. Current depression among adults—United States, 2006 and 2008. Morb Mortal Wkly Rep. 2010;59(38):1229-1235.

12. Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry. 2012;83(5):495-502.

13. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741.

14. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-457.

15. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9(11):853-858.

16. Raison CL, Borisov AS, Broadwell SD, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry. 2005;66(1):41-48.

17. Capuron L, Raison CL, Musselman DL, et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003;160(7):1342-1345.

18. Eisenberger NI, Berkman ET, Inagaki TK, et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68(8):748-754.

19. Pasco JA, Nicholson GC, Williams LJ, et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197(5):372-377.

20. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41.

21. Martinez JM, Garakani A, Yehuda R, et al. Proinflammatory and “resiliency” proteins in the CSF of patients with major depression. Depress Anxiety. 2012;29(1):32-38.

22. Lanquillon S, Krieg JC, Bening-Abu-Shach U, et al. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22(4):370-379.

23. Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry Rep. 2011;13(6):467-775.

24. Maes M, Song C, Lin A, et al. The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and Th1-like response in stress-induced anxiety. Cytokine. 1998;10(4):313-318.

25. Miller GE, Rohleder N, Stetler C, et al. Clinical depression and regulation of the inflammatory response during acute stress. Psychosom Med. 2005;67(5):679-687.

26. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160(9):1554-1565.

27. Tak PP, Firestein GS. NF-êB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7-12.

28. Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12(11):988-1000.

29. Capuron L, Fornwalt FB, Knight BT, et al. Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord. 2009;119(1-3):181-185.

30. Yirmiya R, Pollak Y, Morag M, et al. Illness, cytokines, and depression. Ann N Y Acad Sci. 2000;917(1):478-487.

31. Maes M. The immunoregulatory effects of antidepressants. Hum Psychopharmacol. 2001;16(1):95-103.

32. Szuster-Ciesielska A, Tustanowska-Stachura A, Słotwin`ska M, et al. In vitro immunoregulatory effects of antidepressants in healthy volunteers. Pol J Pharmacol. 2003;55(3):353-362.

33. Maes M, Berk M, Goehler L, et al. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med. 2012;10(1):66.

34. Hestad KA, Tønseth S, Støen CD, et al. Raised plasma levels of tumor necrosis factor [alpha] in patients with depression: normalization during electroconvulsive therapy. J ECT. 2003;19(4):183-188.

35. Maier SF, Watkins LR. Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock. Brain Res. 1995;695(2):279-282.

36. Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol Ther. 2005;22(2):101-110.

37. Mathias SD, Colwell HH, Miller DP, et al. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther. 2000;22(1):128-139.

38. Raison C, Rutherford RE, Woolwine B, et al. The tumor necrosis factor-alpha antagonist infliximab reduces depressive symptoms in patients with treatment resistant depression and high inflammation. Brain, Behavior, and Immunity. 2012;26(suppl 1):S49.

39. Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11(7):680-684.

40. Mendlewicz J, Kriwin P, Oswald P, et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21(4):227-231.

41. Brunello N, Alboni S, Capone G, et al. Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21(4):219-225.

The prevalence of HIV in persons with untreated psychiatric illness may be 10 to 20 times that of the general population.¹ The U.S. Preventive Services Task Force has recommended HIV screening of all persons age 15 to 65 because 20% to 25% of individuals with HIV infection are unaware that they are HIV-positive.² Because >20% of new HIV infections in the United States are undiagnosed,³ it is crucial to educate patients with mental illness about HIV prevention, make condoms available, and offer HIV testing.

As psychiatrists, we have a unique role in caring for patients at risk for or infected with HIV because in addition to comprehensive medical and psychiatric histories, we routinely take histories of substance use, sexual activities, relationships, and trauma, including childhood neglect and emotional, physical, and sexual abuse. We develop long-term, trusting relationships and work with individuals to change behaviors and maximize life potential.

Increasing awareness of stigma, discrimination, and psychiatric factors involved with the HIV pandemic can lead to decreased transmission of HIV infection and early diagnosis and treatment. Compassionate medical and psychiatric care can mitigate suffering in persons at risk for, infected with, or affected by HIV.

Preventing HIV transmission

AIDS differs from other complex, severe illnesses in 2 ways that are relevant to psychiatrists:

•  it is almost entirely preventable

•  HIV and AIDS are associated with sex, drugs, and AIDS-associated stigma and discrimination (“AIDSism”).^4-6

Unsafe exposure of mucosal surfaces to the virus—primarily from exchanging body fluids in unprotected sexual encounters—accounts for 80% of new HIV infections.⁷ HIV transmission via sexual encounters is preventable with condoms. Percutaneous or intravenous infection with HIV—primarily from sharing needles in injection drug use—accounts for 20% of new infections.⁷ Use of alcohol or other substances can lead to sexual coercion, unprotected sex, and exchange of sex for drugs or money. Hence, treating substance use disorders can prevent HIV transmission.

Early diagnosis of HIV can lead to appropriate medical care, quicker onset of antiretroviral (ARV) treatment, and better outcomes. Recent research has shown that pre-exposure prophylaxis with ARV treatment can prevent transmission of HIV⁸; therefore, becoming aware of risk behaviors and prevention can be lifesaving for serodiscordant couples.

One of the most important ways to prevent HIV’s impact on the brain and CNS is to diagnose HIV shortly after transmission at onset of acute infection. If HIV is diagnosed very early—preferably as soon as possible after inoculation with HIV or at onset of the first flu-like symptoms—and treated with ARVs, the brain has less of an opportunity to act as an independent reservoir for HIV-infected cells and therefore to develop HIV-associated neurocognitive disorders.^9,10Table 1 outlines steps psychiatrists can take to help prevent HIV transmission.

Psychiatric disorders and HIV

Psychiatric disorders and distress play a significant role in transmission of, exposure to, and infection with HIV (Table 2).^4-6,11 They are relevant for prevention, clinical care, and adherence throughout every aspect of illness.

Comprehensive, compassionate, nonjudgmental care of persons at risk for or infected with HIV begins with a thorough psychiatric evaluation designed to provide an ego-supportive, sensitive, and comprehensive assessment that can guide other clinicians in providing care.¹² Setting the tone and demonstrating compassion and respect includes shaking hands, which takes on special relevance in the context of AIDSism and stigma. Assessing the impact of HIV seropositivity or AIDS is best done by asking about the individual’s understanding of his or her diagnosis or illness and its impact. For some persons with HIV, verbalizing this understanding can be relieving as well as revealing. It is a chance for the patient to reveal painful experiences encountered in the home, school, camp, workplace, or community and the anguish of AIDSism and stigma.

Pay attention to sensitive and sometimes painful issues related to sexual history and sexuality. Questions related to sexual history and sexuality in heterosexual men and women as well as gay, lesbian, bisexual, and transgender individuals—such as “What is your sexual function like since you have been ill?” “Do feelings about your sexual identity play a role in your current level of distress?” and “What kind of barrier contraception are you using?”—are included in the comprehensive assessment described by Cohen et al.¹²

Comprehensive psychiatric evaluations can provide diagnoses, inform treatment, and mitigate anguish, distress, depression, anxiety, and substance use in persons with HIV and AIDS.¹² A thorough and comprehensive assessment is crucial because HIV has an affinity for brain and neural tissue and can cause CNS complications such as HIV-associated neurocognitive disorders (HAND), even in otherwise healthy HIV-seropositive individuals. See this article at CurrentPsychiatry.com for a discussion of HAND and delirium in patients with HIV.

Some persons with HIV and AIDS do not have a psychiatric disorder, while others have multiple complex psychiatric disorders that are responses to illness or treatments or are associated with HIV/AIDS (such as HAND) or other medical illnesses and treatments (such as hepatitis C, cirrhosis, end-stage liver disease, HIV nephropathy, end-stage renal disease, anemia, coronary artery disease, and cancer). See this article at CurrentPsychiatry.com for case studies of HIV patients with delirium, depression, posttraumatic stress disorder (PTSD), and substance dependence.

Mood disorders. Depression is common among persons with HIV. Demoralization and bereavement may masquerade as depression and can complicate diagnosis and treatment. Depression and other mood disorders may be related to stigma and AIDSism as well as to biologic, psychological, social, and genetic factors. Because suicide is prevalent among persons with HIV and AIDS,¹³ every patient with HIV should be evaluated for depression and suicidal ideation.

PTSD is prevalent among persons with HIV. It is a risky diagnosis because it is associated with a sense of a foreshortened future, which leads to a lack of adequate self-care, poor adherence to medical care, risky behaviors, and comorbid substance dependence to help numb the pain of trauma.^14,15 Persons with PTSD may have difficulty trusting clinicians and other authority figures if their trauma was a high-betrayal trauma, such as incest or military trauma.^14,15

In patients with HIV, PTSD often is overlooked because it may be overshadowed by other psychiatric diagnoses. Intimate partner violence, history of childhood trauma, and childhood sexual abuse are risk factors for HIV infection and PTSD. Increased severity of HIV-related PTSD symptoms is associated with having a greater number of HIV-related physical symptoms, history of pre-HIV trauma, decreased social support, increased perception of stigma, and negative life events.

PTSD also is associated with nonadherence to risk reduction strategies and medical care.^14,15 Diagnosis is further complicated by repression or retrograde amnesia of traumatic events and difficulties forming trusting relationships and disclosing HIV status to sexual partners or potential sexual partners because of fear of rejection. 

Substance use disorders. Dependence on alcohol and other drugs complicates and perpetuates the HIV pandemic. Sharing needles and other drug paraphernalia is instrumental in HIV transmission. The indirect effects of alcohol and substance abuse include:

•  the impact of intimate partner violence, child abuse, neglect, and/or abandonment

•  development of PTSD in adults, with early childhood trauma leading to repeating their own history

•  lack of self-care

•  unhealthy partner choices

•  use of drugs and alcohol to numb the pain associated with trauma.

Persons who are using alcohol or other drugs may have difficulty attending to their health, and substance dependence may prevent persons at risk from seeking HIV testing.

Intoxication from alcohol and drug use frequently leads to inappropriate partner choice, violent and coercive sexual behaviors, and lack of condom use. Substance dependence also may lead individuals to exchange sex for drugs and to fail to adhere to safer sexual practices or use sterile drug paraphernalia.

Treating persons with HIV/AIDS

Several organizations publish evidence-based clinical guidelines for treating depression, anxiety, substance abuse, and other psychiatric disorders in patients with HIV/AIDS. One such set of guidelines is available from the New York State Department of Health AIDS Institute at www.hivguidelines.org. As is the case with patients who do not have HIV, psychotherapy and pharmacotherapy are common first-line treatments.

Psychotherapy. Patients with HIV/AIDS with psychiatric comorbidities generally respond well to psychotherapeutic treatments.^16,17 The choice of therapy needs to be tailored to the needs of individuals, couples, and families coping with AIDS. Options include:

•  individual, couple, family, and group psychotherapy

•  crisis intervention

•  12-step programs (Alcohol Anonymous, Narcotics Anonymous, etc.)

•  adult survivors of child abuse programs (www.ascasupport.org), groups, and workbooks

•  palliative psychiatry

•  bereavement therapy

•  spiritual support

•  relaxation response

•  wellness interventions such as exercise, yoga, keeping a journal, writing a life narrative, reading, artwork, movement therapy, listening to music or books on tape, and working on crossword puzzles and jigsaw puzzles.

Psychopharmacotherapy. Accurate diagnosis and awareness of drug-drug and drug-illness interactions are important when treating patients with HIV/AIDS; consult resources in the literature¹⁸ and online resources that are updated regularly (see Related Resources). Because persons with AIDS are particularly vulnerable to extrapyramidal and anticholinergic side effects of psychotropics, the principle start very low and go very slow is critical. For patients who are opioid-dependent, be cautious when prescribing medications that are cytochrome P450 3A4 inducers—such as carbamazepine, efavirenz, nevirapine, and ritonavir—because these medications can lower methadone levels in persons receiving agonist treatment and might lead to opioid withdrawal symptoms, discontinuation of ARVs, or relapse to opioids.¹⁸ When a person with AIDS is experiencing pain and is on a maintenance dose of methadone for heroin withdrawal, pain should be treated as a separate problem with additional opioids. Methadone for relapse prevention will target opioid tolerance needs and prevent withdrawal but will not provide analgesia for pain.

HIV through the life cycle

From prevention of prenatal transmission to the care of children with HIV to reproductive issues in serodiscordant couples, HIV complicates patients’ development. Table 3 outlines concerns regarding HIV transmission and treatment at different stages of a patient’s life.

Bottom Line

HIV transmission and effective treatment are complicated by a high prevalence of psychiatric comorbidities, including depression and other mood disorders, posttraumatic stress disorder, substance use disorders, and cognitive disorders. With an increased understanding of the issues faced by patients at risk for or infected with HIV, psychiatrists can help prevent HIV transmission, improve adherence to medical care, and diminish suffering, morbidity, and mortality.

Related Resources

• Academy of Psychosomatic Medicine HIV/AIDS Psychiatry Special Interest Group. www.apm.org/sigs/oap.
• New York State Department of Health AIDS Institute. HIV Clinical Resource. www.hivguidelines.org.
• University of Liverpool. HIV drug interactions list. www.hiv-druginteractions.org.
• Toronto General Hospital Immunodeficiency Clinic. Drug interactions tables. www.hivclinic.ca/main/drugs_interact.html.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Nevirapine • Viramune
Carbamazepine • Carbatrol, Tegretol, others
Olanzapine • Zyprexa
Quetiapine • Seroquel
Clonazepam • Klonopin
Ritonavir • Norvir
Efavirenz • Sustiva
Venlafaxine • Effexor
Escitalopram • Lexapro

Disclosure

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

References

1. Blank MB, Mandell DS, Aiken L, et al. Co-occurrence of HIV and serious mental illness among Medicaid recipients. Psychiatr Serv. 2002;53(7):868-873.

2.Moyer VA, on behalf of the U.S. Preventive Services Task Force. Screening for HIV: U.S. Preventive Services Task Force recommendation statement [published online April 30, 2013]. Ann Intern Med. doi:10.7326/0003-4819-159-1-201307020-00645.

3. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the United States. JAMA. 2008;300(5):520-529.

4. Cohen MA. AIDSism, a new form of discrimination. Am Med News. 1989;32:43.

5. Cohen MA, Gorman JM. Comprehensive textbook of AIDS psychiatry. New York, NY: Oxford University Press; 2008.

6. Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010.

7. World Health Organization, United Nations Children’s Fund, Joint United Nations Programme on HIV/AIDS. Global HIV/AIDS response. Epidemic update and health sector progress towards universal access. Progress report 2011. http://www.unaids.org/en/media/unaids/
contentassets/documents/unaidspublication/2011/
20111130_UA_Report_en.pdf. Accessed April 25, 2013.

8. Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep. 2012;61(31):586-589.

9. Cysique LA, Murray JM, Dunbar M, et al. A screening algorithm for HIV-associated neurocognitive disorders. HIV Med. 2010;11(10):642-649.

10. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24(9):1243-1250.

11. Cohen M, Hoffman RG, Cromwell C, et al. The prevalence of distress in persons with human immunodeficiency virus infection. Psychosomatics. 2002;43(1):10-15.

12. Cohen MA, Batista SM, Lux JZ. A biopsychosocial approach to psychiatric consultation in persons with HIV and AIDS. In: Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010:33-60.

13. Carrico AW. Elevated suicide rate among HIV-positive persons despite benefits of antiretroviral therapy: implications for a stress and coping model of suicide. Am J Psychiatry. 2010;167(2):117-119.

14. Cohen MA, Alfonso CA, Hoffman RG, et al. The impact of PTSD on treatment adherence in persons with HIV infection. Gen Hosp Psychiatry. 2001;23(5):294-296.

15. Boarts JM, Sledjeski EM, Bogart LM, et al. The differential impact of PTSD and depression on HIV disease markers and adherence to HAART in people living with HIV. AIDS Behav. 2006;10(3):253-261.

16. Sikkema KJ, Hansen NB, Ghebremichael M, et al. A randomized controlled trial of a coping group intervention for adults with HIV who are AIDS bereaved: longitudinal effects on grief. Health Psychol. 2006;25(5):563-570.

17. Cohen MA. Psychodynamic psychotherapy in an AIDS nursing home. J Am Acad Psychoanal. 1999;27(1):121-133.

18. Cozza KL, Goforth HW, Batista SM. Psychopharmacologic treatment issues in AIDS psychiatry. In: Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010:147-199.

The prevalence of HIV in persons with untreated psychiatric illness may be 10 to 20 times that of the general population.¹ The U.S. Preventive Services Task Force has recommended HIV screening of all persons age 15 to 65 because 20% to 25% of individuals with HIV infection are unaware that they are HIV-positive.² Because >20% of new HIV infections in the United States are undiagnosed,³ it is crucial to educate patients with mental illness about HIV prevention, make condoms available, and offer HIV testing.

As psychiatrists, we have a unique role in caring for patients at risk for or infected with HIV because in addition to comprehensive medical and psychiatric histories, we routinely take histories of substance use, sexual activities, relationships, and trauma, including childhood neglect and emotional, physical, and sexual abuse. We develop long-term, trusting relationships and work with individuals to change behaviors and maximize life potential.

Increasing awareness of stigma, discrimination, and psychiatric factors involved with the HIV pandemic can lead to decreased transmission of HIV infection and early diagnosis and treatment. Compassionate medical and psychiatric care can mitigate suffering in persons at risk for, infected with, or affected by HIV.

Preventing HIV transmission

AIDS differs from other complex, severe illnesses in 2 ways that are relevant to psychiatrists:

•  it is almost entirely preventable

•  HIV and AIDS are associated with sex, drugs, and AIDS-associated stigma and discrimination (“AIDSism”).^4-6

Unsafe exposure of mucosal surfaces to the virus—primarily from exchanging body fluids in unprotected sexual encounters—accounts for 80% of new HIV infections.⁷ HIV transmission via sexual encounters is preventable with condoms. Percutaneous or intravenous infection with HIV—primarily from sharing needles in injection drug use—accounts for 20% of new infections.⁷ Use of alcohol or other substances can lead to sexual coercion, unprotected sex, and exchange of sex for drugs or money. Hence, treating substance use disorders can prevent HIV transmission.

Early diagnosis of HIV can lead to appropriate medical care, quicker onset of antiretroviral (ARV) treatment, and better outcomes. Recent research has shown that pre-exposure prophylaxis with ARV treatment can prevent transmission of HIV⁸; therefore, becoming aware of risk behaviors and prevention can be lifesaving for serodiscordant couples.

One of the most important ways to prevent HIV’s impact on the brain and CNS is to diagnose HIV shortly after transmission at onset of acute infection. If HIV is diagnosed very early—preferably as soon as possible after inoculation with HIV or at onset of the first flu-like symptoms—and treated with ARVs, the brain has less of an opportunity to act as an independent reservoir for HIV-infected cells and therefore to develop HIV-associated neurocognitive disorders.^9,10Table 1 outlines steps psychiatrists can take to help prevent HIV transmission.

Psychiatric disorders and HIV

Psychiatric disorders and distress play a significant role in transmission of, exposure to, and infection with HIV (Table 2).^4-6,11 They are relevant for prevention, clinical care, and adherence throughout every aspect of illness.

Comprehensive, compassionate, nonjudgmental care of persons at risk for or infected with HIV begins with a thorough psychiatric evaluation designed to provide an ego-supportive, sensitive, and comprehensive assessment that can guide other clinicians in providing care.¹² Setting the tone and demonstrating compassion and respect includes shaking hands, which takes on special relevance in the context of AIDSism and stigma. Assessing the impact of HIV seropositivity or AIDS is best done by asking about the individual’s understanding of his or her diagnosis or illness and its impact. For some persons with HIV, verbalizing this understanding can be relieving as well as revealing. It is a chance for the patient to reveal painful experiences encountered in the home, school, camp, workplace, or community and the anguish of AIDSism and stigma.

Pay attention to sensitive and sometimes painful issues related to sexual history and sexuality. Questions related to sexual history and sexuality in heterosexual men and women as well as gay, lesbian, bisexual, and transgender individuals—such as “What is your sexual function like since you have been ill?” “Do feelings about your sexual identity play a role in your current level of distress?” and “What kind of barrier contraception are you using?”—are included in the comprehensive assessment described by Cohen et al.¹²

Comprehensive psychiatric evaluations can provide diagnoses, inform treatment, and mitigate anguish, distress, depression, anxiety, and substance use in persons with HIV and AIDS.¹² A thorough and comprehensive assessment is crucial because HIV has an affinity for brain and neural tissue and can cause CNS complications such as HIV-associated neurocognitive disorders (HAND), even in otherwise healthy HIV-seropositive individuals. See this article at CurrentPsychiatry.com for a discussion of HAND and delirium in patients with HIV.

Some persons with HIV and AIDS do not have a psychiatric disorder, while others have multiple complex psychiatric disorders that are responses to illness or treatments or are associated with HIV/AIDS (such as HAND) or other medical illnesses and treatments (such as hepatitis C, cirrhosis, end-stage liver disease, HIV nephropathy, end-stage renal disease, anemia, coronary artery disease, and cancer). See this article at CurrentPsychiatry.com for case studies of HIV patients with delirium, depression, posttraumatic stress disorder (PTSD), and substance dependence.

Mood disorders. Depression is common among persons with HIV. Demoralization and bereavement may masquerade as depression and can complicate diagnosis and treatment. Depression and other mood disorders may be related to stigma and AIDSism as well as to biologic, psychological, social, and genetic factors. Because suicide is prevalent among persons with HIV and AIDS,¹³ every patient with HIV should be evaluated for depression and suicidal ideation.

PTSD is prevalent among persons with HIV. It is a risky diagnosis because it is associated with a sense of a foreshortened future, which leads to a lack of adequate self-care, poor adherence to medical care, risky behaviors, and comorbid substance dependence to help numb the pain of trauma.^14,15 Persons with PTSD may have difficulty trusting clinicians and other authority figures if their trauma was a high-betrayal trauma, such as incest or military trauma.^14,15

In patients with HIV, PTSD often is overlooked because it may be overshadowed by other psychiatric diagnoses. Intimate partner violence, history of childhood trauma, and childhood sexual abuse are risk factors for HIV infection and PTSD. Increased severity of HIV-related PTSD symptoms is associated with having a greater number of HIV-related physical symptoms, history of pre-HIV trauma, decreased social support, increased perception of stigma, and negative life events.

PTSD also is associated with nonadherence to risk reduction strategies and medical care.^14,15 Diagnosis is further complicated by repression or retrograde amnesia of traumatic events and difficulties forming trusting relationships and disclosing HIV status to sexual partners or potential sexual partners because of fear of rejection. 

Substance use disorders. Dependence on alcohol and other drugs complicates and perpetuates the HIV pandemic. Sharing needles and other drug paraphernalia is instrumental in HIV transmission. The indirect effects of alcohol and substance abuse include:

•  the impact of intimate partner violence, child abuse, neglect, and/or abandonment

•  development of PTSD in adults, with early childhood trauma leading to repeating their own history

•  lack of self-care

•  unhealthy partner choices

•  use of drugs and alcohol to numb the pain associated with trauma.

Persons who are using alcohol or other drugs may have difficulty attending to their health, and substance dependence may prevent persons at risk from seeking HIV testing.

Intoxication from alcohol and drug use frequently leads to inappropriate partner choice, violent and coercive sexual behaviors, and lack of condom use. Substance dependence also may lead individuals to exchange sex for drugs and to fail to adhere to safer sexual practices or use sterile drug paraphernalia.

Treating persons with HIV/AIDS

Several organizations publish evidence-based clinical guidelines for treating depression, anxiety, substance abuse, and other psychiatric disorders in patients with HIV/AIDS. One such set of guidelines is available from the New York State Department of Health AIDS Institute at www.hivguidelines.org. As is the case with patients who do not have HIV, psychotherapy and pharmacotherapy are common first-line treatments.

Psychotherapy. Patients with HIV/AIDS with psychiatric comorbidities generally respond well to psychotherapeutic treatments.^16,17 The choice of therapy needs to be tailored to the needs of individuals, couples, and families coping with AIDS. Options include:

•  individual, couple, family, and group psychotherapy

•  crisis intervention

•  12-step programs (Alcohol Anonymous, Narcotics Anonymous, etc.)

•  adult survivors of child abuse programs (www.ascasupport.org), groups, and workbooks

•  palliative psychiatry

•  bereavement therapy

•  spiritual support

•  relaxation response

•  wellness interventions such as exercise, yoga, keeping a journal, writing a life narrative, reading, artwork, movement therapy, listening to music or books on tape, and working on crossword puzzles and jigsaw puzzles.

Psychopharmacotherapy. Accurate diagnosis and awareness of drug-drug and drug-illness interactions are important when treating patients with HIV/AIDS; consult resources in the literature¹⁸ and online resources that are updated regularly (see Related Resources). Because persons with AIDS are particularly vulnerable to extrapyramidal and anticholinergic side effects of psychotropics, the principle start very low and go very slow is critical. For patients who are opioid-dependent, be cautious when prescribing medications that are cytochrome P450 3A4 inducers—such as carbamazepine, efavirenz, nevirapine, and ritonavir—because these medications can lower methadone levels in persons receiving agonist treatment and might lead to opioid withdrawal symptoms, discontinuation of ARVs, or relapse to opioids.¹⁸ When a person with AIDS is experiencing pain and is on a maintenance dose of methadone for heroin withdrawal, pain should be treated as a separate problem with additional opioids. Methadone for relapse prevention will target opioid tolerance needs and prevent withdrawal but will not provide analgesia for pain.

HIV through the life cycle

From prevention of prenatal transmission to the care of children with HIV to reproductive issues in serodiscordant couples, HIV complicates patients’ development. Table 3 outlines concerns regarding HIV transmission and treatment at different stages of a patient’s life.

Bottom Line

HIV transmission and effective treatment are complicated by a high prevalence of psychiatric comorbidities, including depression and other mood disorders, posttraumatic stress disorder, substance use disorders, and cognitive disorders. With an increased understanding of the issues faced by patients at risk for or infected with HIV, psychiatrists can help prevent HIV transmission, improve adherence to medical care, and diminish suffering, morbidity, and mortality.

Related Resources

• Academy of Psychosomatic Medicine HIV/AIDS Psychiatry Special Interest Group. www.apm.org/sigs/oap.
• New York State Department of Health AIDS Institute. HIV Clinical Resource. www.hivguidelines.org.
• University of Liverpool. HIV drug interactions list. www.hiv-druginteractions.org.
• Toronto General Hospital Immunodeficiency Clinic. Drug interactions tables. www.hivclinic.ca/main/drugs_interact.html.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Nevirapine • Viramune
Carbamazepine • Carbatrol, Tegretol, others
Olanzapine • Zyprexa
Quetiapine • Seroquel
Clonazepam • Klonopin
Ritonavir • Norvir
Efavirenz • Sustiva
Venlafaxine • Effexor
Escitalopram • Lexapro

Disclosure

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

References

1. Blank MB, Mandell DS, Aiken L, et al. Co-occurrence of HIV and serious mental illness among Medicaid recipients. Psychiatr Serv. 2002;53(7):868-873.

2.Moyer VA, on behalf of the U.S. Preventive Services Task Force. Screening for HIV: U.S. Preventive Services Task Force recommendation statement [published online April 30, 2013]. Ann Intern Med. doi:10.7326/0003-4819-159-1-201307020-00645.

3. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the United States. JAMA. 2008;300(5):520-529.

4. Cohen MA. AIDSism, a new form of discrimination. Am Med News. 1989;32:43.

5. Cohen MA, Gorman JM. Comprehensive textbook of AIDS psychiatry. New York, NY: Oxford University Press; 2008.

6. Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010.

7. World Health Organization, United Nations Children’s Fund, Joint United Nations Programme on HIV/AIDS. Global HIV/AIDS response. Epidemic update and health sector progress towards universal access. Progress report 2011. http://www.unaids.org/en/media/unaids/
contentassets/documents/unaidspublication/2011/
20111130_UA_Report_en.pdf. Accessed April 25, 2013.

8. Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep. 2012;61(31):586-589.

9. Cysique LA, Murray JM, Dunbar M, et al. A screening algorithm for HIV-associated neurocognitive disorders. HIV Med. 2010;11(10):642-649.

10. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24(9):1243-1250.

11. Cohen M, Hoffman RG, Cromwell C, et al. The prevalence of distress in persons with human immunodeficiency virus infection. Psychosomatics. 2002;43(1):10-15.

12. Cohen MA, Batista SM, Lux JZ. A biopsychosocial approach to psychiatric consultation in persons with HIV and AIDS. In: Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010:33-60.

13. Carrico AW. Elevated suicide rate among HIV-positive persons despite benefits of antiretroviral therapy: implications for a stress and coping model of suicide. Am J Psychiatry. 2010;167(2):117-119.

14. Cohen MA, Alfonso CA, Hoffman RG, et al. The impact of PTSD on treatment adherence in persons with HIV infection. Gen Hosp Psychiatry. 2001;23(5):294-296.

15. Boarts JM, Sledjeski EM, Bogart LM, et al. The differential impact of PTSD and depression on HIV disease markers and adherence to HAART in people living with HIV. AIDS Behav. 2006;10(3):253-261.

16. Sikkema KJ, Hansen NB, Ghebremichael M, et al. A randomized controlled trial of a coping group intervention for adults with HIV who are AIDS bereaved: longitudinal effects on grief. Health Psychol. 2006;25(5):563-570.

17. Cohen MA. Psychodynamic psychotherapy in an AIDS nursing home. J Am Acad Psychoanal. 1999;27(1):121-133.

18. Cozza KL, Goforth HW, Batista SM. Psychopharmacologic treatment issues in AIDS psychiatry. In: Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010:147-199.

The prevalence of HIV in persons with untreated psychiatric illness may be 10 to 20 times that of the general population.¹ The U.S. Preventive Services Task Force has recommended HIV screening of all persons age 15 to 65 because 20% to 25% of individuals with HIV infection are unaware that they are HIV-positive.² Because >20% of new HIV infections in the United States are undiagnosed,³ it is crucial to educate patients with mental illness about HIV prevention, make condoms available, and offer HIV testing.

As psychiatrists, we have a unique role in caring for patients at risk for or infected with HIV because in addition to comprehensive medical and psychiatric histories, we routinely take histories of substance use, sexual activities, relationships, and trauma, including childhood neglect and emotional, physical, and sexual abuse. We develop long-term, trusting relationships and work with individuals to change behaviors and maximize life potential.

Increasing awareness of stigma, discrimination, and psychiatric factors involved with the HIV pandemic can lead to decreased transmission of HIV infection and early diagnosis and treatment. Compassionate medical and psychiatric care can mitigate suffering in persons at risk for, infected with, or affected by HIV.

Preventing HIV transmission

AIDS differs from other complex, severe illnesses in 2 ways that are relevant to psychiatrists:

•  it is almost entirely preventable

•  HIV and AIDS are associated with sex, drugs, and AIDS-associated stigma and discrimination (“AIDSism”).^4-6

Unsafe exposure of mucosal surfaces to the virus—primarily from exchanging body fluids in unprotected sexual encounters—accounts for 80% of new HIV infections.⁷ HIV transmission via sexual encounters is preventable with condoms. Percutaneous or intravenous infection with HIV—primarily from sharing needles in injection drug use—accounts for 20% of new infections.⁷ Use of alcohol or other substances can lead to sexual coercion, unprotected sex, and exchange of sex for drugs or money. Hence, treating substance use disorders can prevent HIV transmission.

Early diagnosis of HIV can lead to appropriate medical care, quicker onset of antiretroviral (ARV) treatment, and better outcomes. Recent research has shown that pre-exposure prophylaxis with ARV treatment can prevent transmission of HIV⁸; therefore, becoming aware of risk behaviors and prevention can be lifesaving for serodiscordant couples.

One of the most important ways to prevent HIV’s impact on the brain and CNS is to diagnose HIV shortly after transmission at onset of acute infection. If HIV is diagnosed very early—preferably as soon as possible after inoculation with HIV or at onset of the first flu-like symptoms—and treated with ARVs, the brain has less of an opportunity to act as an independent reservoir for HIV-infected cells and therefore to develop HIV-associated neurocognitive disorders.^9,10Table 1 outlines steps psychiatrists can take to help prevent HIV transmission.

Psychiatric disorders and HIV

Psychiatric disorders and distress play a significant role in transmission of, exposure to, and infection with HIV (Table 2).^4-6,11 They are relevant for prevention, clinical care, and adherence throughout every aspect of illness.

Comprehensive, compassionate, nonjudgmental care of persons at risk for or infected with HIV begins with a thorough psychiatric evaluation designed to provide an ego-supportive, sensitive, and comprehensive assessment that can guide other clinicians in providing care.¹² Setting the tone and demonstrating compassion and respect includes shaking hands, which takes on special relevance in the context of AIDSism and stigma. Assessing the impact of HIV seropositivity or AIDS is best done by asking about the individual’s understanding of his or her diagnosis or illness and its impact. For some persons with HIV, verbalizing this understanding can be relieving as well as revealing. It is a chance for the patient to reveal painful experiences encountered in the home, school, camp, workplace, or community and the anguish of AIDSism and stigma.

Pay attention to sensitive and sometimes painful issues related to sexual history and sexuality. Questions related to sexual history and sexuality in heterosexual men and women as well as gay, lesbian, bisexual, and transgender individuals—such as “What is your sexual function like since you have been ill?” “Do feelings about your sexual identity play a role in your current level of distress?” and “What kind of barrier contraception are you using?”—are included in the comprehensive assessment described by Cohen et al.¹²

Comprehensive psychiatric evaluations can provide diagnoses, inform treatment, and mitigate anguish, distress, depression, anxiety, and substance use in persons with HIV and AIDS.¹² A thorough and comprehensive assessment is crucial because HIV has an affinity for brain and neural tissue and can cause CNS complications such as HIV-associated neurocognitive disorders (HAND), even in otherwise healthy HIV-seropositive individuals. See this article at CurrentPsychiatry.com for a discussion of HAND and delirium in patients with HIV.

Some persons with HIV and AIDS do not have a psychiatric disorder, while others have multiple complex psychiatric disorders that are responses to illness or treatments or are associated with HIV/AIDS (such as HAND) or other medical illnesses and treatments (such as hepatitis C, cirrhosis, end-stage liver disease, HIV nephropathy, end-stage renal disease, anemia, coronary artery disease, and cancer). See this article at CurrentPsychiatry.com for case studies of HIV patients with delirium, depression, posttraumatic stress disorder (PTSD), and substance dependence.

Mood disorders. Depression is common among persons with HIV. Demoralization and bereavement may masquerade as depression and can complicate diagnosis and treatment. Depression and other mood disorders may be related to stigma and AIDSism as well as to biologic, psychological, social, and genetic factors. Because suicide is prevalent among persons with HIV and AIDS,¹³ every patient with HIV should be evaluated for depression and suicidal ideation.

PTSD is prevalent among persons with HIV. It is a risky diagnosis because it is associated with a sense of a foreshortened future, which leads to a lack of adequate self-care, poor adherence to medical care, risky behaviors, and comorbid substance dependence to help numb the pain of trauma.^14,15 Persons with PTSD may have difficulty trusting clinicians and other authority figures if their trauma was a high-betrayal trauma, such as incest or military trauma.^14,15

In patients with HIV, PTSD often is overlooked because it may be overshadowed by other psychiatric diagnoses. Intimate partner violence, history of childhood trauma, and childhood sexual abuse are risk factors for HIV infection and PTSD. Increased severity of HIV-related PTSD symptoms is associated with having a greater number of HIV-related physical symptoms, history of pre-HIV trauma, decreased social support, increased perception of stigma, and negative life events.

PTSD also is associated with nonadherence to risk reduction strategies and medical care.^14,15 Diagnosis is further complicated by repression or retrograde amnesia of traumatic events and difficulties forming trusting relationships and disclosing HIV status to sexual partners or potential sexual partners because of fear of rejection. 

Substance use disorders. Dependence on alcohol and other drugs complicates and perpetuates the HIV pandemic. Sharing needles and other drug paraphernalia is instrumental in HIV transmission. The indirect effects of alcohol and substance abuse include:

•  the impact of intimate partner violence, child abuse, neglect, and/or abandonment

•  development of PTSD in adults, with early childhood trauma leading to repeating their own history

•  lack of self-care

•  unhealthy partner choices

•  use of drugs and alcohol to numb the pain associated with trauma.

Persons who are using alcohol or other drugs may have difficulty attending to their health, and substance dependence may prevent persons at risk from seeking HIV testing.

Intoxication from alcohol and drug use frequently leads to inappropriate partner choice, violent and coercive sexual behaviors, and lack of condom use. Substance dependence also may lead individuals to exchange sex for drugs and to fail to adhere to safer sexual practices or use sterile drug paraphernalia.

Treating persons with HIV/AIDS

Several organizations publish evidence-based clinical guidelines for treating depression, anxiety, substance abuse, and other psychiatric disorders in patients with HIV/AIDS. One such set of guidelines is available from the New York State Department of Health AIDS Institute at www.hivguidelines.org. As is the case with patients who do not have HIV, psychotherapy and pharmacotherapy are common first-line treatments.

Psychotherapy. Patients with HIV/AIDS with psychiatric comorbidities generally respond well to psychotherapeutic treatments.^16,17 The choice of therapy needs to be tailored to the needs of individuals, couples, and families coping with AIDS. Options include:

•  individual, couple, family, and group psychotherapy

•  crisis intervention

•  12-step programs (Alcohol Anonymous, Narcotics Anonymous, etc.)

•  adult survivors of child abuse programs (www.ascasupport.org), groups, and workbooks

•  palliative psychiatry

•  bereavement therapy

•  spiritual support

•  relaxation response

•  wellness interventions such as exercise, yoga, keeping a journal, writing a life narrative, reading, artwork, movement therapy, listening to music or books on tape, and working on crossword puzzles and jigsaw puzzles.

Psychopharmacotherapy. Accurate diagnosis and awareness of drug-drug and drug-illness interactions are important when treating patients with HIV/AIDS; consult resources in the literature¹⁸ and online resources that are updated regularly (see Related Resources). Because persons with AIDS are particularly vulnerable to extrapyramidal and anticholinergic side effects of psychotropics, the principle start very low and go very slow is critical. For patients who are opioid-dependent, be cautious when prescribing medications that are cytochrome P450 3A4 inducers—such as carbamazepine, efavirenz, nevirapine, and ritonavir—because these medications can lower methadone levels in persons receiving agonist treatment and might lead to opioid withdrawal symptoms, discontinuation of ARVs, or relapse to opioids.¹⁸ When a person with AIDS is experiencing pain and is on a maintenance dose of methadone for heroin withdrawal, pain should be treated as a separate problem with additional opioids. Methadone for relapse prevention will target opioid tolerance needs and prevent withdrawal but will not provide analgesia for pain.

HIV through the life cycle

From prevention of prenatal transmission to the care of children with HIV to reproductive issues in serodiscordant couples, HIV complicates patients’ development. Table 3 outlines concerns regarding HIV transmission and treatment at different stages of a patient’s life.

Bottom Line

HIV transmission and effective treatment are complicated by a high prevalence of psychiatric comorbidities, including depression and other mood disorders, posttraumatic stress disorder, substance use disorders, and cognitive disorders. With an increased understanding of the issues faced by patients at risk for or infected with HIV, psychiatrists can help prevent HIV transmission, improve adherence to medical care, and diminish suffering, morbidity, and mortality.

Related Resources

• Academy of Psychosomatic Medicine HIV/AIDS Psychiatry Special Interest Group. www.apm.org/sigs/oap.
• New York State Department of Health AIDS Institute. HIV Clinical Resource. www.hivguidelines.org.
• University of Liverpool. HIV drug interactions list. www.hiv-druginteractions.org.
• Toronto General Hospital Immunodeficiency Clinic. Drug interactions tables. www.hivclinic.ca/main/drugs_interact.html.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Nevirapine • Viramune
Carbamazepine • Carbatrol, Tegretol, others
Olanzapine • Zyprexa
Quetiapine • Seroquel
Clonazepam • Klonopin
Ritonavir • Norvir
Efavirenz • Sustiva
Venlafaxine • Effexor
Escitalopram • Lexapro

Disclosure

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

References

1. Blank MB, Mandell DS, Aiken L, et al. Co-occurrence of HIV and serious mental illness among Medicaid recipients. Psychiatr Serv. 2002;53(7):868-873.

2.Moyer VA, on behalf of the U.S. Preventive Services Task Force. Screening for HIV: U.S. Preventive Services Task Force recommendation statement [published online April 30, 2013]. Ann Intern Med. doi:10.7326/0003-4819-159-1-201307020-00645.

3. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the United States. JAMA. 2008;300(5):520-529.

4. Cohen MA. AIDSism, a new form of discrimination. Am Med News. 1989;32:43.

5. Cohen MA, Gorman JM. Comprehensive textbook of AIDS psychiatry. New York, NY: Oxford University Press; 2008.

6. Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010.

7. World Health Organization, United Nations Children’s Fund, Joint United Nations Programme on HIV/AIDS. Global HIV/AIDS response. Epidemic update and health sector progress towards universal access. Progress report 2011. http://www.unaids.org/en/media/unaids/
contentassets/documents/unaidspublication/2011/
20111130_UA_Report_en.pdf. Accessed April 25, 2013.

8. Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep. 2012;61(31):586-589.

9. Cysique LA, Murray JM, Dunbar M, et al. A screening algorithm for HIV-associated neurocognitive disorders. HIV Med. 2010;11(10):642-649.

10. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24(9):1243-1250.

11. Cohen M, Hoffman RG, Cromwell C, et al. The prevalence of distress in persons with human immunodeficiency virus infection. Psychosomatics. 2002;43(1):10-15.

12. Cohen MA, Batista SM, Lux JZ. A biopsychosocial approach to psychiatric consultation in persons with HIV and AIDS. In: Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010:33-60.

13. Carrico AW. Elevated suicide rate among HIV-positive persons despite benefits of antiretroviral therapy: implications for a stress and coping model of suicide. Am J Psychiatry. 2010;167(2):117-119.

14. Cohen MA, Alfonso CA, Hoffman RG, et al. The impact of PTSD on treatment adherence in persons with HIV infection. Gen Hosp Psychiatry. 2001;23(5):294-296.

15. Boarts JM, Sledjeski EM, Bogart LM, et al. The differential impact of PTSD and depression on HIV disease markers and adherence to HAART in people living with HIV. AIDS Behav. 2006;10(3):253-261.

16. Sikkema KJ, Hansen NB, Ghebremichael M, et al. A randomized controlled trial of a coping group intervention for adults with HIV who are AIDS bereaved: longitudinal effects on grief. Health Psychol. 2006;25(5):563-570.

17. Cohen MA. Psychodynamic psychotherapy in an AIDS nursing home. J Am Acad Psychoanal. 1999;27(1):121-133.

18. Cozza KL, Goforth HW, Batista SM. Psychopharmacologic treatment issues in AIDS psychiatry. In: Cohen MA, Goforth HW, Lux JZ, et al, eds. Handbook of AIDS psychiatry. New York, NY: Oxford University Press; 2010:147-199.

When evaluating a patient’s risk of violence, the presence of psychosis is a crucial concern. Douglas et al¹ found that psychosis was the most important predictor of violent behavior in an analysis of 204 studies examining the relationship between psychopathology and aggression. Clinicians need to be familiar with aspects of persecutory delusions and command auditory hallucinations that are associated with an increased risk of aggression because accurately assessing patients who are experiencing these 2 symptoms is an important part of a comprehensive violence risk assessment.

This article highlights the importance of investigating persecutory delusions and command auditory hallucinations when evaluating a psychotic patient’s risk for violence. We provide specific questions to ask to help gauge risk associated with these 2 symptoms.

Evaluating persecutory delusions

Do persecutory delusions increase the risk that a person will behave violently? Research examining delusions’ contribution to violent behavior does not provide a clear answer. Earlier studies suggested that persecutory delusions were associated with an increased risk of aggression.² Delusions noted to increase the risk of violence were characterized by threat/control-override (TCO) symptoms. TCO symptoms are beliefs that one is being threatened (eg, being followed or poisoned) or is losing control to an external source (eg, one’s mind is dominated by forces beyond his or her control).³ Similarly, using data from the Epidemiologic Catchment Area surveys, Swanson et al⁴ found that patients who reported TCO symptoms were approximately twice as likely to engage in assaultive behavior compared with patients with other psychotic symptoms.

In contrast, the MacArthur Study of Mental Disorder and Violence^5,6 showed that the presence of delusions did not predict higher rates of violence among recently discharged psychiatric patients. In particular, researchers did not find a relationship between the presence of TCO delusions and violent behavior. In a study comparing male criminal offenders with schizophrenia found not guilty by reason of insanity with matched non-offending schizophrenia patients, Stompe et al⁷ found no significant association between TCO symptoms and severity of violent behavior; prevalence of TCO symptoms did not differ between the 2 groups. However, nondelusional suspiciousness—such as misperceiving others’ behavior as indicating hostile intent—was associated with subsequent violence.⁶

Nederlof et al⁸ conducted a cross-sectional multicenter study to further examine whether TCO symptoms are related to aggressive behavior. Their study included 124 patients (88% men) who had paranoid schizophrenia (70%), “other forms” of schizophrenia (16%), schizoaffective disorder (3%), delusional disorder (1%), and psychosis not otherwise specified (10%). To measure TCO symptoms in a more detailed manner than in previous research, these researchers developed the Threat/Control-Override Questionnaire (TCOQ), a 14-item, self-report scale. The 7 threat items specific to the TCOQ are:⁸

• I am under the control of an external force that determines my actions.
• Other people have tried to poison me or to do me harm.
• Someone has deliberately tried to make me ill.
• Other people have been secretly plotting to ruin me.
• Someone has had evil intentions against me.
• I have the thought that I was being followed for a special reason.
• People have tried to drive me insane.

The 7 control-override items on the TCOQ are:⁸

• Other people control my way of movements.
• Other people can insert thoughts into my head.
• My thoughts are dominated by an external force.
• I have the feeling that other people can determine my thoughts.
• Other people can insert thoughts into my mind.
• I have the feeling that other people have control over me.
• My life is being determined by something or someone except for myself.

Nederlof et al⁸ determined that TCO symptoms were a significant correlate of aggression in their study sample. When the 2 domains of TCO symptoms were evaluated separately, only threat symptoms made a significant contribution to aggressive behavior. These researchers suggested that varying methods of measuring TCO symptoms may underlie previous studies’ seemingly contradictory findings.⁸ These recent findings indicate that the debate regarding the contribution of TCO symptoms, particularly threat symptoms, to future violence remains active.

Appelbaum et al⁹ used the MacArthur-Maudsley Delusions Assessment Schedule to examine the contribution of non-content-related delusional material to violence in interviews with 328 delusional hospitalized psychiatric patients. The 7 dimensions of the MacArthur-Maudsley Delusions Assessment Schedule are:

• Conviction—the degree of certainty about the delusional belief
• Negative affect—whether the delusional belief makes the patient unhappy, frightened, anxious, or angry
• Action—the extent to which the patient’s actions are motivated by the delusional belief
• Inaction—whether the patient has refrained from any action as a result of the delusional belief
• Preoccupation—the extent to which the patient indicates his or her thoughts focus exclusively on the delusion
• Pervasiveness—the degree to which the delusional belief penetrates all aspects of the patient’s experiences
• Fluidity—the degree to which the delusional belief changed frequently during the interview.

Patients with persecutory delusions had significantly higher scores on “action” and “negative affect” dimensions, indicating that those with persecutory delusions may be more likely to react in response to the dysphoric aspects of their symptoms.⁹ Subsequent research has demonstrated that patients who suffer from persecutory delusions and negative affect are more likely to act on their delusions^2,10 and to act violently¹¹ than patients without these symptoms.

When evaluating a patient who experiences persecutory delusions, inquire if he or she has employed “safety actions.” These are specific behaviors—such as avoiding a perceived persecutor or escaping a fearful situation—the individual has employed with the intention of minimizing a misperceived threat. In a study of 100 patients with persecutory delusions, 96% reported using safety behaviors in the past month.¹² In this study, individuals with a history of violence reported a greater use of safety behaviors.

Table 1 lists 10 questions to ask patients to explore persecutory delusions and associated risk factors for aggression.

Table 1

Evaluating persecutory delusions: 10 questions

Assessing auditory hallucinations

A careful inquiry about hallucinations can help determine whether their presence increases a patient’s risk of committing a violent act. Command hallucinations provide some type of directive to the patient. Approximately 50% of hallucinating psychiatric patients experience command hallucinations.¹³ Most command hallucinations are nonviolent, and patients are more likely to obey nonviolent instructions than violent commands.¹⁴

Research on factors associated with a patient acting on harmful command hallucinations has been mixed. In a review of 7 controlled studies, no study demonstrated a positive relationship between command hallucinations and violence, and 1 found an inverse relationship.¹⁵ In contrast, in a study of 103 psychiatric inpatients, McNiel et al¹⁶ found 30% reported having command hallucinations to harm others during the past year and 22% reported they complied with such commands. These researchers concluded that compared with those without command hallucinations, patients in their study who experienced command hallucinations to harm others were more than twice as likely to be violent.

Much of the literature examining the relationship between a patient’s actions and command hallucinations has examined the patient’s response to all command hallucinations, without delineating factors specific to violent commands. Seven factors are associated with acting on command hallucinations:¹³

• the presence of coexisting delusions¹⁷
• having delusions that relate to the hallucination¹⁸
• knowing the voice’s identity¹⁸
• believing the voices to be real¹⁹
• believing that the voices are benevolent²⁰
• having few coping strategies to deal with the voices¹⁷
• not feeling in control over the voices.²⁰

These factors also have been found to indicate increased compliance with acting on violent command hallucinations.^18,20 Studies that have examined compliance specific to harmful command hallucinations provide additional guidance when evaluating the patient’s risk of harm. Aspects relevant to increased compliance to violent command hallucinations include a belief that the voice is powerful,^13,21 a patient’s sense of personal superiority,²¹ a belief that command hallucinations benefit the patient,¹³ delusions that were congruent with the action described,¹³ and hallucinations that generate negative emotions such as anger, anxiety, and sadness.¹¹

Table 2 lists 10 questions to ask to further investigate general command auditory hallucinations and violent command auditory hallucinations.

Table 2

Evaluating command auditory hallucinations: 10 questions

Related Resources

• MacArthur Research Network on Mental Health and the Law. The MacArthur Violence Risk Assessment Study.http://macarthur.virginia.edu/risk.html.
• Witt K, van Dorn R, Fazel S. Risk factors for violence in psychosis: systematic review and meta-regression analysis of 110 studies [published online February 13, 2013]. PLoS One. 2013;8(2):e55942. doi: 10.1371/journal.pone.0055942.

Disclosure

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

When evaluating a patient’s risk of violence, the presence of psychosis is a crucial concern. Douglas et al¹ found that psychosis was the most important predictor of violent behavior in an analysis of 204 studies examining the relationship between psychopathology and aggression. Clinicians need to be familiar with aspects of persecutory delusions and command auditory hallucinations that are associated with an increased risk of aggression because accurately assessing patients who are experiencing these 2 symptoms is an important part of a comprehensive violence risk assessment.

This article highlights the importance of investigating persecutory delusions and command auditory hallucinations when evaluating a psychotic patient’s risk for violence. We provide specific questions to ask to help gauge risk associated with these 2 symptoms.

Evaluating persecutory delusions

Do persecutory delusions increase the risk that a person will behave violently? Research examining delusions’ contribution to violent behavior does not provide a clear answer. Earlier studies suggested that persecutory delusions were associated with an increased risk of aggression.² Delusions noted to increase the risk of violence were characterized by threat/control-override (TCO) symptoms. TCO symptoms are beliefs that one is being threatened (eg, being followed or poisoned) or is losing control to an external source (eg, one’s mind is dominated by forces beyond his or her control).³ Similarly, using data from the Epidemiologic Catchment Area surveys, Swanson et al⁴ found that patients who reported TCO symptoms were approximately twice as likely to engage in assaultive behavior compared with patients with other psychotic symptoms.

In contrast, the MacArthur Study of Mental Disorder and Violence^5,6 showed that the presence of delusions did not predict higher rates of violence among recently discharged psychiatric patients. In particular, researchers did not find a relationship between the presence of TCO delusions and violent behavior. In a study comparing male criminal offenders with schizophrenia found not guilty by reason of insanity with matched non-offending schizophrenia patients, Stompe et al⁷ found no significant association between TCO symptoms and severity of violent behavior; prevalence of TCO symptoms did not differ between the 2 groups. However, nondelusional suspiciousness—such as misperceiving others’ behavior as indicating hostile intent—was associated with subsequent violence.⁶

Nederlof et al⁸ conducted a cross-sectional multicenter study to further examine whether TCO symptoms are related to aggressive behavior. Their study included 124 patients (88% men) who had paranoid schizophrenia (70%), “other forms” of schizophrenia (16%), schizoaffective disorder (3%), delusional disorder (1%), and psychosis not otherwise specified (10%). To measure TCO symptoms in a more detailed manner than in previous research, these researchers developed the Threat/Control-Override Questionnaire (TCOQ), a 14-item, self-report scale. The 7 threat items specific to the TCOQ are:⁸

• I am under the control of an external force that determines my actions.
• Other people have tried to poison me or to do me harm.
• Someone has deliberately tried to make me ill.
• Other people have been secretly plotting to ruin me.
• Someone has had evil intentions against me.
• I have the thought that I was being followed for a special reason.
• People have tried to drive me insane.

The 7 control-override items on the TCOQ are:⁸

• Other people control my way of movements.
• Other people can insert thoughts into my head.
• My thoughts are dominated by an external force.
• I have the feeling that other people can determine my thoughts.
• Other people can insert thoughts into my mind.
• I have the feeling that other people have control over me.
• My life is being determined by something or someone except for myself.

Nederlof et al⁸ determined that TCO symptoms were a significant correlate of aggression in their study sample. When the 2 domains of TCO symptoms were evaluated separately, only threat symptoms made a significant contribution to aggressive behavior. These researchers suggested that varying methods of measuring TCO symptoms may underlie previous studies’ seemingly contradictory findings.⁸ These recent findings indicate that the debate regarding the contribution of TCO symptoms, particularly threat symptoms, to future violence remains active.

Appelbaum et al⁹ used the MacArthur-Maudsley Delusions Assessment Schedule to examine the contribution of non-content-related delusional material to violence in interviews with 328 delusional hospitalized psychiatric patients. The 7 dimensions of the MacArthur-Maudsley Delusions Assessment Schedule are:

• Conviction—the degree of certainty about the delusional belief
• Negative affect—whether the delusional belief makes the patient unhappy, frightened, anxious, or angry
• Action—the extent to which the patient’s actions are motivated by the delusional belief
• Inaction—whether the patient has refrained from any action as a result of the delusional belief
• Preoccupation—the extent to which the patient indicates his or her thoughts focus exclusively on the delusion
• Pervasiveness—the degree to which the delusional belief penetrates all aspects of the patient’s experiences
• Fluidity—the degree to which the delusional belief changed frequently during the interview.

Patients with persecutory delusions had significantly higher scores on “action” and “negative affect” dimensions, indicating that those with persecutory delusions may be more likely to react in response to the dysphoric aspects of their symptoms.⁹ Subsequent research has demonstrated that patients who suffer from persecutory delusions and negative affect are more likely to act on their delusions^2,10 and to act violently¹¹ than patients without these symptoms.

When evaluating a patient who experiences persecutory delusions, inquire if he or she has employed “safety actions.” These are specific behaviors—such as avoiding a perceived persecutor or escaping a fearful situation—the individual has employed with the intention of minimizing a misperceived threat. In a study of 100 patients with persecutory delusions, 96% reported using safety behaviors in the past month.¹² In this study, individuals with a history of violence reported a greater use of safety behaviors.

Table 1 lists 10 questions to ask patients to explore persecutory delusions and associated risk factors for aggression.

Table 1

Evaluating persecutory delusions: 10 questions

Assessing auditory hallucinations

A careful inquiry about hallucinations can help determine whether their presence increases a patient’s risk of committing a violent act. Command hallucinations provide some type of directive to the patient. Approximately 50% of hallucinating psychiatric patients experience command hallucinations.¹³ Most command hallucinations are nonviolent, and patients are more likely to obey nonviolent instructions than violent commands.¹⁴

Research on factors associated with a patient acting on harmful command hallucinations has been mixed. In a review of 7 controlled studies, no study demonstrated a positive relationship between command hallucinations and violence, and 1 found an inverse relationship.¹⁵ In contrast, in a study of 103 psychiatric inpatients, McNiel et al¹⁶ found 30% reported having command hallucinations to harm others during the past year and 22% reported they complied with such commands. These researchers concluded that compared with those without command hallucinations, patients in their study who experienced command hallucinations to harm others were more than twice as likely to be violent.

Much of the literature examining the relationship between a patient’s actions and command hallucinations has examined the patient’s response to all command hallucinations, without delineating factors specific to violent commands. Seven factors are associated with acting on command hallucinations:¹³

• the presence of coexisting delusions¹⁷
• having delusions that relate to the hallucination¹⁸
• knowing the voice’s identity¹⁸
• believing the voices to be real¹⁹
• believing that the voices are benevolent²⁰
• having few coping strategies to deal with the voices¹⁷
• not feeling in control over the voices.²⁰

These factors also have been found to indicate increased compliance with acting on violent command hallucinations.^18,20 Studies that have examined compliance specific to harmful command hallucinations provide additional guidance when evaluating the patient’s risk of harm. Aspects relevant to increased compliance to violent command hallucinations include a belief that the voice is powerful,^13,21 a patient’s sense of personal superiority,²¹ a belief that command hallucinations benefit the patient,¹³ delusions that were congruent with the action described,¹³ and hallucinations that generate negative emotions such as anger, anxiety, and sadness.¹¹

Table 2 lists 10 questions to ask to further investigate general command auditory hallucinations and violent command auditory hallucinations.

Table 2

Evaluating command auditory hallucinations: 10 questions

Related Resources

• MacArthur Research Network on Mental Health and the Law. The MacArthur Violence Risk Assessment Study.http://macarthur.virginia.edu/risk.html.
• Witt K, van Dorn R, Fazel S. Risk factors for violence in psychosis: systematic review and meta-regression analysis of 110 studies [published online February 13, 2013]. PLoS One. 2013;8(2):e55942. doi: 10.1371/journal.pone.0055942.

Disclosure

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

When evaluating a patient’s risk of violence, the presence of psychosis is a crucial concern. Douglas et al¹ found that psychosis was the most important predictor of violent behavior in an analysis of 204 studies examining the relationship between psychopathology and aggression. Clinicians need to be familiar with aspects of persecutory delusions and command auditory hallucinations that are associated with an increased risk of aggression because accurately assessing patients who are experiencing these 2 symptoms is an important part of a comprehensive violence risk assessment.

This article highlights the importance of investigating persecutory delusions and command auditory hallucinations when evaluating a psychotic patient’s risk for violence. We provide specific questions to ask to help gauge risk associated with these 2 symptoms.

Evaluating persecutory delusions

Do persecutory delusions increase the risk that a person will behave violently? Research examining delusions’ contribution to violent behavior does not provide a clear answer. Earlier studies suggested that persecutory delusions were associated with an increased risk of aggression.² Delusions noted to increase the risk of violence were characterized by threat/control-override (TCO) symptoms. TCO symptoms are beliefs that one is being threatened (eg, being followed or poisoned) or is losing control to an external source (eg, one’s mind is dominated by forces beyond his or her control).³ Similarly, using data from the Epidemiologic Catchment Area surveys, Swanson et al⁴ found that patients who reported TCO symptoms were approximately twice as likely to engage in assaultive behavior compared with patients with other psychotic symptoms.

In contrast, the MacArthur Study of Mental Disorder and Violence^5,6 showed that the presence of delusions did not predict higher rates of violence among recently discharged psychiatric patients. In particular, researchers did not find a relationship between the presence of TCO delusions and violent behavior. In a study comparing male criminal offenders with schizophrenia found not guilty by reason of insanity with matched non-offending schizophrenia patients, Stompe et al⁷ found no significant association between TCO symptoms and severity of violent behavior; prevalence of TCO symptoms did not differ between the 2 groups. However, nondelusional suspiciousness—such as misperceiving others’ behavior as indicating hostile intent—was associated with subsequent violence.⁶

Nederlof et al⁸ conducted a cross-sectional multicenter study to further examine whether TCO symptoms are related to aggressive behavior. Their study included 124 patients (88% men) who had paranoid schizophrenia (70%), “other forms” of schizophrenia (16%), schizoaffective disorder (3%), delusional disorder (1%), and psychosis not otherwise specified (10%). To measure TCO symptoms in a more detailed manner than in previous research, these researchers developed the Threat/Control-Override Questionnaire (TCOQ), a 14-item, self-report scale. The 7 threat items specific to the TCOQ are:⁸

• I am under the control of an external force that determines my actions.
• Other people have tried to poison me or to do me harm.
• Someone has deliberately tried to make me ill.
• Other people have been secretly plotting to ruin me.
• Someone has had evil intentions against me.
• I have the thought that I was being followed for a special reason.
• People have tried to drive me insane.

The 7 control-override items on the TCOQ are:⁸

• Other people control my way of movements.
• Other people can insert thoughts into my head.
• My thoughts are dominated by an external force.
• I have the feeling that other people can determine my thoughts.
• Other people can insert thoughts into my mind.
• I have the feeling that other people have control over me.
• My life is being determined by something or someone except for myself.

Nederlof et al⁸ determined that TCO symptoms were a significant correlate of aggression in their study sample. When the 2 domains of TCO symptoms were evaluated separately, only threat symptoms made a significant contribution to aggressive behavior. These researchers suggested that varying methods of measuring TCO symptoms may underlie previous studies’ seemingly contradictory findings.⁸ These recent findings indicate that the debate regarding the contribution of TCO symptoms, particularly threat symptoms, to future violence remains active.

Appelbaum et al⁹ used the MacArthur-Maudsley Delusions Assessment Schedule to examine the contribution of non-content-related delusional material to violence in interviews with 328 delusional hospitalized psychiatric patients. The 7 dimensions of the MacArthur-Maudsley Delusions Assessment Schedule are:

• Conviction—the degree of certainty about the delusional belief
• Negative affect—whether the delusional belief makes the patient unhappy, frightened, anxious, or angry
• Action—the extent to which the patient’s actions are motivated by the delusional belief
• Inaction—whether the patient has refrained from any action as a result of the delusional belief
• Preoccupation—the extent to which the patient indicates his or her thoughts focus exclusively on the delusion
• Pervasiveness—the degree to which the delusional belief penetrates all aspects of the patient’s experiences
• Fluidity—the degree to which the delusional belief changed frequently during the interview.

Patients with persecutory delusions had significantly higher scores on “action” and “negative affect” dimensions, indicating that those with persecutory delusions may be more likely to react in response to the dysphoric aspects of their symptoms.⁹ Subsequent research has demonstrated that patients who suffer from persecutory delusions and negative affect are more likely to act on their delusions^2,10 and to act violently¹¹ than patients without these symptoms.

When evaluating a patient who experiences persecutory delusions, inquire if he or she has employed “safety actions.” These are specific behaviors—such as avoiding a perceived persecutor or escaping a fearful situation—the individual has employed with the intention of minimizing a misperceived threat. In a study of 100 patients with persecutory delusions, 96% reported using safety behaviors in the past month.¹² In this study, individuals with a history of violence reported a greater use of safety behaviors.

Table 1 lists 10 questions to ask patients to explore persecutory delusions and associated risk factors for aggression.

Table 1

Evaluating persecutory delusions: 10 questions

Assessing auditory hallucinations

A careful inquiry about hallucinations can help determine whether their presence increases a patient’s risk of committing a violent act. Command hallucinations provide some type of directive to the patient. Approximately 50% of hallucinating psychiatric patients experience command hallucinations.¹³ Most command hallucinations are nonviolent, and patients are more likely to obey nonviolent instructions than violent commands.¹⁴

Research on factors associated with a patient acting on harmful command hallucinations has been mixed. In a review of 7 controlled studies, no study demonstrated a positive relationship between command hallucinations and violence, and 1 found an inverse relationship.¹⁵ In contrast, in a study of 103 psychiatric inpatients, McNiel et al¹⁶ found 30% reported having command hallucinations to harm others during the past year and 22% reported they complied with such commands. These researchers concluded that compared with those without command hallucinations, patients in their study who experienced command hallucinations to harm others were more than twice as likely to be violent.

Much of the literature examining the relationship between a patient’s actions and command hallucinations has examined the patient’s response to all command hallucinations, without delineating factors specific to violent commands. Seven factors are associated with acting on command hallucinations:¹³

• the presence of coexisting delusions¹⁷
• having delusions that relate to the hallucination¹⁸
• knowing the voice’s identity¹⁸
• believing the voices to be real¹⁹
• believing that the voices are benevolent²⁰
• having few coping strategies to deal with the voices¹⁷
• not feeling in control over the voices.²⁰

These factors also have been found to indicate increased compliance with acting on violent command hallucinations.^18,20 Studies that have examined compliance specific to harmful command hallucinations provide additional guidance when evaluating the patient’s risk of harm. Aspects relevant to increased compliance to violent command hallucinations include a belief that the voice is powerful,^13,21 a patient’s sense of personal superiority,²¹ a belief that command hallucinations benefit the patient,¹³ delusions that were congruent with the action described,¹³ and hallucinations that generate negative emotions such as anger, anxiety, and sadness.¹¹

Table 2 lists 10 questions to ask to further investigate general command auditory hallucinations and violent command auditory hallucinations.

Table 2

Evaluating command auditory hallucinations: 10 questions

Related Resources

• MacArthur Research Network on Mental Health and the Law. The MacArthur Violence Risk Assessment Study.http://macarthur.virginia.edu/risk.html.
• Witt K, van Dorn R, Fazel S. Risk factors for violence in psychosis: systematic review and meta-regression analysis of 110 studies [published online February 13, 2013]. PLoS One. 2013;8(2):e55942. doi: 10.1371/journal.pone.0055942.

Disclosure

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

Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).^1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.³ These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.

In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.

CYP2D6: Many variants

CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.⁴

Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).^5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).¹⁰

Box

Table

CYP450 enzymes involved in biotransformation of SSRIs

Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.³ These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.¹¹ PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.

Suicide and CYP2D6 status

The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.¹² Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte¹² found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.¹² Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.^13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.¹⁶

A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.¹⁶ The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.¹⁷ The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.

Case reports and observational studies^18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al¹⁸ described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al¹⁹ described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al²⁰ found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al²¹ found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.

Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al²² found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al²³ found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.²⁴ Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.

Effects on serotonin, dopamine

CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.²⁵ This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.^26,27

Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.²⁸ Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.²⁹ Yu et al²⁷ found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.³⁰ Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.

Dopamine also is generated from tyramine through CYP2D6,³¹ and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.³² The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,³³ and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,² which play an important role in the development of anxiety and impulsivity.

CYP2D6 in clinical practice

Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.

Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.³⁴ The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.

Related Resources

• Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
• Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.

Drug Brand Names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft

Disclosure

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

Acknowledgment

The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.

Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).^1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.³ These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.

In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.

CYP2D6: Many variants

CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.⁴

Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).^5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).¹⁰

Box

Table

CYP450 enzymes involved in biotransformation of SSRIs

Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.³ These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.¹¹ PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.

Suicide and CYP2D6 status

The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.¹² Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte¹² found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.¹² Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.^13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.¹⁶

A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.¹⁶ The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.¹⁷ The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.

Case reports and observational studies^18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al¹⁸ described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al¹⁹ described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al²⁰ found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al²¹ found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.

Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al²² found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al²³ found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.²⁴ Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.

Effects on serotonin, dopamine

CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.²⁵ This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.^26,27

Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.²⁸ Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.²⁹ Yu et al²⁷ found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.³⁰ Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.

Dopamine also is generated from tyramine through CYP2D6,³¹ and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.³² The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,³³ and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,² which play an important role in the development of anxiety and impulsivity.

CYP2D6 in clinical practice

Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.

Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.³⁴ The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.

Related Resources

• Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
• Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.

Drug Brand Names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft

Disclosure

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

Acknowledgment

The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.

Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).^1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.³ These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.

In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.

CYP2D6: Many variants

CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.⁴

Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).^5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).¹⁰

Box

Table

CYP450 enzymes involved in biotransformation of SSRIs

Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.³ These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.¹¹ PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.

Suicide and CYP2D6 status

The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.¹² Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte¹² found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.¹² Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.^13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.¹⁶

A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.¹⁶ The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.¹⁷ The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.

Case reports and observational studies^18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al¹⁸ described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al¹⁹ described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al²⁰ found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al²¹ found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.

Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al²² found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al²³ found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.²⁴ Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.

Effects on serotonin, dopamine

CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.²⁵ This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.^26,27

Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.²⁸ Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.²⁹ Yu et al²⁷ found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.³⁰ Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.

Dopamine also is generated from tyramine through CYP2D6,³¹ and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.³² The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,³³ and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,² which play an important role in the development of anxiety and impulsivity.

CYP2D6 in clinical practice

Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.

Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.³⁴ The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.

Related Resources

• Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
• Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.

Drug Brand Names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft

Disclosure

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

Acknowledgment

The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.

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.

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Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.¹ Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,² hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.

Table 1

Select genes and their functions

Table 2

Glossary of genetic terms

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).³ GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).

Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.⁴ Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.⁵ Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.^6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.⁸ A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).⁹ DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients¹⁰ as well as in control subjects.¹¹ Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007,¹² >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10^-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS,¹³ and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.¹⁴ The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.¹⁵ More work is needed to understand how this gene increases schizophrenia susceptibility.

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,^16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.¹⁸ However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137,¹⁹ coding for microRNA 137, which was associated with schizophrenia at P=1.6×10^-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.²⁰ More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.²¹ Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia.^22,23

Although genes such as DISC1 and CACNA1C are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not “schizophrenia genes.” Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy. This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5’ promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DRD2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample²⁴ and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients.²⁵ A 2010 meta-analysis of approximately 700 patients²⁶ showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with ≥1 copy of the Del allele.