That total includes patients who have received deep brain stimulation (DBS) leads placed in six different brain regions. However, the results suggest that one of the better target locations for DBS in patients with treatment-resistant depression (TRD) is in the nucleus accumbens, Dr. Bruno Millet said at the annual congress of the European College of Neuropsychopharmacology.

“The nucleus accumbens is a very good target that we will continue to study. It is very safe, and the surgery is easy and rapid. The nucleus accumbens has a good benefit-to-risk ratio,” said Dr. Millet, professor of psychiatry at the University of Rennes (France). “This is a strength of this target.”

The nucleus accumbens became a target because it is “at the center of a circuit involved in major depressive disorder,” and plays a “central role in reward circuitry and its dysfunctions,” he added.

All patients who have received DBS had stage 5 TRD, which meant that their depression was unresponsive to all possible drug classes, including monamine oxidase inhibitors. These patients also failed to adequately respond to electroconvulsive therapy.

Dr. Millet and his associates at nine other French centers ran a pilot study with four patients who received DBS in the nuclear accumbens starting in 2009. Patients received stimulation at a level of 1.5-4 V. All four patients showed gradual improvement in their depression during the first 6 months after treatment. After 1 year of follow-up, all patients had responded, with response defined as at least a 50% decline from the baseline Hamilton Rating Scale for Depression (HRSD) score. One patient went into remission, defined as an HRSD score of less than 10. None of the patients had somatic adverse effects during 15 months of follow-up, but one patient had worsening mood and anxiety and made a suicide attempt; one patient had worsening mood and sleep and increased food intake; and one patient developed paresthesia.

The largest patient series and the longest follow-up of patients who received DBS in their nucleus accumbens for TRD involved 11 patients treated in Germany. The patients had minimal adverse effects, and 5 of the 11 responded, with the response remaining stable during 4 years of follow-up (Neuropsychopharmacology 2012;37:1975-85).

Another target that produced notable results is the medial forebrain bundle, which led to good DBS results in seven patients treated by the same German team. Earlier this year, the investigators reported that six of the seven patients had responded and four patients had reached remission of their depression after 3-7 months of follow-up (Biol. Psychiatry 2013;73:1204-12). Two other brain targets that have been used by other groups with success are the subgenual cingulate gyrus, and the ventral capsule and ventral striatum.

But “one of the striking things in DBS for the moment is the lack of any randomized controlled trials,” Dr. Millet said. He and his French associates have expanded their network to 12 centers, including one in Geneva, and they have designed and are now starting a trial that will place DBS leads in all patients but will withhold active stimulation in half the patients for the first 7 months after lead placement. This trial is sponsored by Medtronic, a company that markets the DBS device Reclaim.

Medtronic primarily markets its DBS device for the treatment of Parkinson’s disease, essential tremor, and dystonia, but in 2009, the Food and Drug Administration also approved its use to treat obsessive-compulsive disorder under a humanitarian device exemption. Some medical ethicists, psychiatrists, and neurosurgeons have questioned the growing use of DBS for obsessive-compulsive disorder in the absence of evidence for its efficacy in a randomized controlled trial, calling this practice “misuse” of the device. One of these critics, Dr. Thomas E. Schlaepfer of Bonn, Germany, also is head of the group with perhaps the largest experience in using DBS to treat patients with depression.

Dr. Millet said he has received grant support from Medtronic, marketer of the Reclaim DBS therapy device. He also said he has been a consultant to, has been a speaker for, or has received research funding from nine other drug or device companies.

The impact of MDD on quality of life can be as great as or greater than that of chronic medical diseases such as diabetes.^9,10 Depending on depression severity, an average of 59% of patients with MDD report severe or very severe role impairment in at least 1 of the following domains: work, home, relationship, and social roles (AV 2).¹

Suicidality is also associated with MDD. Patients with affective disorders have a 2.2% lifetime risk of suicide compared with less than 0.05% for those without affective disorders.¹¹

Impact of MDD on Medical Illness

The presence of MDD is associated with an increased incidence of a number of medical conditions, including diabetes,¹² hypertension,¹³ and stroke.¹⁴ In patients who have existing medical conditions, the presence of MDD is associated with increased morbidity/mortality. For example, patients with stable coronary artery disease¹⁵ or with unstable angina¹⁶ are more likely to experience fatal or nonfatal cardiac events (eg, myocardial infarction) if they have comorbid depression. Survival after myocardial infarction appears to be reduced among patients with depression, especially those with first-episode depression.¹⁷ Among patients with congestive heart failure, the risk of death after 30-month follow-up is 8 times greater in depressed patients than in those without depression.¹⁸

The presence of depression appears to increase the risk of rehospitalization among patients with general medical conditions. A study¹⁹ of inpatients with a history of at least 1 prior admission within the previous 6 months found that those who screened positive for depression were 3 times more likely to be rehospitalized within 90 days.

Impact of MDD on Neuropathology

Depression may have a significant impact on brain physiology. A 3-year study²⁰ found a decrease in gray matter density in depressed patients relative to control subjects in areas of the brain associated with higher cognitive functioning, executive functioning, and emotional functioning, including the hippocampus, the anterior cingulum, the right dorsomedial prefrontal cortex, and the left amygdala. Patients who achieved remission during the prospective study had less decrease in gray matter density than patients who were not able to achieve remission. Hippocampal volume, which is involved in memory processing and the use of memory in terms of our response to the world, decreases as the number of episodes of depressive illness increases.²¹

A number of individuals experience major depression as a component of Alzheimer’s disease, but MDD also increases the risk of dementia. A 30-year study²² found that individuals with 3 or more depression episodes that led to hospital admission had a greater incidence of subsequent dementia compared with those who had had 1 or 2 hospitalizations for depression (AV 2). A postmortem study²³ of patients with Alzheimer’s disease showed that MDD was associated with a significant increase in both neuritic plaques (P<.005) and neurofibrillary tangles (P<.002)—the hallmark pathologies of Alzheimer’s disease—compared with patients without MDD. Among the patients with Alzheimer’s disease, those with a history of depression had had faster cognitive decline than those without depression (P<.004).

Burden of Treatment-Resistant MDD

A subset of patients with MDD has treatment-resistant depression,²⁴ defined as depression that has not responded to at least 2 different antidepressants administered at an adequate dose for an adequate duration.²⁵ Treatment-resistant depression leads to increased health care utilization and incurs higher costs than nonresistant depression. A study²⁶ found that patients with treatment-resistant depression were hospitalized at least twice as often and, on average, had total medical costs that were 6 times greater than patients whose depression was not resistant. Additionally, among outpatients with treatment-resistant depression, more than half of patients reported suicidal ideation and prominent hopelessness.²⁷

Treatment-resistant depression is associated not only with decreased quality of life but also with increased mortality.²⁸ In patients with coronary heart disease, especially those who have had acute coronary syndrome, cardiac morbidity and mortality are greater among those with treatment-resistant depression.²⁹ One 7-year follow-up study³⁰ found a doubling of cardiac mortality among patients whose depression failed to improve during the 6 months following acute coronary syndrome. Treatment-resistant depression is also associated with about a 2-fold increase in mortality in patients with stable COPD³¹ and, in patients with diabetes, about a 2-fold increase in the likelihood of poor adherence to medications for diabetes, dyslipidemia, and hypertension.³²

Conclusion

The burden of MDD on individuals includes impaired role functioning, decreased quality of life, the development of medical conditions, increased morbidity and mortality, and increased health care services utilization and cost. The burden is increased across all areas for individuals not achieving remission and especially for those with treatment-resistant depression. Low rates of remission and high rates of relapse and recurrence demonstrate the inadequacy of available treatment options. However, as many patients receive no treatment or suboptimal treatment for MDD, outcomes for many patients may still be improved while more effective treatments are being developed. For information about implementing up-to-date practice recommendations for MDD screening and treatment so as to minimize the burden of MDD on individuals and the health care system, see the rest of this series on “Depression: When Initial Therapy Fails.”

For Clinical Use

• To reduce the burden of depression, provide adequate treatment to improve the chances of full remission
• Screen patients with MDD, especially those with treatment resistance, for medical sequelae

Drug Names

No drugs were mentioned in this activity

Abbreviations

COPD = chronic obstructive pulmonary disease, MDD = major depressive disorder, QIDS-SR = Quick Inventory of Depressive Symptomatology Self-Report, SDS = Sheehan Disability Scale, STAR*D = Sequenced Treatment Alternatives to Relieve Depression

References

1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095–3105.
2. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-1475.
3. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593–602.
4. Birrer RB, Vemuri SP. Depression in later life: a diagnostic and therapeutic challenge. Am Fam Physician. 2004;69(10):2375–2382.
5. Lynch JW, Kaplan GA, Shema SJ. Cumulative impact of sustained economic hardship on physical, cognitive, psychological, and social functioning. N Engl J Med. 1997;337(26):1889–1895.
6. Price RH, Choi JN, Vinokur AD. Links in the chain of adversity following job loss: how financial strain and loss of personal control lead to depression, impaired functioning, and poor health. J Occup Health Psychol. 2002;7(4):302–312.
7. Rush AJ, Kraemer HC, Sacheim HA, et al. Report by the ACNP Task Force on Response and Remission in Major Depressive Disorder. Neuropsychopharmacology. 2006;31(9):1841–1853.
8. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs. 2009;23(8):627–647.
9. Alonso J, Angermeyer MC, Bernert S, et al. Disability and quality of life impact of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl. 2004(420):38–46.
10. Bonicatto SC, Dew MA, Zaratiegui R, et al. Adult outpatients with depression: worse quality of life than in other chronic diseases in Argentina. Soc Sci Med. 2001;52(6):911–919.
11. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry. 2000;157(12):1925–1932.
12. Golden SH, Williams JE, Ford DE, et al. Depressive symptoms and the risk of type 2 diabetes: the Atherosclerosis Risk in Communities Study. Diabetes Care. 2004;27(2):429–435.
13. Jonas BS, Franks P, Ingram DD. Are symptoms of anxiety and depression risk factors for hypertension? Longitudinal evidence from the National Health and Nutritional Examination Survey I Epidemiologic Follow-up Study. Arch Fam Med. 1997;6(1):43–49.
14. Larson SL, Owens PL, Ford D, et al. Depressive disorder, dysthymia, and the risk of stroke: thirteen-year follow-up from the Baltimore epidemiologic catchment area study. Stroke. 2001;32(9):1979–1983.
15. Frasure-Smith N , Lespérance F. Depression and anxiety as predictors of 2-year cardiac events in patients with stable coronary artery disease. Arch Gen Psychiatry. 2008;65(1):62–71.
16. Lespérance F, Frasure-Smith N, Juneau M, et al. Depression and 1-year prognosis in unstable angina. Arch Intern Med. 2000;160(9):1354–1360.
17. Carney RM, Freedland KE, Steinmeyer B, et al. History of depression and survival after acute myocardial infarction. Psychosom Med. 2009;71(3):253–259.
18. Jünger J, Schellberg D, Müller-Tasch T, et al. Depression increasingly predicts mortality in the course of congestive heart failure. Eur J Heart Fail. 2005;7(2):261–267.
19. Kartha A, Anthony D, Manasseh CS, et al. Depression is a risk factor for rehospitalization in medical inpatients. Prim Care Companion J Clin Psychiatry. 2007;9(4):256–262.
20. Frodl TS, Koutsouleris N, Bottlender R, et al. Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry. 2008;65(10):1156–1165.
21. MacQueen GM, Campbell S, McEwen BS, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA. 2003;100(3):1387–1392.
22. Kessing LV, Andersen PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry. 2004;75(12):1662–1666.
23. Rapp MA, Schnaider-Beeri M, Grossman HT, et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry. 2006;63(2):161–167.
24. Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatr Clin North Am. 2007;30(1):13–29.
25. Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52(1):46–54.
26. Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry. 2002;63(11):963–971.
27. Papakostas GI, Petersen T, Pava J, et al. Hopelessness and suicidal ideation in outpatients with treatment-resistant depression: prevalence and impact on treatment outcome. J Nev Ment Dis. 2003;191(7):444–449.
28. Fekadu A, Wooderson SC, Markopoulo K, et al. What happens to patients with treatment-resistant depression: a systematic review of medium to long term outcome studies. J Affect Disord. 2009;116(1):4–11.
29. Carney RM, Freedland KE. Treatment-resistant depression and mortality after acute coronary syndrome. Am J Psychiatry. 2009;166(4):410–417.
30. Glassman AH, Bigger JT Jr, Gaffney M. Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression: seven-year follow-up of SADHART participants. Arch Gen Psychiatry. 2009;66(9):1022–1029.
31. de Voogd JN, Wempe JB, Koëter GH, et al. Depressive symptoms as predictors of mortality in patients with COPD. Chest. 2009;135(3):619–625.
32. Katon W, Russo J, Lin EH, et al. Diabetes and poor disease control: is comorbid depression associated with poor medication adherence or lack of treatment intensification? Psychosom Med. 2009;71(9):965–972.

All trial participants suffered from major depression and had previously failed to respond to therapeutic treatments or could not tolerate antidepressant medication owing to side effects.

Brainsway says it expects the study results will support its application for FDA approval to market its deep TMS system for the treatment of major depression in the United States.