Max Fink, MD

is Associate Professor of Psychiatry, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD

is Chief of Electroconvulsive Therapy, New York Community Hospital, Brooklyn, NY

 is Professor Emeritus, Departments of Psychiatry and Neurology, Stony Brook University, Stony Brook, NY.

Since its introduction 8 decades ago, ECT has been a standard treatment for severe affective and psychotic illness, as well as less common indications including catatonia, 

, neuroleptic malignant syndrome, and status epilepticus. A new indication for ECT has 

 for intractable self-injurious behavior (SIB) among individuals with autism and intellectual disabilities.

 Response to ECT is typically swift and robust, with great benefit for patients and their families.

SIB is defined as any act toward the self that causes physical injury, and has been recognized for decades to occur among individuals with autism spectrum disorders and intellectual disability. Estimates of SIB prevalence vary widely, with higher rates usually found among those with greater cognitive and communication impairments, and psychiatric and medical comorbidities. Common manifestations of SIB include head banging; hand-to-head, knee-to-head, and hand-to-body hitting; self-pinching; scratching and biting; and body slamming against hard surfaces. The frequency of SIB varies widely, from occasional, to daily, hourly, or even a per-minute basis. Frank bodily injury is common and includes bleeding, bruising, swelling, fracture, infection, disfigurement, traumatic ossification, cataract development, retinal detachment with associated loss of vision, and concussion or intracranial damage. Other deleterious consequences of SIB include reduced social, educational, family, and occupational functioning, with higher risk of placement in more restrictive settings and limited life opportunities.

Standard treatments of SIB in autism and intellectual disability are behavioral and psychopharmacological interventions. While many individuals respond to these modalities, there has long remained a subgroup of treatment-refractory patients who have exhausted dozens of psychotropic medications, years of intensive behavioral therapy, and multiple out-of-home placements and hospitalizations. Such patients may be padded and immobilized head-to-toe in protective equipment, and frequently receive psychotropic medications as chemical restraint-often with limited benefit and high risk of adverse effects. Despite such efforts, these patients often sustain permanent injuries including blindness from retinal detachment and cerebral hemorrhage.

Recent suggestions that SIB might be one of many symptoms of catatonia in autism spectrum disorders-including mutism, negativism, posturing, rigidity, and repetitive speech and acts-led to treatment trials with ECT, the long-recognized effective treatment for catatonia, with 

Jay is a 19-year-old man with autism and intellectual disability. He was initially hospitalized at age 12 after several years of severe head- and body-directed SIB with frequent facial bleeding, as well as aggressive behaviors toward his family, caregivers, and school staff. SIBs were so intense that a caregiver inadvertently broke Jay’s arm while attempting to block hand-to-head striking. Jay also displayed mood instability with sobbing and wild laughter, irritability, physical hyperactivity, agitation, and insomnia.

He had exhausted multiple drug trials from all US-available psychotropic classes, as well as years of intensive behavioral services. He demonstrated affective and behavioral improvement of a few months’ duration on lithium carbonate, aripiprazole, and riluzole, but deteriorated again with such behavioral dyscontrol that his parents feared their only option to maintain his safety was placement in a locked residential facility.

A trial of 3 times per week bilateral ECT was initiated. Jay demonstrated dramatic reduction in SIBs after just a few treatments, as well as improved sleep and more stable mood. ECT frequency was gradually reduced while monitoring for recurrence of SIB or mood deterioration; ultimately, a maintenance ECT regimen of every 9 or 10 days was established.

Jay was able to remain at home, where he participated fully and safely in family life with his parents and 2 siblings. He continued in a program emphasizing community-based living and functioning activities, and was able to master skills never thought possible for him before, such as independent grocery shopping from a list, followed by check-out with a debit card and meal preparation.

He tolerates ECT well and is able to go to school without incident after early-morning treatment. He remains on a concomitant regimen of lithium and aripiprazole; SIB is limited to rare incidents of hand-biting with no resultant injuries. Jay has received an estimated 290 sessions of ECT over the past 8 years.

The resolution of SIB with ECT was first documented in a 1982 report of a 25-year-old man with severe mental retardation and head-directed SIB of several years’ duration.

 In 1999, a report presented a 14-year-old boy with mental retardation whose persistent head-banging and self-scratching were alleviated by ECT, which allowed discharge after many months in a restricitve institutional setting.

The relationship between self-injury, catatonia, and ECT was first questioned in the 2008 case report of an autistic girl with posturing, rigidity, mutism, stupor, grimacing, food refusal, and global skill regression, alternating with bursts of extreme self-injury that led to bilateral traumatic cataract formation and retinal detachment.

 ECT resulted in resolution of catatonic symptoms, as well as nearly complete eradication of SIB, which allowed for vision preservation in one eye.

The following year, the case of an 8-year-old autistic boy with ongoing agitation and stereotyped movements (in the form of nearly 110 SIBs per hour) was reported.7 After treatment with ECT, he averaged only 20 SIBs per hour. It was postulated that his SIB was a manifestation of catatonia.

 proposed that self-injury in autism represented a variant of catatonia. They reviewed the history of these conditions, exploring self-injury as a stereotypy common to both catatonia and autism, and further connecting catatonia, autism, tic disorders, and the self-injury that occurs in the 3 conditions. Subsequent reports have continued to call for recognition of repetitive SIB as a sign of catatonia, with clear implications for the use of ECT in its treatment.

ECT for adolescents with autism spectrum disorder and SIB includes standard ECT protocols of general anesthesia with propofol or methohexital, muscle relaxation with succinylcholine, and continuous oxygenation via face mask. Flumazenil, the benzodiazepine reversal agent, may be used at the time of treatment when patients have recently taken these medications. 

 is typically bilateral, and stimulation is with modern brief-pulse devices.

Moderately suprathreshold stimulus dosing takes into account the lower seizure threshold of younger patients. Seizure adequacy is monitored by the duration and quality of the recorded EEG. The ECT course begins with seizures 3 times per week, until SIB frequency has been markedly reduced; ECT frequency is then gradually reduced over the ensuing weeks, while monitoring for sustained SIB reduction. For these patients, ECT is a procedure analogous to renal dialysis, with frequency of treatment guided by objective symptom evaluation, and the need to optimize the quality of patient and family life.

While the mechanism of the relief of catatonia by ECT is unclear, the neuroendocrine studies of melancholia offer potential clues. Studies of cortisol and thyroid functions in these patients find chemical abnormalities that resolve with repeated ECT, suggesting that seizures normalize the hypothalamic-pituitary-adrenal axis and other endocrine functions. While we know little about the specific neuroendocrine disturbances in autism spectrum disorder or in catatonia, there are likely commonalities in the underlying physiology between these disorders and melancholia. At present, the best understanding of the mechanism of the beneficial effect of ECT in adolescents with SIB is the neuroendocrine explanation developed for melancholia. Additional mechanistic theories are enhanced neurogenesis, angiogenesis, and neuronal connectivity.

ECT came into widespread use at a time when psychodynamic thinking dominated child and adolescent psychiatry and the application of the somatic therapies was considered anathema. Since the 1990s, this attitude hurdle has been slowly overcome with the realization that some severe childhood and adolescent disorders-notably, melancholia, mania, and catatonia-are safely and effectively relieved by modern ECT procedures. Recognizing SIB in autism spectrum disorder as a form of catatonia has encouraged this application. Indeed, ECT has been documented as nothing short of lifesaving for many children and young adults with autism spectrum disorder who were previously wholly incapacitated by SIB.

Wachtel L, Shorter E. Self-injurious behaviour in children: a treatable catatonic syndrome. 

Wachtel L, Dhossche D. ECT for self-injurious behavior. In: Ghaziuddin N, Walter G, eds. 

Electroconvulsive Therapy in Children and Adolescents

. New York: Oxford University Press; 2013:247-280.

 Fink M. Rediscovering catatonia: the biography of a treatable syndrome. 

 Bates WJ, Smeltzer DJ. Electroconvulsive treatment of psychotic self-injurious behavior in a patient with severe mental retardation. 

 Wachtel LE, Kahng S, Dhossche DM, et al. ECT for catatonia in an autistic girl. 

Wachtel LE, Contrucci-Kuhn SA, Griffin M, et al. ECT for self-injury in an autistic boy. 

Wachtel L, Dhossche D. Self-injury in autism as an alternative sign of catatonia. 

 Fink M. The mechanism of action of ECT. In: Ghaziuddin N, Walter G, eds. 

. New York: Oxford University Press; 2013:18-28.

Optimizing ECT technique in treating catatonia

Articles

ECT has been found effective in mitigating the deleterious consequences of SIB.

ECT for Self-Injurious Behavior in Autism: A New Indication

ECT remains a standard treatment in modern psychiatric medicine for a range of severe psychiatric illnesses because of its unmatched efficacy and speed of response. Recent changes in psychiatric nosology and practice clarify the role of ECT for catatonia and melancholia-2 syndromes for which ECT is a most effective and often lifesaving treatment. For these syndromes, optimally administered ECT typically provides relief within 1 to 3 weeks.

Catatonic patients, especially those with febrile malignant catatonia or the neuroleptic malignant syndrome and those who refuse feeding, should be treated without delay. Unfortunately, antidepressant medications are prescribed for many melancholic patients-often multiple trials of up to 6 weeks each-before ECT is recommended. More severely depressed patients, who are agitated, suicidal, and losing weight, should be referred for ECT as a primary treatment.

Indeed, the remarkable, well-replicated efficacy of ECT for these 2 syndromes raises questions about accepted treatment algorithms that call for 2 or more medication trials, often with multiple medications combined with psychotherapy. Many clinicians question the ethics of such treatment algorithms that ask patients to suffer weeks, even months, of trials before the effective treatment of ECT is prescribed. For both ethical and economic reasons, when patients are acutely ill with catatonia and melancholia, ECT is best considered sooner rather than later.

A century ago, following the images created by Emil Kraepelin, catatonia was seen as a marker of schizophrenia and classified as one of its recognized types. By the 1990s, DSM-IV recognized catatonia as secondary to a medical condition; in the latest iteration, DSM-5 discarded the class of catatonia as a type of schizophrenia and retained it mainly as a systemic medical condition. Much has been learned.

Catatonia rating scales identify more than 20 motor behaviors, including posturing, rigidity, staring, mutism, and repetitive thoughts and acts that mark the stuporous form. Two or more signs that last for 24 hours suggest the presence of the syndrome. The diagnosis can be verified by rapid relief, a 50% reduction in the rating scale scores, with the intravenous administration of 1 to 2 mg of lorazepam. Catatonia is first treated with increasing doses of a benzodiazepine; for lorazepam, often up to 30 mg/d. Up to 80% of patients respond to high-dose lorazepam treatment.

For those who do not respond or for those with a malignant form of catatonia-with fever, autonomic dysfunction, and stupor-ECT is the primary treatment. ECT can be optimized in several ways. For febrile patients, daily treatment may be necessary.

High-dose benzodiazepines can raise seizure thresholds and interfere with the efficacy of ECT seizures. The most effective ECT uses bilateral electrode placement, and for those who have received benzodiazepines, the protocol may include the benzodiazepine antagonist flumazenil, administered in the sequence of oxygenation, anesthetic, flumazenil, and succinylcholine. Effective seizures are those that are of adequate duration, allowing the full sequence of buildup in the recorded EEG of slow waves, slow waves and spikes, followed by a definable sharp endpoint. Evidence on the use of right unilateral electrode placement to treat seriously ill patients with catatonia, while intriguing, is not compelling enough to change standard practice.

Catatonia is also recognized in an excited, delirious manic form. These patients are often febrile, medically ill, and behaviorally difficult to manage. An intramuscular ketamine injection may be a safe initial sedating agent, allowing placement of the intravenous line and the subsequent administration of the standard sequence of ECT medications. Daily ECT until the condition is stabilized is necessary and often lifesaving. The benefits are best sustained by continuation of ECT over weeks or months. In some instances, continued high-dose benzodiazepine treatment has been useful.

Before 1980 and the adoption of DSM-III, 2 depressive mood disorders were commonly identified: a severe life-threatening psychotic depression, “melancholia,” and the more commonly recognized “psychoneurotic” form. Melancholia was recognized by mood severity, acute onset, suicide risk, psychosis, and vegetative signs such as insomnia and weight loss. Psychoneurotic depression was marked by anxiety, fears, phobias, and obsessive thoughts. Since DSM-III, these conditions have been lumped together as “major depressive disorder.” Melancholia has been of limited interest, classified as a specifier for mood disorders (“with melancholic features”) and no longer recognized as a distinct illness.

Clinical scientists in the 1970s and 1980s reported that hypothalamic-pituitary-adrenal axis function, measurable by serum cortisol levels, was abnormal in melancholia and offered the dexamethasone suppression test as an index to identify and measure the severity of the syndrome.

 The loss of interest in melancholia resulted in the abandonment of cortisol measurement, including the dexamethasone suppression test, in the clinic.

Definitions of melancholia have varied over decades, and this is likely the reason that the evidence for its utility as a predictor of ECT response has been inconsistent. For the purposes of this article, melancholia refers to a severe primary mood disorder, usually episodic, with anhedonia, psychomotor disturbance, impaired concentration, disrupted sleep, poor appetite with weight loss, and often with psychotic thinking (guilty delusions) as well as suicidal ideation and intent.

Patients with melancholia often score in the “severe” range on depression rating scales such as the Hamilton (HAM-D) or Montgomery-Asberg (MADRS). Because the dexamethasone suppression test is no longer used, the diagnosis is made solely on the basis of clinical features, that is, by the severity of symptoms, progressive course, and presence of suicidal intent and psychosis, along with the other mood and motor features of the syndrome.

Effective ECT for severe melancholia, like that for catatonia, is based on optimizing ECT treatment parameters, which favor bilateral electrode placement, 3-times-per-week treatments, and monitored EEG seizures for duration and pattern. To sustain the benefits, continuation treatments over weeks or months are often required. Alternative strategies, of continuation treatment with pharmacotherapy combinations (eg, lithium plus nortriptyline or venlafaxine) or pharmacotherapy combinations along with continuation/maintenance ECT, have also been reported as effective in sustaining remission.

 that documents the efficacy of ECT in reducing hospital readmission rates adds to our understanding of the public health benefits of ECT.

 An accompanying editorial forcefully makes the argument that modern ECT is a safe and well-tolerated treatment that is underutilized in American psychiatry.

 We agree-and hope that highlighting the appropriate place of ECT in treatment algorithms for catatonia and melancholia helps practitioners to consider ECT for their most seriously ill patients.

Dr. Kellner is Chief of Electroconvulsive Therapy, New York Community Hospital, Brooklyn, NY. Dr. Fink is Professor Emeritus, Departments of Psychiatry and Neurology, Stony Brook University, Stony Brook, NY.

 Sienaert P, Dhossche DM, Vancampfort D, et al. A clinical review of the treatment of catatonia. 

 Albala AA, Greden JF, Tarika J, Carroll BJ. Changes in serial dexamethasone suppression tests among unipolar depressive receiving electroconvulsive treatment. 

 Kellner CH, Husain MM, Knapp RG, et al. A novel strategy for continuation ECT in geriatric depression: phase 2 of the PRIDE study. 

 Slade EP, Jahn DR, Regenold WT, Case BG. Association of electroconvulsive therapy with psychiatric readmissions in US hospitals. 

 Sackeim HA. Modern electroconvulsive therapy: vastly improved yet greatly underused. 

Fink M, Kellner CH, McCall WV. Optimizing ECT technique in treating catatonia. 

Krystal AD, Watts BV, Weiner RD, et al. The use of flumazenil in the anxious and benzodiazepine-dependent ECT patient. 

Luchini F, Medda P, Mariani MG, et al. Electroconvulsive therapy in catatonic patients: efficacy and predictors of response. 

For ethical and economic reasons, when patients are acutely ill with catatonia and melancholia, ECT is best considered sooner rather than later. 

ECT for Catatonia and Melancholia: No Need for Ambivalence

A Hollywood movie almost killed an important psychiatric treatment. After clinicians and members of the public saw the film 

, which premiered in 1975, many swore “never again.” The fantasy bore no relationship to the actual conduct of an effective psychiatric treatment, yet almost wrote its death warrant.

Years later we are still dealing with the fallout from that fantasy. Although many clinicians have accepted ECT, the public harbors the image of Jack Nicholson being forcibly subjected to treatment without his informed consent, and they do not wish this for one of their family members. As a consequence, serious cases of depression, mania, and catatonia-unresolved by medications and psychotherapies-are haphazardly denied evidence-based treatment.

The effective component of the treatment is the cerebral seizure itself and not the electricity. There are other ways of eliciting seizures, however, without putting electrodes on fearful patients. Flurothyl, an anesthetic, offers an effective treatment by inhalation or by infusion.

Chemical infusions to treat MDD began in the late 1950s, as soon as the antidepressant efficacy of oral imipramine was recognized. Rapid relief was temporary, and adverse effects of dry mouth and skin, increased heart rate, and impaired vision deterred its use. In 1982, the Swiss psychiatrist Paul Kielholz optimistically reviewed infusion therapy with an emphasis on the antidepressants clomipramine and maprotiline.

 Brightening of mood occurred but was transient, and the procedure was discarded. Recently, infusions of the anesthetic ketamine have been tested but, again, the benefits are short-lived.

Studies from the 1930s found minimal concentrations of brain glia in those who died with schizophrenia and a surfeit in those with epilepsy.

 A concept of an antagonism between these disorders encouraged the search for ways to safely induce seizures. Introduced in 1934, intramuscular injections of camphor were successful, but dosing was difficult and the delay to seizure was worrisome. Many injections failed to elicit a seizure. Intravenous pentylenetetrazol (Metrazol) was tested the same year and quickly adopted because of its greater efficiency. By 1938, the induction of seizures by electricity was found to be more efficient, giving rise to the worldwide use of ECT.

In 1957, an alternative seizure-inducing agent, flurothyl (Indoklon), a congener of the inhalant anesthetic diethyl ether, was tested.

 With a few inhalations consciousness was lost, and with a few more the electroencephalogram (EEG) showed the slow waves and spikes characteristic of a seizure. Extensive clinical experiences and 4 well-documented controlled trials comparing flurothyl with ECT reported that from 3 to 10 inhalations over a few weeks successfully relieved severe depression and psychosis.

Durations of the EEG seizure were longer and the effects on cognition and memory were less with flurothyl than with ECT. Motor movements accompanied the EEG seizures, and as in modified ECT, they were readily blocked by pretreatment with succinylcholine. Neither spontaneous tardive seizures nor missed treatments were reported. Pharmacological studies found no systemic toxicity.

Yet, flurothyl infusions were discarded, not because of inefficacy or adverse effects but because of fears among clinicians who administered the therapy and breathed the exhaled anesthetic that gave the treatment room a characteristic pungent ethereal aroma. The discarding of this treatment, with its relative lack of adverse effects and considerable benefit, was an error.

The most effective treatment for medication-resistant mood disorders today is ECT; the principal deterrent to its use is the widespread fear of loss of memories. To be sure, in the flurothyl and ECT trials, mild and transitory cognitive impairment was noted during the acute phase. With flurothyl, however, the therapeutic effects were greater, observed earlier, and persisted longer than with ECT. In addition, flurothyl avoided the direct effects of electricity on brain function above and beyond the seizure.

Many efforts have been made to reduce the impact of electric currents on brain function. The form of the current, dosing, placements of electrodes, frequency of seizures, and replacement of electricity by magnetic currents have occupied clinicians and researchers for decades.

 Progress has been made, but public fears have not been allayed.

Flurothyl is a unique and rapidly effective anesthetic that has a favorable therapeutic balance. Safe air handling of inhalant anesthetics has been resolved and the fears that inhibited the use of flurothyl are no longer an issue. Seizure management, and control of motor effects and systemic cardiac risks are no longer deterrents to seizure induction with flurothyl.

Much has been learned about the neuroendocrine abnormalities in hypothalamic, pituitary, adrenal, and thyroid functions that accompany mood disorders. Each seizure elicits an outpouring of endocrine peptides. With repeated seizures, the hormone irregularities are redressed and the abnormal mood syndrome relieved. The mechanism of the relief is not known, but the effect is extensively documented.

A reexamination of flurothyl infusions holds promise for improved resolution of severe mood disorders, as well as for a greater understanding of the mechanism of their pathophysiology. A reassessment of the flurothyl experience using present-day anesthesia facilities is encouraged.

Acknowledgement-We are indebted to Kathryn Cooper, BS, Class of 2016 of the University of Rochester School of Medicine in New York for a detailed review of the clinical experience with chemical inductions of seizures in man.

Dr Fink is Professor of Psychiatry and Neurology Emeritus, Stony Brook University School of Medicine, NY. Dr Shorter is Jason A. Hannah Chair in the History of Medicine, Faculty of Medicine, University of Toronto, Ontario, Canada. They report no conflicts of interest concerning the subject matter of this article.

 Cooper K, Fink M. The chemical induction of seizures in psychiatric therapy: were Flurothyl and Metrazol abandoned prematurely? 

 Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. 

 Meduna L. Autobiography of L. J. Meduna. 

Shock Therapy: A History of Electroconvulsive Therapy in Mental Illness

. New Brunswick, NJ: Rutgers University Press; 2007.

 Kurlan AA, Hanlon TE, Esquibel AJ, et al. A comparative study of hexafluorodiethyl ether (Indoklon) and electroconvulsive therapy. 

 Fink M, Kahn RL, Karp E, et al. Inhalant-induced convulsions: significance for the theory of the convulsive therapy process.

 Small JG, Small IF, Sharply P, Moore DF. A double-blind comparative evaluation of flurothyl and ECT. 

 Laurell B. Flurothyl convulsive therapy. 

 Fink M. What was learned: studies by the Consortium for Research in ECT (CORE) 1997-2011. 

Endocrine Psychiatry: Solving the Riddle of Melancholia

. New York: Oxford University Press; 2010.

A reexamination of flurothyl infusions holds promise for improved resolution of severe mood disorders, as well as for a greater understanding of the mechanism of their pathophysiology.

Revive Flurothyl Inhalation Therapy

 highlight the race to patent bio-tests for schizophrenia and depression. Alas,  this drive is destined to fail for the same reason that earlier biotests  failed-the heterogeneity of the populations for these disorders as defined by  the DSM criteria. The failure of the STAR*D, STEP-BD, and CATIE studies to find  assured efficacy for the treatments in the trials is sufficient evidence to  question the DSM criteria.

Dr Akiskal notes that “the dexamethasone  suppression test [DST]  was considered to have acceptable sensitivity and specificity for  melancholia, rather than broadly defined depression.”

  But it was the  view of  key opinion leaders    of an NIMH committee in 1982 and the 1986 Glassman APA Commission  that the failure of the DST to define “major depression” doomed it for  rejection in the clinic.

In the past decade, the question has been asked whether the  DST could be used to identify the melancholic patients who fail to respond to  SSRI, SNRI, MAOI, and the psychotherapies, but do respond to tricyclic  antidepressants (TCAs) and elecroconvulsive therapy (ECT). The evidence  that hypercortisolemia is a biomarker of melancholic mood disorders is  compelling.

In the STAR*D study, the patient records were examined for  the DSM “melancholia specifier.”

 Overall 42% to 55% of the sample  were considered treatment failures. Additionally, 23.5% were positive for the  melancholic specifier; their inclusion reduced the remission rates by 24.1%.  Had they been excluded and treated by TCA and ECT, the overall remission rate  for the SSRI would have been salvaged.

The sad history of the rejection of the DST and its present  exclusion from clinical use (failure of reimbursement by insurers is a tragic  consequence of the present teaching) is described by Edward Shorter and Max  Fink in 

 Additional references (all not  reviewed by the major journals) are Taylor and Fink’s 

 and the proceedings of the 2006 Copenhagen  conference on Melancholia published as “Melancholia: Beyond DSM, Beyond  Neurotransmitters.”

Dr Asiskal’s opinion that “biomarkers for mental disorders [are a] field whose time has come” is correct. We have many  markers that are in use-EEG criteria for epilepsy, serum tests for  neurosyphilis, the lorazepam test for catatonia. Tests for hypercortisolemia  are freely available  for melancholia and warrant  study and use.

It is timely to reconsider the DSM division of major  depression and bipolar disorder that serve patients and doctors poorly and seek  a new split of the mood disorders as melancholia and non-melancholia.

Blood tests for schizophrenia and depression: not ready for prime time

Biomarkers for mental disorders: a field whose time has come

McGrath PJ, Khan AY, Trivedi MH, et al. Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report. 

Endocrine Psychiatry: Solving the Riddle of Melancholia.

Melancholia: The Diagnosis, Pathophysiology, and Treatment of Depressive Illness. 

New York: Cambridge University Press; 2006.


Melancholia: Beyond DSM, Beyond Neurotransmitters. Proceedings of a conference, May 2006, Copenhagen, Denmark. 

The articles by Arline Kaplan and Hagop Akiskal, MD, in the November 2011 issue of Psychiatric Times highlight the race to patent bio-tests for schizophrenia and depression. 

The Race to Patent Bio-tests for Schizophrenia and Depression

Alfred Freedman was an eminent psychiatric educator, a leader of his profession, and a man willing to challenge public prejudice. He was also one of my closest friends. Appointed to the chairmanship of the struggling Department of Psychiatry at New York Medical College in 1960, he found limited facilities and constant challenges. His guiding philosophy in life was to reject conflict and search for a third way, by mediation. When New York City’s Department of Hospitals reeled from the aftermath of publicity on the inadequacy of the city’s psychiatric care, rather than point fingers or become defensive, he saw this as his opportunity to establish psychiatric units at Metropolitan Hospital. He developed the first Community Mental Health Center in New York City. When a crisis in marijuana and heroin abuse challenged the city, he added a drug addiction unit for adults followed a year later by a second unit for adolescents. Seeing the need for community education in substance abuse, he launched a Social and Community Division and a center for Urban Education in the Department.

He graduated from Cornell College in 1937 and received his doctor of medicine degree from the University of Minnesota in 1941. Alfred was called into the army; he studied the effects of anticholinergic drugs on humans while he served his country. During residencies in child psychiatry at Bellevue Hospital in New York, he trained in psychoanalysis at the William Alanson White Institute.

He broadened the psychiatry medical school teaching program at New York Medical College to all 4 years. Needing an eclectic text that embodied his philosophy, he developed the

 a work that has been repeatedly updated and translated into many languages. In a large residency training program, he set up a flexible fellowship program for women psychiatrists, to encourage specialist certification in 4 or 5 years instead of 3.

Alfred was an enthusiastic participant in psychiatric organizations and was elected President of the American Psychopathological Association in 1971 and of the American College of Neuropsychopharmacology in 1972. By membership petition, he was elected President of the American Psychiatric Association in 1973. During his APA tenure, he supported the efforts of gay rights groups and psychiatrists to destigmatize homosexuality and led the APA Trustees to approve the recommendation of its DSM committees that homosexuality was not a psychiatric disorder in the official nomenclature. This important step was taken in the face of strong opposition by doctrinaire Freudians. For those of us who knew him best, this was the paradigmatic example of his “third way.” Homosexuality was part of the human condition, neither a sickness nor a perversion. Recognizing the importance of legal developments in psychiatry, he created the APA’s Commission on Judicial Action and gave psychiatry a voice in the Supreme Court.

On the scientific side, he strongly supported clinical research and human experimentation. He encouraged studies of narcotic antagonists. The use of naloxone as a standard treatment in the emergency room grew out of his research. When marijuana use became a public issue in New York, he supported an international study of hashish and marijuana in users in New York and Athens. During the years that the public and colleagues disparaged my advocacy of electroshock therapy, Alfred supported the research efforts.

His interests were also international. He became an active member of the CINP in 1960. At the APA, he helped organize the visit to the Soviet Union to examine allegations of political misuse of psychiatry. At the College, he organized an annual lectureship for leading international psychiatrists. He was a member of the jury of the Anna-Monika Foundation. In these international efforts, he was strongly encouraged by his wife, Marcia, who accompanied him on his travels.

He retired from the New York Medical College in 1988, turning his attention to the international struggle to advance human rights. Despite all of his scientific and social achievements, Alfred never lost his willingness to listen, to learn, and to search for the third way. Our profession has lost not just a leader but a fine role model.

On his death, he left Marcia, his wife of 68 years, 2 sons, 3 grandchildren, and hundreds of admirers.


• Freedman AM. Almost fifty years in psychopharmacology: a memoir. In: Ban TA, Healy D, Shorter E, eds.

 The Triumph of Psychopharmacology and the Story of CINP

. Budapest: Animula Publishing; 2000:261-264.


• Grimes W. Alfred Freedman, a leader in psychiatry, dies at 94.

 Alfred Freedman was an eminent psychiatric educator, a leader of his profession, and a man willing to challenge public prejudice. He was also one of my closest friends.

Alfred M. Freedman, MD, 1917-2011

Convulsive therapy, with chemically induced seizures, was first demonstrated in 1934 in Europe to relieve psychosis-particularly the catatonic type. Within 4 years, electrical induction (also known as electroconvulsive therapy, or ECT) was shown to be as effective and much easier to use. For the next 2 decades, ECT became the principal treatment for the severely mentally ill, especially the many thousands warehoused in state hospitals. Its use in psychiatric practice allowed many patients to avoid the stigma of hospital admission and remain at home to lead normal lives.

Introduced concurrently with insulin coma (1933) and lobotomy (1935), these 3 treatments were conflated in the public and professional psyche. As insulin coma and lobotomy fell into disuse because of their high morbidity and mortality rates, their demise contaminated the appreciation of ECT. Competition from psychotherapies and then from psychotropic drugs led to the widespread abandonment of ECT in the 1960s and 1970s.

Since the mid-1980s, doctors have gradually recognized that ECT can effectively relieve life-threatening conditions that would not otherwise be treated. This change in perspective, coupled with improvements in technique and safety, has resurrected its use throughout the world. Three recent books document this perplexing roller-coaster story.

Shock Therapy: A History of Electroconvulsive Treatment in Mental Illness

 medical historians Edward Shorter and David Healy offer a verifiable history that is based on archival records and supplemented by interviews with cooperating researchers and clinicians. In 

Shock: The Healing Power of Electroconvulsive Therapy,

 Kitty Dukakis (wife of Michael Dukakis, former Governor of Massachusetts and the 1988 Democratic presidential candidate) reports how ECT relieved her depression, alcoholism, and suicidal tendencies and how continuation treatments sustained her mental health. Her chapters, favorable to ECT, alternate with chapters by popular writer Larry Tye, who provides a history of the treatment.

Doctors of Deception: What They Don’t Want You to Know About Shock Treatment,

 written by public activist Linda Andre, is a different patient memoir that chastises psychiatry for promoting ECT on the (untrue) grounds that it leads to widespread and devastating memory loss.

Despite these divergent books, it is important to avoid characterizing ECT as controversial. The Shorter-Healy and Dukakis books should dampen the controversy, because they characterize ECT as a safe, effective, and important treatment that psychiatry almost forgot. With its emotion-laden accusations and name-calling, the Andre book will inflame opinions.

 Shorter and Healy describe the discoveries of ECT, insulin coma, and lobotomy; the personalities and experiences of the originators; the hazards of early treatments; and the dramatic changes that followed the introduction of anesthesia, muscle relaxants, and oxygenation. These modifications in technique reduced the risks of ECT and changed its negative image. Much attention is paid to the accuracy (or rather inaccuracy) of complaints of permanent, severe memory loss that deter the use of ECT; the role critics of ECT have played to restrict the treatment; and the social consequences of these restrictions. The book documents the irrational arguments that weaken its use and act as a bar to badly needed research in psychiatry.

The memoir by Dukakis and Tye describes Kitty Dukakis’s decades-long painful experiences with a complex depressive illness and the many unsuccessful medication trials that finally ended when she was treated with ECT. She describes the immediate relief following her first treatments and the sustained benefits of ongoing treatment. She also tells readers about the losses of familiarity and orientation that plagued her following the first ECT treatments and the ways that she coped and returned to healthy functioning as wife, mother, and active community member. Her writing is personal, similar in intensity to prize-winning writer William Styron’s memoir,

 in which he recounts his experience with mental illness. The chapters written by Tye offer details of the medical and social history of ECT.

 Andre presents a very different story of ECT. She has often come onto the public stage as an implacable critic of ECT, motivated by a personal agenda. She became depressed when she was a young woman. Plagued by suicidal thoughts, she was hospitalized, was treated with ECT, and recovered from serious psychiatric illness. Complaining that she suffered losses of early life memories and claiming she had not been fully informed about the risks of the treatment, she sued her treating psychiatrists and hospital for malpractice, but her suit failed. She found a calling in the public advocacy group Committee for Truth in Psychiatry, and when founder Marilyn Rice died, Andre became the group’s leader. Andre’s account is filled with inaccuracies about the medical aspects of the history of ECT, with equally unfounded personal attacks on the clinicians who sustained interest in ECT.

These books present disparate images of a much disparaged and censured-yet widely practiced-medical treatment. Shorter and Healy present a well-documented, carefully indexed, and readable classic history that is a guide for those interested in medical history, clinicians seeking the story behind psychiatric practice, and the patients and families seeking to understand the obstacles they face in search of effective psychiatric care.

Dukakis and Tye present a personal, warm, and encouraging story of the pain and suffering associated with severe depressive illness and of the attendant relief with the alleviation of symptoms, the fear of ECT by both the public and professionals, and the success when effective treatment is properly applied. This is a very useful guide for family members torn by the doubts of practitioners and friends and the intemperate condemnation by critics on the Internet when treatment is recommended.

Andre’s anger vilifies psychiatry and the psychiatrists who continue to offer ECT. Her Web site is strident as well, filled with the kinds of misconceptions that have successfully restricted and continue to obstruct the availability of the treatment. Her book is a triumph of misinformation.

All 3 books are essential reading for anyone interested in ECT. These books offer dramatically contrasting views of a psychiatric issue that is of interest to the public. At the end of the day, patients who have serious depression and other ill-nesses responsive to ECT-together with their friends and loved ones-should read these books and decide for themselves.

The Perplexing History of ECT in Three Books

 Michael First relates the sad fact that the reorganization of 

 is still without formal guidelines and continues to be subject to the vicissitudes of groupthink and vocal constituencies. He relates that he and Allen Frances envisioned the application of biologically based diagnostic criteria when summarizing the work of 

, but complains that no criteria are forthcoming as yet.

At least 2 diagnostic groups, catatonia and melancholia, are established within the medical model of diagnosis as the identification of a syndrome by symptoms, signs, and course; verified by laboratory tests; and validated by treatment response. Both syndromes have been described in 

Melancholia is a disturbance in mood characterized by depression, mania, or the combination, often of acute onset, with severe vegetative abnormalities (insomnia, anorexia, weight loss, etc) and motor disturbance (lassitude, inactivity, agitation, pacing). The condition is accompanied by a severe disturbance in cortisol metabolism that is measurable by hypercortisolemia and abnormal suppression of cortisol synthesis with corticosteroids (eg, the dexamethasone suppression test), which verifies the psychiatric diagnosis.

Remarkably, the manifestations of melancholia respond to adequate treatment with tricyclic antidepressants (TCAs) and, when these fail, to electroconvulsive therapy (ECT). Validation by treatment response is a feature of the medical model and is clearly applicable to this psychiatric illness. Indeed, rates of remission of melancholic depression treated with ECT exceed 85%-life-saving identification that justifies the classification of melancholia as an independent syndrome.

-identified depressive subtypes, such as psychotic depression, abnormal bereavement, and puerperal depression, fulfill the criteria for a diagnosis of melancholia. The incidence of vegetative signs, abnormal cortisol metabolism, and response to TCAs and ECT clearly place these subtypes within the category of melancholia.

The second formulation of a definable disorder that meets the medical model of diagnosis is catatonia.

 The inclusion of catatonia by Kraepelin and Bleuler as a type of schizophrenia was an error of heroic proportions; it was sustained in 

 despite extensive contrary evidence. Catatonia is a motor dysregulation syndrome that is associated with mental changes, and it has roots in mood, seizure, medical, and toxic disorders. It is only rarely a type of schizophrenia. (Indeed, the present 

 equation that catatonia is schizophrenia that must be treated with antipsychotic drugs and not with benzodiazepines and ECT has done a gross disservice to many patients described in case reports cited in the literature.)

Catatonia is identified by the presence of 2 or more motor abnormalities (mutism, negativism, posturing, rigidity, stereotypy, staring, etc) for 24 hours or longer. Its diagnosis is verified by the rapid response to intravenous lorazepam and is validated by symptom remission with either high doses of lorazepam or ECT. Catatonia is recognized in a malignant form and as the neuroleptic malignant and toxic serotonin syndromes. Self-injurious behavior is a feature of autism spectrum disorders and mental retardation that responds to treatment for catatonia. The stereotypies of Tourette syndrome and obsessive-compulsive disorder are best explored as catatonia.

A small nudge to understanding catatonia as a distinct syndrome was made in 

 by the inclusion of the category of 293.89-catatonia secondary to a medical disorder. A more important delineation of catatonia as a syndrome of its own, similar to delirium and dementia in the present classifications, is a full step forward in the dream envisioned by Frances and First in their hopes for the future after 

While these formulations of melancholia and catatonia are small steps in the development of a verifiable and medical classification, they warrant consideration in 

. Separation of melancholia from non-melancholic mood disorders will do much to improve diagnosis, treatment, and the inadequacies of large clinical trials (eg, STAR*D, STEP-BD) that seem unable to define the application and efficacy of some highly touted medication treatments.

Michael First’s call for applying the medical model to 

 categorization is to be applauded, and these 2 syndromes are well-documented starting points.

Fink M. Catatonia and NMS: Recognition and treatment. 

Fink M. Catatonia in adolescents and children. 

 Fink M. Should the diagnosis of melancholia be revived? 

Melancholia: The Diagnosis, Pathophysiology and Treatment of Depressive Illness.

 New York: Cambridge University Press; 2006.


Catatonia: A Clinician’s Guide to Diagnosis and Treatment.

 New York: Cambridge University Press; 2003.

In “Changes in Psychiatric Diagnosis” (Psychiatric Times, November 2008, page 14) Michael First relates the sad fact that the reorganization of DSM is still without formal guidelines and continues to be subject to the vicissitudes of groupthink and vocal constituencies. He relates that he and Allen Frances envisioned the application of biologically based diagnostic criteria when summarizing the work of DSM-IV, but complains that no criteria are forthcoming as yet.

DSM-V: Applying the Medical Model

Evidence-based medicine (EBM) is rapidly becoming the norm. It is taught in medical schools and is encouraged by both government agencies and insurance plan providers. Yet, there is little proof that this model can be adapted to fit psychiatry.

EBM supposedly allows the clinician to offer the most effective treatment for each patient.

 This goal is laudable, but the model is not appropriate for psychiatry because precise and stable diagnostic criteria are lacking in our specialty. Treatment outcomes in psychiatry are not defined by remission or cure. Instead, fractional reductions in the number and severity of symptoms are accepted, as measured by rating scale scores. Evidence-based psychiatry (EBP) is an untested hypothesis; for this theory to be either useful or valid, 3 basic assumptions must be examined.

• Is the diagnostic system valid?
• Are the data from clinical trials assessing efficacy and safety sound?
• Are the conclusions in a form that can be applied in clinical practice?




The paradigms that define EBM (and EBP) are based on data in published clinical studies. Each study is assessed according to the methods used to collect the data and a value placed (by the reviewer) on its quality. EBM uses 3 types of evidence

 Randomized clinical trials, homogeneous populations, placebo-controlled.


 Randomized clinical trials, heterogeneous populations, not placebo-controlled.


 Observational studies, case collections, open clinical trials.

The strength of the evidence decreases from Grade A to Grade C, with more weight given to Grade A than to Grade C studies.



 represents diagnostic groupings developed through discussion and consultation. These groupings are not based on experimental evidence. The manner in which the 

 creates diagnoses assumes that psychiatric illnesses can be divided into separate categories and that each illness is unique. The process is circular. It begins by assuming that discrete categories exist and produces a document that divides psychiatric illness into discrete categories.

The illnesses in the 

 are delineated by phenotypic features, with a contribution from the patient's recall of the course of the illness. The separation of classes based on these criteria is, by its nature, imprecise. Although these criteria are intended to separate clinical entities, their descriptions are overlapping. The judgments introduced by the clinician's need to decide which of several conditions best meets the diagnostic criteria are subjective, putting the system in doubt. It is not surprising that overlaps are common.



 classification divides psychiatric diseases into discrete entities based on cross-sectional symptoms and signs. These disorders exist as syndromes and not as specific illnesses. Psychosis, for example, may result from drug toxicity, neurological illness, trauma, or as a feature of delusional depression and isolated delusional states. The genetic predispositions for schizophrenia and affective illness overlap.

 has demonstrated that most patients have characteristics of both groups and that our diagnostic concepts are based on the extremes of what is better visualized as a continuum.

EBP relies on categories that call for specified algorithms for treatment.

 However, in clinical practice the emphasis is not on treating syndromes or diseases but on applying empirically derived prescriptions for symptoms and symptom complexes. Psychiatry lacks antischizophrenia, antidepression, or antianxiety disorder medications. What exist are medications that symptomatically treat psychosis, depressed mood, and anxiety. The severity and associations of the symptoms vary greatly depending on genetic traits, environmental influences, and duration. The genetic traits are particularly subtle; the substitution of a single nucleic acid markedly alters symptoms.

 Variations in genetic polymorphism influence phenotypic presentations of illnesses over a spectrum of clinical syndromes. It is difficult to reconcile these observations with the current diagnostic system's separation of these conditions into distinct categories and subcategories.

Several conditions exhibit such high rates of comorbidity that one must be skeptical of the idea that we are dealing with discrete entities. The overlap between attention-deficit disorder (ADD), oppositional defiant disorder, and conduct disorder is an example.

 Separating these syndromes into distinct entities obscures the possibility that they may be expressions of a single genotype. This is also the case with obsessive-compulsive disorder (OCD), generalized anxiety disorder, panic disorder, and major depressive disorder, in which patients may display symptoms of each condition, with the dominant symptom changing with time and circumstance.



This relationship frequently causes problems when the nosological diagnosis obscures the possibility of a common biological substrate. A common example of this occurs in patients with OCD in whom manic symp- toms develop when they are taking antidepressants.



If a nosological approach were reliable, we would expect greater homogeneity in treatment response. That is, if depressive mood disorders were a single entity, we would expect that a single treatment agent would be effective in all or almost all patients who receive this diagnosis. Such uniformity of diagnosis and treatment response is expected, for example, in bacterial infections and in diabetes. However, this is not the case in psychiatric disorders. Lacking effective predictors or tests, the clinician searches for clues for treatment selection in personal and family history or engages in multiple drug trials, augmentation strategies, and polypharmacy.

Syndromes that are separated by 

Evidence-based medicine (EBM) is rapidly becoming the norm. It is taught in medical schools and is encouraged by both government agencies and insurance plan providers. Yet, there is little proof that this model can be adapted to fit psychiatry.

Author | Max Fink, MD

Articles

New content coming soon, please check back later.