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Editorial   |    
Changing Tides in Neurosurgical Interventions for Treatment-Resistant Depression
Stuart C. Yudofsky, M.D.
Am J Psychiatry 2008;165:671-674. doi:10.1176/appi.ajp.2008.08020298

The evil men do lives after them. The good is oft interred with their bones.

Julius Caesar by William Shakespeare

Psychiatrists swim in—and against—constantly changing tides of trade-off. We ask ourselves, “What is of greater risk to the first-trimester fetus: exposure to a mood stabilizer or a mother who is rapidly cycling from mania to depression?” and “Will hospitalization provide needed support and safety for my patient with suicidal ideation, or will it promote dependency, social withdrawal, and avoidance of ‘real-life’ stresses?” Rarely in clinical practice are the tides of trade-off more tricky and treacherous than in our care for patients with severe, treatment-resistant depression, a clinical condition that we are now learning is not so rare. The Sequenced Treatment of Alternatives to Relieve Depression (STAR*D) studies evaluated the responses of patients with depression to switching, augmenting, and combining psychiatric medications (1). The STAR*D results demonstrated that, even after four sequential trials of medication change, augmentation, and combination strategies, approximately 50% of the patients did not achieve remission and would merit the diagnosis of treatment-resistant depression (1, 2). As our patients with treatment-resistant depression sink into the cold, cramping depths of failed medication trials and ineffective psychotherapies, we psychiatrists struggle along with them in the savage currents between the Scylla of therapeutic adventurism and the Charybdis of defeatism and clinical abandonment.

In this issue of the Journal, Neimat et al. (3) present a 55-year-old woman whose depression began at age 9 and intensified relentlessly through most of her life. Her psychiatrist cared assiduously for her for 23 years with trials—with adequate doses and durations—of 15 different antidepressants, 10 diverse medications for augmentation or adjunctive therapy, and a course of bilateral ECT. Although experiencing a sustained remission from her disabling depression from ages 36 to 48, she was described as being “incapacitated” by depression for the 7 years before being referred to the authors of this article for consideration of alternative, more invasive treatments. In their Clinical Case Conference, Neimat et al. share with the reader their decision-making deliberations and therapeutic protocols as they first treat this patient with bilateral stereotactic ablative cingulotomy. Unfortunately, her symptomatic improvement proved transitory during the year following cingulotomy, and the treatment team then recommended and deployed a second neurosurgical procedure: deep brain stimulation in the Cg25 region of this patient’s brain. She experienced significant amelioration of her depressive symptoms during the approximately 2 years of ongoing Cg25 stimulation subsequent to deep brain stimulation surgery, with an improvement in her Hamilton Depression Rating Scale scores from 17 just before surgery to 7 at the time of this report. This article also includes an excellent review of the scientific literature on both cingulotomy and deep brain stimulation for major depression as well as clear descriptions of the neurosurgical techniques and neuroanatomy involved in each of these interventions.

Even more remarkable than the report of, perhaps, the only person who has ever been treated with both cingulotomy and deep brain stimulation for depressive symptoms are the ethical, scientific, and clinical implications that this case raises about neurosurgical interventions for treatment-resistant depression and other intractable neuropsychiatric disorders. Any consideration of neurosurgical interventions for neuropsychiatric conditions must begin—and often will end—with the history of the controversial practice of lobotomy in the United States between the 1930s and 1970s. Of importance, this historical context must be balanced with the reality that during this prepsychopharmacological era, untold numbers of patients while being housed indefinitely in mammoth state psychiatric hospitals for serious and persistent psychiatric disorders suffered unbearably without realistic hope for remediation. In assessing this balance, Barron H. Lerner, M.D., Ph.D., reviewed the story of American neurologist Walter J. Freeman, M.D., who devised a procedure, the transorbital lobotomy, in which an ice pick was hammered into a patient’s brain through the ocular orbit and manipulated in such a fashion as to sever nerve fibers emanating from the prefrontal cortex (4). Like a Johnny Appleseed for psychosurgery, Dr. Freeman traveled widely through the United States and performed thousands of these procedures on patients with vast arrays of psychiatric symptom profiles, ranging from chronic psychoses of patients in state psychiatric hospitals to less vexing indications in “otherwise healthy adolescent boys who had been diagnosed with anxiety” (4, p. 120). He trained other physicians in his procedure for lobotomy and, manifestly, became an enthusiast for a treatment with which he was so closely identified professionally. It is estimated that tens of thousands of lobotomies were performed in the United States before the procedure was largely replaced by the use of chlorpromazine and other psychotropic medications by the 1960s (4, p. 119), and it has been well documented that over 10,000 lobotomies were performed in Britain in the 1940s and early 1950s (5).

The use and misuse of lobotomy for psychiatric disorders in the 20th century led to so-called psychosurgery becoming synonymous with the nefarious exploitation of people with psychiatric disorders by callous, unethical, and unchecked mental health professionals. In the minds of the general public and even of psychiatrists and neurologists, the “good” of such procedures became submerged in the murky, lowering tides of the “evil” of their abuses (6). In the 1975 Academy Award-winning best picture based on Ken Kesey’s 1962 novel, One Flew Over the Cuckoo’s Nest, lobotomy was used to transform the willful, cantankerous, and captivating protagonist, played by Jack Nicholson, into an obedient, zombie-like, tragic character. By the 1990s, not only the practice of but also the innovation in neurosurgical treatments of neuropsychiatric disorders had slowed almost to a standstill in the United States and Canada (7).

The term psychosurgery has become both imprecise and outdated. Not only does this appellation evoke emotions that clouded rather than clarified therapeutic options for our patients, but we certainly were unable to perform surgery on the mind. My colleague Fred Ovsiew and I have recommended a more neutral term, “neurosurgical and related interventions for the treatment of patients with psychiatric disorders” (8). We also predicted that advances in functional and structural brain imaging would increase our understanding of relevant brain structures and pathways involved in depression. Such advances have indeed occurred and were used by Neimat et al. to guide the neurosurgical treatment (9–11). Advances in technology have also led to newer, safer, and more effective devices and ways of delivering treatment, such as the improved electrodes used for the patient’s deep brain stimulation. Thus, as exemplified by Neimat and colleagues’ clinical report, novel neurosurgical interventions for treatment-resistant depression and an increasing number of other neuropsychiatric conditions are being refined, and their uses appear to be on the rebound (12–14).

One issue that this case illuminates is the problem of determining the outcome and safety of invasive procedures. Unlike new drugs that require study before Food and Drug Administration approval for marketing, cingulotomy and deep brain stimulation can be practiced as long as hospital care committees and/or relevant committees of their affiliated medical schools approve them. Neimat et al. use the outcome of this single case to argue for deep brain stimulation, a reversible procedure, over cingulotomy, an irreversible procedure. Although this logic seems eminently reasonable, single case examples are also a limited source of information. Large double-blind, placebo-controlled case series are obviously not possible or desirable for highly invasive procedures, but scientifically rigorous methods for collecting and assessing both failed and successful outcomes are needed.

Both patients who suffer from treatment-resistant neuropsychiatric disorders and psychiatrists should be hopeful about a robust, rising tide of safer and more effective neurosurgical treatments for these conditions. Nonetheless, our field must also be perennially vigilant for the trade-offs that most assuredly will accompany increased applications of neurosurgical interventions in treatment-resistant depression and other intractable neuropsychiatric disorders. Special attention must be devoted to predicting, preventing, and identifying side effects and complications of these procedures. For example, a high rate of suicide has been detected in patients treated with deep brain stimulation, giving rise to the recommendation that patients should be carefully assessed for suicide risk before undergoing surgery and monitored carefully for suicidal ideation and intent postoperatively (15). In light of lobotomy’s lamentable history of inexcusable professional excesses and undeniable harm to many patients, special emphasis must also be placed on elucidating and eliminating conflicts of interest of the researchers and clinicians who advocate, recommend, or administer neurosurgical treatments of neuropsychiatric disorders.

1.Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:1905–1917
 
2.Kennedy SH, Giacobbe P: Treatment resistant depression: advances in somatic therapies. Ann Clin Psychiatry 2007; 19:279–287
 
3.Neimat JS, Hamani C, Giacobbe P, Merskey H, Kennedy SH, Mayberg HS, Lozaro AM: Neural stimulation successfully treats depression in patients with prior ablative cingulotomy. Am J Psychiatry 2008; 165:687–693
 
4.Lerner BH: Last-ditch medical therapy: revisiting lobotomy. N Engl J Med 2005; 353:119–121
 
5.Tooth GC, Newton MP: Leucotomy in England and Wales, 1942–1954: Reports on Public Health and Medical Subjects, Number 104. London, London Ministry of Health, 1961
 
6.Mathew SJ, Yudofsky SC, McCullough LB, Teasdale TA, Jankovic J: Attitudes towards neurosurgical procedures for Parkinson’s disease and obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 1999; 11:259–267
 
7.Bridges P: Psychosurgery revisited. J Neuropsychiatry Clin Neurosci 1990; 2:326–331
 
8.Yudofsky S, Ovsiew F: Neurosurgical and related interventions for the treatment of patients with psychiatric disorders. J Neuropsychiatry Clin Neurosci 1990; 2:253–255
 
9.Drevts WC, Raichle ME: Neuroanatomical circuits in depression: implications for treatment mechanisms. Psychopharmacol Bull 1992; 28:261–274
 
10.Kennedy SH, Konarski JZ, Segal ZV, Lau MA, Bieling PJ, McIntyre RS, Mayberg HS: Differences in glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatry 2007; 164:778–788
 
11.Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH: Deep brain stimulation for treatment-resistant depression. Neuron 2005; 3:651–660
 
12.Rauch SL, Dougherty DD, Cosgrove GR, Cassem EH, Alpert NM, Price BH, Nierenberg AA, Mayberg HS, Baer L, Jenike MA, Fischman AJ: Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive-compulsive disorder. Biol Psychiatry 2001; 50:659–667
 
13.Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR, George MS, Charney DS, Brannan SK: VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology 2006; 31:1345–1355
 
14.Dougherty DD, Baer L, Cosgrove GR, Cassem EH, Price BH, Nierenberg AA, Jenike MA, Rauch SL: Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am J Psychiatry 2002; 159:269–275
 
15.Appleby BS, Duggan PS, Regenberg A, Rabins PV: Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: a meta-analysis of ten years’ experience. Mov Disord 2007; 22:1722–1728
 

+Address correspondence and reprint requests to Dr. Yudofsky, Baylor College of Medicine, One Baylor Plaza, BCM 350, Houston, TX 77030; stuarty@bcm.tmc.edu (e-mail). Editorial accepted for publication March 2008 (doi: 10.1176/appi.ajp.2008.08020298).

+Dr. Yudofsky participated in an APA-sponsored CME course at an annual meeting of the APA that was sponsored by Bristol-Myers Squibb, and he is vice president of Diamond Healthcare Corporation. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.

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References

1.Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:1905–1917
 
2.Kennedy SH, Giacobbe P: Treatment resistant depression: advances in somatic therapies. Ann Clin Psychiatry 2007; 19:279–287
 
3.Neimat JS, Hamani C, Giacobbe P, Merskey H, Kennedy SH, Mayberg HS, Lozaro AM: Neural stimulation successfully treats depression in patients with prior ablative cingulotomy. Am J Psychiatry 2008; 165:687–693
 
4.Lerner BH: Last-ditch medical therapy: revisiting lobotomy. N Engl J Med 2005; 353:119–121
 
5.Tooth GC, Newton MP: Leucotomy in England and Wales, 1942–1954: Reports on Public Health and Medical Subjects, Number 104. London, London Ministry of Health, 1961
 
6.Mathew SJ, Yudofsky SC, McCullough LB, Teasdale TA, Jankovic J: Attitudes towards neurosurgical procedures for Parkinson’s disease and obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 1999; 11:259–267
 
7.Bridges P: Psychosurgery revisited. J Neuropsychiatry Clin Neurosci 1990; 2:326–331
 
8.Yudofsky S, Ovsiew F: Neurosurgical and related interventions for the treatment of patients with psychiatric disorders. J Neuropsychiatry Clin Neurosci 1990; 2:253–255
 
9.Drevts WC, Raichle ME: Neuroanatomical circuits in depression: implications for treatment mechanisms. Psychopharmacol Bull 1992; 28:261–274
 
10.Kennedy SH, Konarski JZ, Segal ZV, Lau MA, Bieling PJ, McIntyre RS, Mayberg HS: Differences in glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatry 2007; 164:778–788
 
11.Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH: Deep brain stimulation for treatment-resistant depression. Neuron 2005; 3:651–660
 
12.Rauch SL, Dougherty DD, Cosgrove GR, Cassem EH, Alpert NM, Price BH, Nierenberg AA, Mayberg HS, Baer L, Jenike MA, Fischman AJ: Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive-compulsive disorder. Biol Psychiatry 2001; 50:659–667
 
13.Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR, George MS, Charney DS, Brannan SK: VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology 2006; 31:1345–1355
 
14.Dougherty DD, Baer L, Cosgrove GR, Cassem EH, Price BH, Nierenberg AA, Jenike MA, Rauch SL: Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am J Psychiatry 2002; 159:269–275
 
15.Appleby BS, Duggan PS, Regenberg A, Rabins PV: Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: a meta-analysis of ten years’ experience. Mov Disord 2007; 22:1722–1728
 
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