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Psychosomatics 43:310-316, August 2002
© 2002 The Academy of Psychosomatic Medicine

Elevated Cholesterol Levels Associated With Nonresponse to Fluoxetine Treatment in Major Depressive Disorder

Shamsah B. Sonawalla, M.D., George I. Papakostas, M.D., Timothy J. Petersen, Ph.D., Albert S. Yeung, M.D., Megan M. Smith, B.A., Andrea H. Sickinger, B.A., Johanna Gordon, B.A., Joshua A. Israel, M.D., Joyce R. Tedlow, M.D., Stefania Lamon-Fava, M.D., Ph.D., and Maurizio Fava, M.D.

Received December 22, 2000; revised January 24, 2002; accepted January 31, 2002. From the Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, WACC 812, 15 Parkman Street, Boston, Massachusetts 02114. Address correspondence and reprint requests to Dr. Sonawalla, Department of Psychiatry, Massachusetts General Hospital, WACC 812, 15 Parkman Street, Boston, MA 02114; ssonawalla{at}partners.org (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Previous studies have suggested that patients with major depressive disorder may have lower cholesterol levels compared to healthy controls. The purpose of this study was to examine the relationship between pretreatment serum cholesterol levels and clinical response to treatment with fluoxetine among outpatients with major depression. Three hundred and twenty-two depressed outpatients meeting DSM-III-R criteria for major depressive disorder were enrolled in an 8-week, fixed-dose, open trial of fluoxetine 20 mg/day. Nonfasting serum cholesterol levels were obtained for all patients before starting fluoxetine. All patients were drug free for a minimum of 2 weeks prior to the onset of the study. Clinical response was defined as a 50% or greater decrease in the 17-item Hamilton Rating Scale for Depression (HAM-D-17) score at endpoint compared to baseline. Cholesterol levels were classified as either elevated (defined as a level equal to or greater than 200 mg/dL) or nonelevated (defined as a level less than 200 mg/dL). Among the 322 outpatients, 51.6% were classified as having elevated and 48.4% as having nonelevated cholesterol levels at baseline (mean cholesterol level 238.6 ± 33.4 mg/dL vs. 170.4 ± 22.2 mg/dL, respectively). Depressed patients with elevated cholesterol levels did not significantly differ in gender ratio but were significantly older than depressed patients with nonelevated cholesterol levels (P < .0001). After adjusting for age, gender, and Body Mass Index (BMI), depressed patients with elevated cholesterol levels were significantly more likely to be nonresponders to fluoxetine treatment than were depressed patients with nonelevated cholesterol levels (P < 0.05). Elevated serum cholesterol levels appear to be associated with poorer response to fluoxetine treatment. Further studies are needed to confirm our findings.

Key Words: Cholesterol Levels • Fluoxetine Treatment

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Previous studies have suggested that patients with major depressive disorder (MDD) may have significant differences in cholesterol levels compared to healthy controls. Early studies reported elevated cholesterol levels among adults with MDD,1,2 although in some studies cholesterol levels were found to be normal.3–5 A study by Oxenkrug and colleagues, for instance, reported that while age and gender influenced serum cholesterol levels, the diagnosis of major depression did not.5 The majority of recent studies, however, suggest that depression is associated with low cholesterol levels,6–17 including a large Finnish study involving over 29,000 men.18 Maes and colleagues reported significantly lower serum high-density lipoprotein cholesterol levels in subjects with major depression than in normal controls.6 Low esterified cholesterol levels are also found in relatives of depressed patients,13 suggesting a possible genetic component for this phenomenon. Furthermore, low cholesterol levels have been reported to increase the risk of MDD,18 to correlate with the severity of depressive symptoms,12,14,15 and to increase the risk of death from suicide12,18,19 in depression. Finally, Ghaemi and colleagues assessed cholesterol levels in patients with various mood disorders, including bipolar disorder, MDD, and schizoaffective disorder, and found significantly lower cholesterol levels in patients with current manic and depressive episodes than in mixed episodes.20

Several studies point out a link between cholesterol homeostasis and serotonergic function. It is hypothesized that a decrease in total serum cholesterol levels may lead to a decrease in brain serotonin levels.21–25 A low content of cholesterol within cell membranes is shown to experimentally decrease the number of serotonin receptors.26 Monkeys subject to a low-fat/low-cholesterol diet had a blunted prolactin response to fenfluramine, a 5-HT agonist, indicating reduced central 5-HT activity.27 Depletion of cholesterol in human embryonic kidney cells resulted in a decrease in 5-HT transporter (5HTT) activity,28 while a study of elderly athletes revealed an association between serum cholesterol levels and certain polymorphisms in the promoter region of the 5HTT (HTTPR).29

Recent studies have also revealed a direct connection between serotonergic receptor function and cholesterol. Meta-chlorophenylpiperazine (m-CPP), a metabolite of the antidepressant trazodone, preferentially binds to serotonin 2C receptors (5HT2C).30 Administration of m-CPP results in cortisol release, and the degree of cortisol release is a reflection of the sensitivity of the 5HT2C receptor.20 Two studies report that serum cholesterol levels positively correlate with cortisol response to m-CPP, suggesting that higher cholesterol levels are associated with a more sensitive serotonergic receptor,30,31 while in a third study a blunted cortisol response to m-CPP was associated with low cholesterol levels.32 The sensitivity of serotonergic receptors, as evidenced by an elevated secretion of cortisol or prolactin after administration of d-fenfluramine, is found to confer good prognosis to antidepressant treatment in two studies.33,34

To date, studies exploring the implication of cholesterol status in the treatment of depression are lacking. Keeping in mind the relationship between 5HT receptor sensitivity and cholesterol on one hand and clinical response on the other, we wanted to test whether cholesterol can serve as a marker of clinical response to antidepressant treatment in major depression. To our knowledge, this is the first study examining the relationship between serum cholesterol levels and response to fluoxetine among outpatients with MDD.


  METHODS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Three hundred twenty-two outpatients, ages 18–65 years, who met criteria for a current major depressive episode according to the Structured Clinical Interview for DSM-III-R (SCID–patient edition)35 were recruited through radio advertisements, newspaper advertisements, or colleague referrals into an ongoing two-phase antidepressant trial conducted at the Massachusetts General Hospital Depression Clinical and Research Program (DCRP). For the first phase of the trial, patients were treated openly with a fixed dose of 20 mg of fluoxetine a day for 8 weeks. Patients who responded in the first phase of the trial continued on for follow-up treatment at the DCRP, while non- or partial responders became eligible for the second phase of the trial, a 4-week, double-blind, double-dummy, randomized study comparing high-dose fluoxetine with augmentation of fluoxetine with either desipramine or lithium. The present study focuses on the first phase of the trial only. Open treatment implies that all patients received active medication, and this was known to both the physician as well as the patient. All patients met primary DSM-III-R criteria for MDD on the SCID, which was administered by trained study psychiatrists. Since this study was designed before 1992, the DSM-III-R version of the SCID–patient edition was used. All patients had a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17)36 score >=16. All patients were medication free for at least 2 weeks prior to study entry. The HAM-D is a physician-administered rating scale consisting of up to 31 questions focusing on the measurement of a variety of depressive symptoms, including sleep, guilt, appetite, energy, concentration, mood, suicidal ideation, psychic and somatic anxiety, libido, obsessions, and psychomotor activity, among others. The 17-item HAM-D is most commonly used in clinical trials, as it focuses on the core symptoms of depression, including mood, thoughts of suicide, insomnia, decreased appetite, psychic and somatic anxiety, guilt, and psychomotor activity, among others.36 Clinical assessment with the HAM-D-17 scale was carried out every 2 weeks by a study psychiatrist.

The following patients were excluded from the study: pregnant women; lactating women or women taking oral contraceptive pills; patients with serious suicidal risk or serious, unstable medical illness; and patients with a history of seizure disorder, organic mental disorders, active substance use disorder within the last year, schizophrenia, or other psychotic disorders. Patients with bipolar disorder, antisocial personality disorder, multiple adverse drug reactions or allergy to the study drugs, current use of other psychotropic drugs, and clinical or laboratory evidence of current hypothyroidism were also excluded from the study. Patients who had not responded during the course of their current major depressive episode to at least one adequate antidepressant trial (>=6 weeks of treatment with either >=150 mg of imipramine or its tricyclic equivalent, >=60 mg of fluoxetine or its SSRI equivalent, or >=60 mg of phenelzine or its MAOI equivalent) were also excluded. In light of the second phase of the trial, patients with a history of prior nonresponse to or intolerance of fluoxetine (60–80 mg/day) or to fluoxetine in combination with lithium or desipramine were excluded from the study.

Prior to beginning the study, a written informed consent was obtained from all patients. A medical and psychiatric history, serum chemistries, hematological measures, electrocardiogram (EKG), a physical examination, and urine pregnancy test were performed at baseline. Blood pressure, pulse, and weight were recorded at each study visit. Nonfasting serum cholesterol levels were obtained as part of routine clinical laboratory tests. The Clinical Global Impression—Severity (CGI-S) and Improvement (CGI-I) scales37 and the 17-item Hamilton Rating Scale for Depression (HAM-D-17) were administered every 2 weeks throughout the study. Compliance was assessed on the basis of pill count and office appointments. Acceptable compliance necessary for a patient to be able to continue participating in the study was defined as no less than 85% compliance from visit to visit, including no more than 3 consecutive days without medication.

Cholesterol levels were defined as elevated if they were greater than or equal to 200 mg/dL and nonelevated if they were less than 200 mg/dL. The National Cholesterol Education Program (NCEP) Adult Treatment Panel II recommends a total cholesterol level of less than 200 mg/dL as desirable, a level of 200–239 mg/dL as borderline, and a level of greater than or equal to 240 mg/dL as high.38 MDD has long been regarded as a factor contributing to an increased risk of CAD.39–41 Hence, we used a total cholesterol level of 200 mg/dL as a cutoff for defining elevated versus nonelevated cholesterol levels in our patients. Furthermore, a review by Boston and colleagues focusing on the role of cholesterol in mental illness suggests that there may be a threshold effect for low cholesterol and depressive symptoms rather than as a linear association.42 For these reasons, we chose to define serum cholesterol in a dichotomous manner rather than as a continuous variable.

Statistical Analysis
For the purpose of the analysis, cholesterol levels were dichotomized as elevated and nonelevated. Response was defined as a >=50% decrease in HAM-D-17 scores at endpoint. Our definition of clinical response is the standard definition used for depression in the literature.43 The intent-to-treat analyses included a chi-square test, analysis of variance (ANOVA), and logistic regression.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
The mean age of our sample was 39.8 ± 10.2 years and consisted of 52.8% women (170/322) and 47.2% men (152/322). Fourteen percent of the patients (46/322) dropped out of the study. The mean HAM-D-17 score at baseline was 19.7 ± 3.3. The mean BMI at baseline was 26.5 ± 6.0 kg/m2. The mean cholesterol level of the study subjects was 205.6 ± 44.4 mg/dL. Among the 322 outpatients, 51.6% (166/322) were classified as having elevated cholesterol levels (mean level 238.6 ± 33.4 mg/dL) and 48.4% (156/322) as having nonelevated cholesterol levels (mean level 170.4 ± 22.2 mg/dL).

Depressed patients with elevated cholesterol levels did not differ significantly in gender ratio; however, they were significantly older (P < .0001, ANOVA; mean age: 42.7 ± 9.3 years) than depressed patients with nonelevated cholesterol levels (mean age: 36.8 ± 10.3 years). The two groups also did not differ across baseline depression severity on the HAM-D-17 scores (Table 1).


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TABLE 1. Age, gender, baseline HAM-D-17 scores, and mean cholesterol levels among patients with elevated and nonelevated cholesterol levels



After adjusting for age, gender, and BMI, we found that depressed patients with elevated cholesterol levels were significantly more likely to be nonresponders to fluoxetine treatment than were depressed patients with nonelevated cholesterol levels (logistic regression; odds ratio = 1.60; P < 0.05) (Figure 1). Specifically, we found that 46% of patients with elevated cholesterol levels responded to fluoxetine treatment, while 54% of patients with nonelevated cholesterol levels were responders.



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FIGURE 1. Response rates among patients with elevated and nonelevated cholesterol levels.


Thyroid function tests were obtained in all but 22 patients. Specifically, 270 patients had T3 reuptake (T3RU) levels, and 30 had thyroid stimulation hormone (TSH) levels. The normal TSH and T3RU range was defined as 0.5–5 µU/mL and 22%–35%, respectively. Patients were classified as hyperthyroid if they had either a TSH lower than 0.5 µU/mL or a T3RU higher than 35% or both. Patients were classified as hypothyroid if they had either a TSH higher than 5 µU/mL or a T3RU lower than 22% or both. Patients were classified as euthyroid if they had both a TSH and a T3RU within normal limits. According to this trichotomy, 281 patients were classified as euthyroid, 13 as hypothyroid, and 6 as hyperthyroid. There was no statistically significant difference between these three groups with respect to the number of patients in each group who had elevated or nonelevated cholesterol values.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
To our knowledge, this is the first study of the relationship between lipid status and antidepressant response. Contrary to our initial hypothesis, which was based on the relationship between cholesterol, 5HT receptor sensitivity, and clinical response, we found that depressed patients with elevated cholesterol levels were significantly more likely to be nonresponders to fluoxetine treatment than depressed patients with nonelevated cholesterol levels. Forty-six percent of patients with elevated cholesterol levels responded to fluoxetine treatment, while 54% of those with nonelevated cholesterol levels were responders, a finding that was significant after adjusting for age, gender, and BMI (Figure 1).

One possibility that would explain this finding may involve the presence of other axis I comorbidity in nonresponders, particularly anxiety disorders or anger attacks. While a number of studies report low cholesterol in patients with major depression, several studies report high cholesterol levels in patients with anxiety disorders. Patients with panic disorder (PD), for instance, are found to have higher cholesterol levels compared to patients with MDD and healthy subjects.44,45 Patients with PD alone are found to have higher cholesterol levels than patients with comorbid PD and MDD.46 Similarly, patients with generalized anxiety disorder (GAD) alone are found to have higher serum cholesterol levels than are patients with comorbid GAD and MDD.47,48 Patients with posttraumatic stress disorder (PTSD) were also reported to have elevated cholesterol levels.49 Finally, patients with comorbid depression and anger attacks are also found to have higher cholesterol levels after adjustment for age, body mass index (BMI), and gender.50 The effects of anxiety on cholesterol may perhaps be mediated through an increase in the activity of lipoprotein lipase51 secondary to an increase in noradrenergic tone seen in GAD52 and PD,53 resulting in an increase of free fatty acids.45

Depressed patients with high anxiety levels have a more chronic and severe presentation, with poor outcome and a higher rate of suicide compared to nonanxious depressed patients.54–58 In our sample, the difference in the rate of SCID-diagnosed anxiety disorder between the two cholesterol groups was not statistically significant for any single diagnosis (Table 2). There was a tendency for patients in the high-cholesterol group to have lower rates of panic disorder, but this difference did not reach statistical significance with Bonferroni correction. However, we did not use any scales that directly measure anxiety. Future studies assessing anxiety levels with specific scales may help to further elucidate the impact of anxiety on serum cholesterol.


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TABLE 2. Comorbid anxiety disorders versus cholesterol status (controlling for gender, age, and BMI)



Other factors may also help explain our findings. Cholesterol is widely distributed in tissues and is abundant in the CNS; it is important for cellular structure and function and affects fluidity of cell membranes, membrane permeability, and exchange processes.42 It also is an important aspect of second messenger systems in the brain and is essential for neurotransmission.42 Elevated cholesterol levels may be a marker of poor nutrition or vascular disease, either of which may be associated with poor response to antidepressants. In addition, cholesterol is also known to play a pervasive physiological role, and elevated cholesterol may also have a direct impact on antidepressant activity.

The main clinical implication of our study is that depressed patients with high cholesterol levels are more likely to be fluoxetine nonresponders, and this may be due to a combination of factors, including comorbid anxiety or medical illness. Limitations of our study include the use of a retrospective analysis, the use of a dichotomous classification of clinical response, and the lack of systematic data on the smoking and dietary habits, alcohol intake, socioeconomic status, and presence of psychosocial stressors of these individuals. We assessed nonfasting serum cholesterol levels; however, serum cholesterol levels are typically minimally affected by the nonfasting status.59 Another limitation is that of sampling bias. Clinical trials have a number of inclusion and exclusion criteria, and as a result, patients in clinical trials do not directly reflect the typical outpatient population. There may also be a referral bias since academic centers are more likely to have referred cases of refractory depression. Our patients were either referred from other clinicians or recruited through radio and newspaper advertisements, and this may have also contributed to a sampling bias.


  CONCLUSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Within the framework of these limitations, we conclude that elevated serum cholesterol levels appear to be associated with a relatively poorer response to fluoxetine treatment. If replicated, these findings warrant further investigation of such a relationship. A specific relationship between high cholesterol and lack of clinical response would motivate further study of the relationship between cholesterol and antidepressant activity at the cellular level.


  ACKNOWLEDGMENTS

 
Supported by NIMH grant #R01-MH-48-483-05.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

  1. Bajwa WK, Asnis GM, Sanderson WC, et al: High cholesterol levels in patients with panic disorder. Am J Psychiatry 1992; 149:376-378[Abstract/Free Full Text]
  2. Weidner G, Connor SL, Hollis JF, et al: Improvements in hostility and depression in relation to dietary change and cholesterol lowering: The Family Heart Study. Ann Intern Med 1992; 117:820-823
  3. Freedman DS, Byers T, Barrett DH, et al: Plasma lipid levels and psychologic characteristics in men. Am J Epidemiol 1995; 141:507-517[Abstract/Free Full Text]
  4. McCallum J, Simons L, Simons J, et al: Low serum cholesterol is not associated with depression in the elderly: Data from an Australian community study. Aust N Z J Med 1994; 24:561-564[Medline]
  5. Oxenkrug GF, Branconnier RJ, Harto-Traux N, et al: Is serum cholesterol a biological marker for major depressive episode? Am J Psychiatry 1983; 140:920-921[Abstract/Free Full Text]
  6. Maes M, Smith R, Christophe A, et al: Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: Relationship with immune inflammatory markers. Acta Psychiatr Scand 1997; 95:212-221[Medline]
  7. Olusi SO, Fido AA: Serum lipid concentrations in patients with major depressive disorder. Biol Psychiatry 1996; 40:1128-1131[CrossRef][Medline]
  8. Cadeddu G, Fioravanti P, Antonicelli R, et al: Relationship between cholesterol levels and depression in the elderly. Minerva Med 1995; 86:251-256[Medline]
  9. Lindberg G, Larsson G, Setterlind S, et al: Serum lipids and mood in working men and women in Sweden. Epidemiol Community Health 1994; 48:360-363
  10. Horsten M, Wamala SP, Vingerhoets A, et al: Depressive symptoms, social support, and lipid profile in healthy middle-aged women. Psychosom Med 1997; 59:521-528[Abstract/Free Full Text]
  11. Suarez EC: Relations of trait depression and anxiety to low lipid and lipoprotein concentrations in healthy young adult women. Psychosom Med 1999; 61:273-279[Abstract/Free Full Text]
  12. Rabe-Jablonska J, Poprawska I: Levels of serum total cholesterol and LDL-cholesterol in patients with major depression in acute period and remission. Med Sci Monit 2000; 6:539-547[Medline]
  13. Maes M, Delanghe J, Meltzer HY, et al: Lower degree of esterification of serum cholesterol in depression: Relevance for depression and suicide research. Acta Psychiatr Scand 1994; 90:252-258[Medline]
  14. Rafter D: Biochemical markers of anxiety and depression. Psychiatry Res 2001; 103:93-96[CrossRef][Medline]
  15. Steegmans PH, Hoes AW, Bak AA, et al: Higher prevalence of depressive symptoms in middle-aged men with low serum cholesterol levels. Psychosom Med 2000; 62:205-211[Abstract/Free Full Text]
  16. Terao T, Iwata N, Kanazawa K, et al: Low serum cholesterol levels and depressive state in human dock visitors. Acta Psychiatr Scand 2000; 101:231-234[CrossRef][Medline]
  17. Morgan RE, Palinkas LA, Barrett-Connor EL, et al: Plasma cholesterol and depressive symptoms in older men. Lancet 1993; 341:75-79[CrossRef][Medline]
  18. Partonen T, Haukka J, Virtamo J, et al: Association of low serum total cholesterol with major depression and suicide. Br J Psychiatry 1999; 175:259-262[Abstract/Free Full Text]
  19. Sarchiapone M, Camardese G, Roy AC, et al: Cholesterol and serotonin indices in depressed and suicidal patients. J Affect Disord 2001; 62:217-219[CrossRef][Medline]
  20. Ghaemi SM, Shields GS, Hegarty JD, et al: Cholesterol levels in mood disorders: High or low?. Bipolar Disord 2000; 2:60-64[CrossRef][Medline]
  21. Bilici M, Efe H, Koroglu MA, et al: Antioxidative enzyme activities and lipid peroxidation in major depression: Alterations by antidepressant treatment. J Affect Disord 2001; 64:43-51[CrossRef][Medline]
  22. Maes M, De Vos N, Pioli R, et al: Lower serum vitamin E concentrations in major depression: Another marker of lowered antioxidant defenses in that illness. J Affect Disord 2000; 58:241-246[CrossRef][Medline]
  23. Maes M, Christophe A, Delanghe J, et al: Lowered omega 3 polyunsaturated fatty acids in serum phospholipids and cholesterol esters of depressed patients. Psychiatry Res 1999; 85:275-291[CrossRef][Medline]
  24. Maes M, Smith R, Christophe A, et al: Fatty acid composition in major depression: Decreased omega 3 fractions in cholesterol esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesterol esters and phospholipids. J Affect Disord 1996; 38:35-46[CrossRef][Medline]
  25. Steegmans PHA, Fekkes D, Hoes AW, et al: Low serum cholesterol concentration and serotonin metabolism in men. Br Med J 1996; 312:21[Free Full Text]
  26. Engelberg H: Low serum cholesterol and suicide. Lancet 1992; 339:727-729[CrossRef][Medline]
  27. Muldoon MF, Rossouw JE, Manuch SB, et al: Effects of a low-fat diet on brain serotonergic responsivity in cynomolgus monkeys. Biol Psychiatry 1992; 31:739-742[CrossRef][Medline]
  28. Scanlon SM, Williams DC, Schloss P: Membrane cholesterol modulates serotonin transporter activity. Biochemistry 2001; 40:10507-10513[CrossRef][Medline]
  29. Comings DE, MacMurray JP, Gonzalez N, et al: Association of the serotonin transporter gene with serum cholesterol levels and heart disease. Mol Genet Metab 1999; 67:248-253[CrossRef][Medline]
  30. Terao T, Nakamura J, Yoshimura RO, et al: Relationship between serum cholesterol levels and meta-chlorophenylpiperazine-induced cortisol responses in healthy men and women. Psychiatry Res 2000; 96:167-173[CrossRef][Medline]
  31. Terao T, Yoshimura R, Ohmori O, et al: Effect of serum cholesterol levels on meta-chlorophenylpiperazine-evoked neuroendocrine responses in healthy subjects. Biol Psychiatry 1997; 41:974-978[CrossRef][Medline]
  32. Buydens-Branchey L, Branchey M, Hudson J, Fergeson P: Low HDL cholesterol, aggression and altered central serotonergic activity. Psychiatry Res 2000; 93:93-102[CrossRef][Medline]
  33. Malone KM, Thase ME, Mieczkowski T, et al: Fenfluramine challenge test as a predictor of outcome in major depression. Psychopharmacol Bull 1993; 29:155-161[Medline]
  34. Cleare AJ, Murray RM, O'Keane V: Assessment of serotonergic function in major depression using d-fenfluramine: Relation to clinical variables and antidepressant response. Biol Psychiatry 1998; 44:555-561[CrossRef][Medline]
  35. Spitzer RL, Williams JBW, Gibbon M, et al: Structured Clinical Interview for DSM-III-R-Patient edition (SCID-P). Biometrics Research Department, New York State Psychiatric Institute, New York, NY, 1989
  36. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56-62
  37. Guy W, ed: ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, MD, National Institute of Mental Health, 1976, pp 76-338
  38. Expert Panel. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285:2486-2497[Free Full Text]
  39. O'Connor CM, Gurbel PA, Serebruany VL: Depression and ischemic heart disease. Am Heart J 2000; 140(Suppl 4):63-69
  40. Glassman AH, Shapiro PA: Depression and the course of coronary artery disease. Am J Psychiatry 1998; 155:4-11[Abstract/Free Full Text]
  41. Ford DE, Mead LA, Chang PP, et al: Depression is a risk factor for coronary artery disease in men: The precursors study. Arch Intern Med 1998; 158:1422-1426[Abstract/Free Full Text]
  42. Boston PF, Dursun SM, Reveley MA: Cholesterol and mental disorder. Br J Psychiatry 1996; 169:682-695[Abstract/Free Full Text]
  43. Tedlow J, Fava M, Uebelacker L, et al: Outcome definitions and predictors in depression. Psychother Psychosom 1998; 67:266-270[CrossRef][Medline]
  44. Bajwa WK, Asnig GM, Sanderson WC, et al: High cholesterol levels in patients with panic disorder. Am J Psychiatry 1992; 149:376-378
  45. Hayward C, Taylor CB, Roth WT, et al: Plasma lipid levels in patients with panic disorder or agorophobia. Am J Psychiatry 1989; 146:917-919[Abstract/Free Full Text]
  46. Agargun MY, Algun E, Sekeroglu R, et al: Low cholesterol level in patients with panic disorder: The association with major depression. J Affect Disord 1998; 50:29-32[CrossRef][Medline]
  47. Kuczmierczyk AR, Barbee JG, Bologna NA, et al: Serum cholesterol levels in patients with generalized anxiety disorder (GAD) and with GAD and comorbid depression. Can J Psychiatry 1996; 41:465-468[Medline]
  48. Sevincok L, Buyukozturk A, Dereboy F: Serum lipid concentrations in patients with comorbid generalized anxiety disorder and major depressive disorder. Can J Psychiatry 2001; 46:68-71[Medline]
  49. Kagan BL, Leskin G, Haas B, et al: Elevated lipid levels in Vietnam veterans with chronic posttraumatic stress disorder. Biol Psychiatry 1999; 45:374-377[CrossRef][Medline]
  50. Fava M, Abraham M, Pava J, et al: Cardiovascular risk factors in depression: The role of anxiety and anger. Psychosomatics 1996; 37:31-37[Abstract/Free Full Text]
  51. Freedman DS, Byers T, Barrett DH, et al: Plasma lipid levels and psychologic characteristics in men. Am J Epidemiol 1995; 141:507-517
  52. Charney DS, Redmond EE: Neurobiological mechanisms in human anxiety: Evidence supporting central noradrenergic hyperactivity. Neuropharmacology 1983; 22:1531-1536[CrossRef][Medline]
  53. Villacres EC, Hollifield M, Katon WJ: Sympathetic nervous system activity in panic disorder. Psychiatry Res 1987; 21:213-221[CrossRef][Medline]
  54. Bakish D: The patient with comorbid depression and anxiety: The unmet need. J Clin Psychiatry 1999; 60 (Suppl 6):20-24
  55. Fava M, Uebelacker LA, Alpert JE, et al: Major depressive subtypes and treatment response. Biol Psychiatry 1997; 42:568-576[CrossRef][Medline]
  56. Flint AJ, Rifat SL: Anxious depression in elderly patients: Response to antidepressant treatment. Am J Geriatr Psychiatry 1997; 5:107-115[Abstract/Free Full Text]
  57. Clayton PJ, Grove WM, Coryell W, et al: Follow-up and family study of anxious depression. Am J Psychiatry 1991; 148:1512-1517[Abstract/Free Full Text]
  58. Sonawalla SB, Fava M: Severe depression: is there a best approach? CNS Drugs Adis International 2001; 15(10):765-776
  59. Cohn JS, McNamara JR, Schaefer EJ: Lipoprotein cholesterol concentrations in the plasma of human subjects as measured in the fed and fasted state. Clin Chem 1988; 34:2456-2459[Abstract/Free Full Text]



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* Depression
* Antidepressants

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