1. Depression in Medical Settings
APM Resident Education Curriculum
Revised 2019: Christopher Wilson, DO, Iqbal Ahmed, MD
Revised 2013: Sermsak Lolak, MD
Revised 2011: Robert C. Joseph, MD, MS
Original version: Pamela Diefenbach, MD, FAPM, Lead Psychiatrist, Mental Health Integration in Primary Care, Veterans Affairs Greater Los Angeles Healthcare System, Clinical Professor of Psychiatry & Biobehavioral Sciences,
UCLA David Geffen School of Medicine & UCLA Semel Institute of Neuroscience
Version of March 15, 2019

2. Learning Objectives
By the end of the lecture, the viewer will be able to:
Describe the types and characteristics of depression in a variety of medical settings
Appreciate the diverse medical conditions, medication therapies and psychiatric conditions that contribute to depressive symptoms
List the evidence-based therapies for depression in the medically ill

3. Overview Classification of depression Prevalence in medical Settings
Evaluation
Time course and associations
Treatment

4. Depressive Disorders (DSM-5)
Major Depressive Disorder
Persistent Depressive Disorder (Dysthymia)
Adjustment disorder With depressed mood
Depressive Disorder Due to Another Medical Condition
Substance/Medication-Induced Depressive Disorder
Premenstrual Dysphoric Disorder

5. Some Medical Conditions Closely Associated with Depressive Symptoms
Stroke
Parkinson’s disease
Multiple sclerosis
Epilepsy
Huntington’s disease
Pancreatic and lung cancer
Diabetes
Heart disease
Hypothyroidism
Hepatitis C
HIV/AIDS

6. Difficulties in Diagnosing Depression in the Medically Ill
Medical symptoms can overlap with depressive symptoms
Fatigue
Anorexia and/or weight loss
Poor concentration
Anhedonia and or apathy
Difficult to make the attribution to either the psychological or medical conditions
Medications and interactions can contribute to depressive symptoms

7. Depression Criteria Controversy
Exclusive criteria Substitutive criteria Inclusive criteria
(Bukberg, et. al, 1984)

8. Exclusive Criteria
Exclusive proponents: The clinician excludes those criteria they can directly attribute to the medical condition
Difficult to weigh and decide
Identifies the most severe forms of depression
May miss milder forms of depression & thus missing opportunities to intervene
Bukberg J, Penman D, Holland JC: Depression in hospitalized cancer patients. Psychosomatic Medicine. 46: , 1984.

9. Substitutive Criteria
More weight is given to the psychological symptoms of depression, not the somatic symptoms of depression
Substitution of symptoms such as irritability, tearfulness, social withdrawal
Unclear which symptoms to include or exclude
Excludes some somatic symptoms
May miss severe forms of depression
Approach not widely adopted
Cavanaugh S, Clark DC, Gibbons RD. Diagnosing depression in hospitalized medically ill. Psychosomatics 24:

10. Inclusive Criteria
Inclusive approach: all symptoms are included without any weight to medical condition
Shown to be the most sensitive and reliable approach
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

11. Depression in medical illness
Coexistence
Induced by illness or medications
Causes or exacerbates somatic symptoms

12. Prevalence in Medical Settings

13. Prevalence in Primary Care Clinics
5-15% depends on population, settings
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

14. Depression and Heart Disease
Major depression: 16-23%
Depressed mood: 37-35%
Depression associated with:
Myocardial infarction
Angioplasty
Congestive heart failure
Coronary bypass graft surgery
Coronary artery disease
Independent risk factor for sudden death and morbidity
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

15. Depression and Cancer
Associated more with pancreatic, lung, brain and oropharyngeal cancers
Prevalence 25% (17-32%) in meta-analysis of 24 studies
Comorbid with anxiety in half of patients
Depression is associated with a decrease in treatment compliance
Can also be side effects of chemotherapy/steroids
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

16. Depression and Diabetes
Up to one-third of patients with Type 2 DM has depression
Depression can lead to poor compliance and poor medical outcomes
Among patients with Type 2 DM, those with comorbid depression appear to be at greater risk for death from non-cardiovascular, non-cancer causes compared to those without depression
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

17. Depression in Neurological Diseases
Parkinson’s disease: up to 50%
Multiple sclerosis: Up to 50%
Huntington’s disease: Up to 32%
Epilepsy: 10-55%
Post-stroke depression: 9-13%
Alzheimer’s dementia: 10-32%
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

18. Other Conditions With Increased Depression
Chronic hepatitis C infection
Peptic ulcer disease
Inflammatory bowel disorders
Fibromyalgia
Chronic fatigue syndrome
Sleep apnea
Systemic lupus erythematosus
Rheumatoid arthritis
Scleroderma
Pain syndromes
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

19. Evaluation

20. Common Causes of a “Depression” Consult
DEPRESSIONS
MEDICAL
NEUROLOGIC
OTHER
Major Depression
Persistent Depressive
Disorder (DSM5)
Adjustment disorders
Demoralization
Bereavement
“Minor Depression”
Mixed- Anxiety/Depression
Delirium
Hypothyroidism
Diabetes Mellitus
Addison’s Disease
Endocrine Tumors
Renal Disease
Cardiac Disease
HCV Interferon Treatment
Depression secondary to other medications/medical conditions
Post Stroke
Parkinson’s Disease
Multiple Sclerosis
HIV/AIDS
Huntington’s Disease
Dementia
Alcohol & Drug intoxication and/or withdrawal
Bipolar Affective Disorder
Schizophrenia
Schizoaffective
PTSD
ADHD
Personality Disorder/Poor Coping/Conflicts with team

21. Medical Symptoms Mimicking Depressive Symptoms
Apathy
Weight loss
Change in sleep
Psychomotor retardation
Fatigue
Difficulty concentrating
Thoughts of death but not depressed mood
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

22. Medications commonly associated with depressive symptoms
Antiepileptics * = studies showing mixed/inconclusive results. Angiotensin-converting enzyme inhibitors* (Boal et al, 2016; Gerstman et al, 1996) Antihypertensives (especially clonidine, methyldopa, thiazides) Antimicrobials (amphotericin, ethionamide, metronidazole) Antineoplastics (procarbazine, vincristine, vinblastine, asparaginase) Benzodiazepines, sedative–hypnotic agents Beta-blockers* (Boal et al, 2016; Gerstman et al, 1996) Calcium channel blockers Corticosteroids Endocrine modifiers (especially estrogens, leuprolide) Interferon Isotretinoin Metoclopramide Nonsteroidal anti-inflammatory drugs (especially indomethacin) Opiates Statins * (Parsaik et al, 2013)(Thompson et al, 2016)
There continues to be mixed studies regarding statins:
-You H, et al, (2013) comment on the possibility of statin use and depression: PMID:
-Thompson P, et. al. (2016)Review discusses positive correlation of statin use and depressive symptoms possibly d/t cholesterol role in membrane seratonin receptor function.
-Parsaik A, et al. (2013) review found statin use to be associated with lower risk of depression.
ACE-Inhibitors have also had mixed studies::
-Habra m, et (2010) based on CREATE trial results showed that ACE-I and B-Blockers showed depression had decrease response to antidepressants when on these medications but no comment on association between induction of depressive symptoms.
-Gerstman B, et. al (1996) reviewed incidence of depression with use of ACE-I and B-Blockers and found no increase in depression risk.
-Boal A, et. al (2016) large study suggests that ACE-inhibitors may be associated with decrease risk of mood disorders, and B-Blockers/Calcium channel blockers are associated with increased risk. These were looking at patients that were admitted to hospital for mood disorders.
(Rackley & Bostwick Psych Clin North Am, 2012)

23. Differential Diagnosis
Uncomplicated bereavement
Demoralization syndrome
Adjustment disorders
Alcohol and other drugs intoxication or withdrawal
Major depression
Depression secondary to general medical illness or treatment
Psychological Factors Affecting Other Medical Conditions
Delirium, particularly the hypoactive type
Untreated pain
Koenig HG, George LK, Peterson BL et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry , 1997.

24. Demoralization Syndrome
Jerome Frank “Persuation and Healing” 1960s – main reason for people seeking psychotherapy Goerge Engel – Rochester group 1960s
From Wellen M, Current Psych Report 2010

25. Demoralization
May be the most common reason for psychiatric evaluation of medically-ill patients, though their physicians typically request a “depression” evaluation.
Demoralization is an understandable response, albeit very distressing, to the situation (serious illness, hospitalization, agonizing treatment)
Symptoms include anxiety, guilt, shame, depression, somatic complaints or preoccupation
Can cause extreme frustration, anger, discouragement, non-compliance, and even thoughts of suicide / death wish

26. Demoralization
Perhaps more common than MDD in medical patients (Mangelli et al, J Clin Psych 2005)
Some overlap with but clinically distinct from the diagnosis of major depressive disorder (Mangelli, 2005)
Clues to differentiate between MDD and demoralization (Wellen, 2010)
Major Depression: Anhedonia and nihilistic thinking coming from “within” (i.e., not responding to the external situation), severe neurovegetative symptoms
Demoralization: Mood reactivity (e.g. happy when family is around, or pain is better controlled)

27. Psychiatric Evaluation: Inpatient Challenges
Lack of privacy in shared rooms
Lack of confidentiality if family at bedside
Interruptions:
Patient off to procedures
Other staff coming to see patient
Patient resistant to see psychiatry
Lack of privacy is very common in patient setting. If there are other patients or family members, confidentiality may be compromised.
Other patients also may have the TV volume on loud and be disruptive talking loudly on the phone.
If the patient is mobile or can use a wheelchair, consider asking nursing staff if you can use a separate room to interview the patient. If the other patient is mobile, consider asking them to leave the room
You can request that family stay for part of the interview and this is helpful to get collateral information and then leave for part of the interview so that the patient can talk freely.
You may need to be flexible and garner information in stages.
If patient is resistant to seeing psychiatry, always remind them that in fact they have the right not to be interview but that their doctor asked for psychiatry to see the patient to help his doctor help the patient. Often placing the onus and the evaluation request to the treating team helps make the psychiatrist part of the team. Also many patients have ideas and “fantasies” about why the consult was requested and to ask the patient about this and help clarify the purpose of the consult may in fact help the patient agree to the evaluation.

28. Psychiatric Interview: Outpatient Challenges
Patient may not show for the appointment
Cognitive impairment
Doesn’t want the evaluation
May not have access to extensive chart
Resistance to seeing psychiatry
“I’m not crazy! You need to help someone who’s really sick”
Stigma
Treatment non-adherence
Decision to include family if available
Outpatient evaluations have their own unique issues. Patients are not a captive audience in a bed. They can decide not to show up to the appointment.
Each clinic site has their unique issues relating to processing the appointment, availability or charts, access to treating staff who know the patient etc.
As in the inpatient setting, patients may be reluctant to see due to the stigma or afraid their run into people they know. Even in the outpatient setting it is surprising how many times when ask the question, “Why do you think your doctor wanted me to see you?” that patients will respond ,”He/she probably thinks I’m crazy.” a little clarification and explanation of the consult can be helpful to increase the cooperation and then alliance with the patient.
If the outpatient site is co-located with a medical/surgical clinic, patients may be concerned about “running into” other patients they may know.
As with the inpatient setting, family and friends are very helpful in getting a full picture of the patient. However the patient may not fully reveal information when they are present and there are issues of confidentiality to be addressed.

29. Time Course and Associations

30. Impact of Depression in Chronic Medical Illness
Increased prevalence of major depression in the medically ill
Depression amplifies ( increased both number and severity of) physical symptoms associated with medical illness
Comorbidity increases impairment in functioning
Depression decreases adherence to prescribed regimens
Depression is associated with increased heath care utilization and cost
Depression is associated with adverse health behaviors (diet, exercise, smoking)
Depression increases mortality associated with certain medical illness (e.g., heart disease)
(adapted from Katon and Ciechanowski , 2002)

31. “It is important that somatic symptoms associated with depression should not be confused with somatoform disorders Indeed, results from several surveys suggest that depression, rather than somatoform disorders, may account for most of the somatization symptoms seen in primary care.”
(Tylee A, Gandhi P. The importance of somatic symptoms in depression in primary care. Prim Care Companion J Clin Psychiatry, 2005)

32. Factors associated with suicide in medical-surgical patients
Comorbid psychiatric illness, esp. Depression, Substance abuse, Personality disorder
Chronic illness, Debilitating illness
Painful illness, Disfiguring illness
History of recent loss of emotional support
Interpersonal problems with family or staff
Impulsivity
(Rundell and Wise, 2000)

33. Service Utilization and Outcomes for Patients with Depression
Increased E.R. visits
Lost days from work
Increased suicide attempts
Higher reports of poor physical health
(Johnson: 1992, Broadhead: 1990, Rundell and Wise: 2000)

34. Treatment of depression in medical setting
Identifying possible organic causes, e.g., thyroid, HIV, medications
Appropriate management requires first establishing the most likely diagnosis that has caused depression (Rackley and Boswick, 2012)

35. Treatment of depression in medical setting
Utilize medications, psychotherapies, and psychoeducation
Be aware of pharmacokinetic (e.g., binding, CYP 450, clearance) and pharmacodynamic (neurotransmitter receptor and transporter effects) factors
Be mindful of additive sedative, anticholinergic effects from several medications ( e.g., pain meds, H2 blockers, antibiotics, antihistamines, steroids, TCAs)

36. Evidenced Based Treatments for Depression
Biological treatments
Antidepressant medications
Psychostimulants
Psychological interventions
Cognitive behavioral therapy
Interpersonal therapy
Supportive-expressive therapy
Electroconvulsive therapy
Transcranial magnetic stimulation

37. First Line Medication Treatment
Dose Range
P450 inhibitor
Substrate
Fluoxetine (Prozac)
10mg-40mg
2D6(s), 2C19(s),
3A4(w)
2C9,2C19,2D6
Mirtazapine (Remeron)
15mg-60mg
-----
1A2, 2D6
Bupropion (Wellbutrin)
150mg-450mg
2D6(s)
2B6,
Sertraline (Zoloft)
25mg-200mg
2D6(w), 2C9(w)
Paroxetine (Paxil)
20mg-60mg
2D6(s), 2C9(m), 2C19(w)
2D6
Citalopram (Celexa)
20mg-40mg
2D6(w)
2C19,2D6
Escitalopram (Lexapro)
2C19 ,2D6
Duloxetine (Cymbalta)
20mg-60 mg
2D6(m)
Venlafaxine (Effexor)
75mg-300mg
Trazodone (Desyrel)
50mg-600mg
3A4, 2D6
(s)= strong inhibitor, (m)= moderate inhibitor, (w) weak inhibitor
Cytochrome P450 Drug Interaction Table.  Indiana University School of Medicine, 2017.
Cozza KL, Armstrong SC, Oesterheld JR: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-Glycoproteins, Second Edition. Washington, DC, American Psychiatric Publishing, 2003
Note Substrate: the P450 route(s) the drug is metabolized
Inhibitor: decreases the metabolism and thus functionally increases the levels of medications that use this pathway (Substrates).
Note: high dose bupropion can reduce seizure threshold and cause seizures.
Watch for sustained elevated blood pressures in patients taking venlafaxine and bupropion.
Watch for prostate and urinary symptoms in patients taking paroxetine and venlafaxine.
First line agents are the SSRIs .
Fluoxetine and Paxil do the most inhibition and be careful that beta blockers and other medications may be potentiated.
Sertraline, citalopram, escitalopram and duloxetine tend to have most of their P450 inhibition at higher doses.
Mirtazapine is inert and does NOT effect other medications. It can be affected by others
(s)= strong inhibitor, (m)= moderate inhibitor, (w) weak inhibitor

38. Clinical Concerns
2D6 inhibitors can affect beta-blockers and potentiate fall in blood pressure and pulse (orthostasis)
Cigarette smokers may need higher doses of mirtazapine through CYP 1A2 induction
Users of oral contraceptives may have more antidepressant side effects and need lower doses of many medications
Antidepressants with CYP 2D6 inhibition may decrease effectiveness of Tamoxifen and Codeine (which are pro-drugs)
May want to consider alternatives such as venlafaxine and mirtazapine
Many cardiac patients are on beta blocks thus you have to carefully follow pulse and blood pressure so that they don’t become too low->may need to DECREASE the beta blocker dose.

39. Clinical Concerns
Combining serotonergic and/or MAOI medications may cause Serotonin syndrome
E.g., SSRI, TCAs, venlafaxine, mirtazapine, triptans, linezolid, tramadol, meperidine
Citalopram FDA warning (8/23/2011)
Citalopram should not be used in doses >40mg qday due to concerns of QT prolongation
Citalopram should not be used in doses >20mg qday in patients with hepatic impairment, >60 years of age, 2C19 or 2D6 poor metabolizers

40. General Principles
Know the drug interactions of the medications you use most often
Look up drug interactions with any and all medicines
Be careful of hidden inhibitors or inducers
Grapefruit juice
Cigarette smoking
Oral contraceptive medications
Herbal medicines
Many cardiac patients are on beta blocks thus you have to carefully follow pulse and blood pressure so that they don’t become too low->may need to DECREASE the beta blocker dose.

41. Other adjunct agents
Psychostimulants can be helpful in anergic, depressed patients with cancer or organ transplants
Low dose atypical antipsychotic medications, particularly quetiapine and aripiprazole, may also be helpful
Augmentation
Sleep
Anxiety/Agitation
Low dose atypical anti-psychotic medications can be helpful with severe medical disease, Chronic Pulmonary disease and for patients with history of alcohol and drug addiction.
They should be used with caution or not at all in the elderly with a history or stroke.
Even at low doses patients can develop Neuroleptic Malignant Syndrome

42. In Transplant and Cancer Populations
Antidepressants can be helpful: be careful of metabolism and the organ affected by the transplant or cancer
Psychostimulants can be safe and effective
Cognitive behavioral therapy can be helpful for depression and anxiety
Low dose atypical anti-psychotic medications can be helpful with severe medical disease, Chronic Pulmonary disease and for patients with history of alcohol and drug addiction.
They should be used with caution or not at all in the elderly with a history or stroke.
Even at low doses patients can develop Neuroleptic Malignant Syndrome

43. In Chronic Kidney Disease
SSRI: Sertraline considered to have least dependence on renal function
Bupropion: decrease dose – authorities advise caution as increased levels may produce seizure
Mirtazapine: decrease dose - 75% excreted unchanged in urine
SNRI: Venlafaxine may require dose reduction in renal impairment or dialysis
Duloxetine contraindicated in severe renal disease: active metabolite may accumulate and produce confusion

44. In Heart Disease
SADHART: Sertraline appeared safe on cardiac parameters and effective in treating depression
Not powered to detect morbidity or mortality.
Secondary analysis show some advantage in subgroup with recurrent depression.
Subanalysis of SADHART data suggested that onset of depression before ACS, hx of MDD, baseline severity predicted sertraline response. (Glassman et al, 2002)(Joynt & O’Connor, 2005)
CREATE: Citalopram effective in treating depression in cardiac patients
Interpersonal therapy not superior to placebo.
Not designed to test effects on cardiac outcomes, mortality. (CREATE, 2007)
ENRICHD: CBT reduced depression modestly at 6 months, but did not reduce mortality
- No benefit of CBT at 30 months. - (ENRICHD, 2003)
MIND-IT: Mirtazapine safe for post-MI depression, and showed efficacy vs placebo on some primary and secondary outcome measures at 24 weeks. - Tricyclic and heterocyclic anti-depressants are not considered safe post-MI (van den Brink RH, et. al 2002)
Low dose atypical anti-psychotic medications can be helpful with severe medical disease, Chronic Pulmonary disease and for patients with history of alcohol and drug addiction.
They should be used with caution or not at all in the elderly with a history or stroke.
Even at low doses patients can develop Neuroleptic Malignant Syndrome

45. In Primary Care Populations
STAR*D: Protocol for treating treatment-refractory patients with medical and psychiatric co-morbidities
Modest effects starting with citalopram and moving to adjunct medications or changing medications
Collaborative Care / Integrated Models
PCP, Depression care manager, consulting psychiatrist working together
Low dose atypical anti-psychotic medications can be helpful with severe medical disease, Chronic Pulmonary disease and for patients with history of alcohol and drug addiction.
They should be used with caution or not at all in the elderly with a history or stroke.
Even at low doses patients can develop Neuroleptic Malignant Syndrome

46. Treatment Resistance Factors
These studies point to the importance of regular close follow up in the initial stages of treatment in order to assess for compliance, side effects and suicidality.

47. Up to 50% of patients stop antidepressants within three months
(Simon,1993; Lin,1995; Sansone, 2012)

48. The Following Messages Improved Medication Compliance in the First Month
Take the medication daily
Antidepressants must be taken for 2 to 4 weeks for a noticeable effect
Continue to take medicine even if feeling better
Do not stop taking antidepressant without checking with the physician
Provide specific instructions regarding what to do to resolve questions regarding antidepressants
In addition: discussions about prior experience with antidepressants and discussions about scheduling pleasant activities also were related to early adherence

49. Take Home Messages
Depression in medically ill can be complex and multifactorial, and needs a thorough evaluation
Check drug-drug interactions for all the patient’s medications
Computer programs, mobile apps widely available
Medical conditions and depression affect each others’ symptoms and course, and affect the patient’s health related quality of life
Depression may be successfully treated by addressing medical conditions and medical drugs, and utilizing biological, psychological and educational interventions

50. References
Boal AH, et al. Monotherapy with major antihypertensive drug classes and risk of hospital admissions for mood disorders. Hypertension 2016;
Bukberg J, Penman J, Holland J. Depression in hospitalized cancer patients. J Psychosomatic Medicine 1984; 46(3):
Broadhead WE, Blazer DG, George LK, et al. Depression, disability days, and days lost from work in a prospective epidemiologic survey. JAMA 1990;264(19):
Carney RM, Blumenthal JA, Freedland KE, et.al. Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Psychosom Med 2004;66(4):
Coleman SM, Katon W, Lin E.Depression and Death in Diabetes; 10-Year Follow-Up of All-Cause and Cause-Specific Mortality in a Diabetic Cohort Psychosomatics 2013 ;54,( 5) :
Cozza KL, Armstrong SC, Oesterheld JR: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-Glycoproteins, Second Edition. Washington, DC, American Psychiatric Publishing, 2003
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed October 26, 2017.
Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival. JAMA 1993;270(15):
Gerstman BB, et al. The incidence of depression in new users of beta-blockers and selected antihypertensives. Journal of Clinical Epidemiology 1996; 49(7):
Glassman AH, O'Connor CM, Califf RM, et.al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):
Griffith JL, Gaby L. Brief psychotherapy at the bedside: countering demoralization from medical Illness. Psychosomatics Mar-Apr;46(2):

51. References
Horwath E, Johnson J, Klerman GL, et al. Depressive symptoms as relative and attributable risk factors for first-onset major depression. Archives of General Psychiatry 1992;49(10):
Johnson J, Weissman MM, Klerman GL. Service utilization and social morbidity associated with depressive symptoms in the community. JAMA 1992; 267(11):
Joynt KE, O’Connor CM. Lessons from SADHART, ENRICHD, and other trials. Psychosomatic Medicine 2005; 67(1): S63-S66.
Katon W, Ciechanowski P. Impact of major depression on chronic medical illness. J Psychosom Res Oct;53(4):859-63
Levenson JL. Textbook of Psychosomatic Medicine, Second edition . The American Psychiatric Publishing, Inc. Washing DC, 2011.
Lin EHB, VonKorff M, Katon W, Bush W, Simon T, et al. The role of the primary care physician in patients’ adherence to antidepressant therapy. Medical Care 1995, 33(1):
Parsaik AK et al. Statin use and risk of depression: a systematic review and meta-analysis. Journal of Affective Disorder 2014; 160:62-67.
Regier DA, Narrow WE, Rae DS, et al. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Archives of General Psychiatry 1993; 50(2):
Sansone RA, Sansone LA. Antidepressant adherence: are patients taking their medications? Innov Clin Neurosci 2012; 9(4-5):41-46.
Simon GE, Katon WJ, Von Korff M, et.al. Cost-effectiveness of a collaborative care program for primary care patients with persistent depression. Am. J. Psych. 2001; 158(10):
Slavney PR. Diagnosing demoralization in consultation psychiatry. Psychosomatics 1999;40(4):325-9.
Thompson PD, et al. Statin-associated side effects. Journal of American College of Cardiology 2016;67:

52. References
Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. American Journal of Psychiatry 2006; 163(1):
Wells KB; Burnam MA; Rogers W; Hays R; Camp P. The course of depression in adult outpatients. Results from the Medical Outcomes Study. Archives of General Psychiatry 1992; 49(10):
Writing Committee for the ENRICHD Investigators. The effects of treating depression and low perceived social support on clinical events after myocardial infarction: the enhancing recovery in coronary heart disease patients (ENRICHD) Randomized Trial. JAMA 2003; 289:
Writing Committee for the CREATE Investigators. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease. The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) Trial. American Medical Association 2007; 297(4):
Van den Brink RH, et. al. Treatment of depression after myocardial infarction and the effects of cardiac prognosis and quality of life: rational and outline of the Myocardial Infarction and Depression-Intervention trial (MIND-IT). Am. Heart J 2002: 144: