Mayo Clin Proc, June 2002, Vol 77 Treatment of Medication-Refractory Mental Illness 553 Figure 1. Bitemporal electrode placement (left), unilateral el

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1 552 Concise Review for Clinicians Electroconvulsive Therapy and Newer Modalities for the Treatment of Medication-Refractory Mental Illness KEITH G. RASMUSSEN, MD; SHIRLENE M. SAMPSON, MD; AND TERESA A. RUMMANS, MD Severe mental illnesses often remain chronic and refractory to medication, leading to substantial morbidity and mortality. For more than 60 years, electroconvulsive therapy has been the only nonpharmacological psychiatric procedure available to treat severe or medication-refractory major depressive disorder and other psychiatric conditions. Memory dysfunction remains the most serious adverse effect, and current research focuses on attempts to ameliorate this complication. Transcranial magnetic stimulation and vagus nerve stimulation, 2 new neuropsy- chiatric technologies, are emerging as possible additions to our therapeutic armamentarium. Besides providing therapeutic benefits, these 3 methods may help elucidate the pathophysiology of psychiatric illness. Mayo Clin Proc. 2002;77: ECT = electroconvulsive therapy; EEG = electroencephalogram; TMS = transcranial magnetic stimulation; VNS = vagus nerve stimulation The use of chemically induced seizures for treatment of mental disorders is documented in various reports dating back centuries. 1 The first systematic descriptions of convulsive therapy were provided in 1934 by Ladislaus von Meduna, who used injections of camphor liniment to induce seizures in patients with schizophrenia, many of whom responded dramatically. 1 His technique was quickly recognized for its value in psychiatric therapeutics and was adopted worldwide within a few years of its introduction. Other chemicals, such as pentylenetetrazol, were also used to induce seizures. This pharmacoconvulsive therapy, although beneficial, was fraught with problems, such as unreliable induction of seizures, and was frightening to patients. Thus, when Cerletti and Bini introduced the technique of electrically induced seizures in 1938, it was welcomed and quickly became the preferred method. 1 ELECTROCONVULSIVE THERAPY Methods The fundamental principle of electroconvulsive therapy (ECT) is the application of an electrical current through electrodes applied to the patient s head to induce a seizure. The patient is first anesthetized with a short-acting intravenous agent, usually methohexital or another barbiturate. From the Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minn. A question-and-answer section appears at the end of this article. Individual reprints of this article are not available. Address correspondence to Keith G. Rasmussen, MD, Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN ( rasmussen.keith@mayo.edu). Next, muscular paralysis is achieved with use of succinylcholine to block the strong muscular contractions that ordinarily would occur in a generalized tonic-clonic seizure. Oxygen is administered via positive pressure ventilation; intubation is not routinely used in ECT. The electrocardiogram, pulse oximetry, and vital signs are monitored continuously throughout the procedure. After anesthesia and muscular paralysis are achieved, the 2 treatment (or stimulus) electrodes, which are about the size of a silver dollar, are applied to the patient s head. They are connected to the ECT machine via cables. When the treatment button on the machine is pressed, a series of brief pulses of electrical current is passed through the stimulus electrodes into the brain, causing a generalized seizure. The amount of electricity needed to induce a seizure varies considerably from patient to patient. Modern ECT machines are equipped so that the electrical stimulus is quantified precisely. At the first treatment session, a small amount, or dose, of electricity is applied. If no seizure ensues within 20 seconds or so, a larger dose is applied. This stepwise progression of successively increasing doses of electricity is continued until a seizure occurs. This method of titrating the electrical dose ensures that each patient receives the appropriate amount of electrical charge. After the electrical stimulus is passed, the resultant seizure is detectable by inspection of the continuously displayed electroencephalogram (EEG), equipped on all modern ECT machines. A second method for confirming the presence of the seizure is to observe the convulsive movements in a limb with a blood pressure cuff (either on the forearm or the calf) inflated well above systolic pressure Mayo Clin Proc. 2002;77: Mayo Foundation for Medical Education and Research

2 Mayo Clin Proc, June 2002, Vol 77 Treatment of Medication-Refractory Mental Illness 553 Figure 1. Bitemporal electrode placement (left), unilateral electrode placement (middle), and bifrontal electrode placement (right). before succinylcholine is injected, thus isolating the muscles distal to the cuff from the paralyzing effects of the succinylcholine. The seizure usually lasts 30 to 60 seconds. Seizure termination is confirmed by cessation of the spikeand-wave activity on the EEG and of convulsive movements in the cuffed limb. Within a few minutes thereafter, the patient breathes independently and is ready to be taken to the recovery room. Usually within half an hour, the patient is sufficiently awake and alert to go back to the hospital room or to go home if on outpatient status and accompanied by a responsible adult. The treatments are repeated 2 or 3 times per week until there is maximal clinical improvement. Typical courses of ECT are 8 to 10 treatments. After this series of treatments is completed, the patient is then treated with medication therapy or continued weekly to monthly ECT treatments for up to 6 months, a technique known as continuation ECT, to prevent relapse of the psychiatric condition. If the intermittent schedule of treatments extends beyond 6 months, it is referred to as maintenance ECT. Several aspects of the ECT technique affect efficacy and adverse effects. The most prominently studied is the site of stimulus electrode placement on the head (Figure 1). The original placement was bilateral, in which each electrode is placed on the temporal fossa on each side of the head (the so-called bitemporal position). One alternative placement currently in use is the unilateral position, in which 1 electrode is placed on the temporal fossa on the right side as in the bitemporal position, but the other electrode is placed just to the right of the vertex of the head. In this placement, the electrical current is concentrated away from the language areas on the left side of the brain, thus lessening the memory impairment that is common with ECT (see subsequent discussion). Another electrode placement, also designed to lessen ECT-induced memory impairment, is bifrontal, in which the electrodes are placed on either side of the forehead. In this placement, electrical current is concentrated away from mesial temporal lobe structures involved with memory formation. Whether the well-known therapeutic efficacy of traditional bitemporal ECT is preserved with unilateral or bifrontal ECT is unclear. A second technical factor is the dose of electrical charge used during ECT. Typical electrical doses used in ECT range from 25 to 504 mc, most of which is shunted across the scalp and does not reach the brain. The electrical dose may affect both therapeutic efficacy and cognitive adverse effects. For example, in unilateral ECT, giving a dose of electricity barely enough to induce a seizure (the seizure threshold) is associated with low therapeutic efficacy, whereas giving too much electrical charge results in excessive cognitive dysfunction. 2 Precise quantification of the electrical dose ensures that the correct amount is administered. A third technical issue in ECT concerns treatment frequency. Usually in the United States, treatment frequency is thrice weekly, but several studies have shown that twice weekly may yield equivalent therapeutic benefit (albeit more slowly) with much less cognitive impairment. 1 The choice of electrode placement, stimulus dose, and treatment frequency is individualized and depends on such factors as patient age and severity of illness. Indications Electroconvulsive therapy is the most effective treatment for major depression, with average response rates of 70% to 90% compared with about 60% to 70% for antidepressant medications. 1 It is given to patients whose condition is refractory to or who are intolerant of antidepressant medications, who are so ill (eg, suicidal, catatonically stuporous, refusing food and fluids) that the most rapid treatment is

3 554 needed, or who express preference for it based on past experience. 3 Additionally, ECT is highly effective for mania and certain cases of schizophrenia. 3 An intriguing series of reports suggests that ECT can help ameliorate the motor symptoms of Parkinson disease and various other movement disorders, such as tardive dystonia, tardive dyskinesia, and neuroleptic-induced malignant catatonia (also termed neuroleptic malignant syndrome). 1 Risks and Adverse Effects Electroconvulsive therapy is actually a safe procedure. In fact, the death rate due to treatment is approximately 1 per 10,000 patients. 1 Although ECT has no absolute contraindications, relative contraindications include presence of brain tumor with increased intracranial pressure, unstable myocardial function, and American Society of Anesthesiology risk level 4 or 5. 3 During the seizure, heart rate and blood pressure increase sharply. Thus, patients with cardiac disease, such as coronary atherosclerosis, congestive heart failure, or cardiac dysrhythmias, have a higher risk of cardiovascular complications. Therefore, any patient with suspected unstable or untreated cardiac illness should undergo evaluation before ECT. Additionally, any unstable vascular malformation, such as an arteriovenous fistula or a leaky aneurysm, would be at risk of rupture during ECT. Thorough evaluation and stabilization of any existing cardiovascular condition before treatment make ECT safe even for many patients with advanced disease. For patients with a known increase in intracranial pressure, such as those with brain tumors, ECT is relatively contraindicated. 3 However, ECT has been used safely in patients with various neurologic conditions, such as dementia and epilepsy. In contrast to the rarity of medical complications associated with ECT, memory disturbance of varying severity is common and is by far the most bothersome adverse effect. Electroconvulsive therapy induced memory impairment takes 3 forms. The first is posttreatment confusion. Typically, it takes a few minutes to half an hour for a patient to become fully alert and oriented after treatment. Occasionally, especially in elderly patients receiving thrice-weekly treatment with bitemporal electrode placement, the period of posttreatment confusion persists for several hours or even days. This interictal delirium is reversible with cessation of treatment. The second type of memory impairment with ECT is anterograde amnesia. This refers to the inability to recall information learned after the treatments have begun. An example is when a patient has a conversation with somebody early in the day and then forgets it later on that day. Extensive research has documented that ECT-induced anterograde amnesia is temporary. 2 The third and most bothersome type of ECT-induced memory impairment is retrograde amnesia, forgetting things that happened before the course of treatments. An example is forgetting a movie that was seen a week before the first treatment. Events of several months before treatment are most likely forgotten. Usually, only a few events, such as conversations, are forgotten, but patients occasionally forget most of the events of this period. Additionally, patients sometimes have sporadic episodes of forgetting personal life events that happened several years before treatment. Some of the forgotten events may never be remembered. Thus, during the informed consent process, it is important to discuss this issue with patients and to monitor their memory function during the course of treatments. Mechanism of Action The precise mechanism of action of ECT is unknown. Traditional theories have been based on neurotransmitter and neuroreceptor studies in animals and probably have limited utility in extrapolation to humans. However, some of the consistent findings in the animal literature include down-regulation of postsynaptic β-receptors and up-regulation of postsynaptic serotonin type 2 receptors. 1 An intriguing finding in humans is that potent reduction of cerebral blood flow in the frontal lobes along with induced slowing of EEG frequencies in the same region correlates strongly with therapeutic outcome in ECT. 4,5 Thus, the effects of treatments on frontal lobe function, an area implicated in the pathophysiology of depressive illness, may be relevant in the mechanism of action of ECT. Current Research A particularly common problem in ECT practice is the high relapse rates of depressive illness after a successful course of treatments. 6 Standard practice is to give patients antidepressant medications after ECT. Another strategy is continuation and maintenance ECT, in which treatments are continued at spaced intervals (eg, weekly, biweekly, or monthly) for a few months or even years after the successful treatment sessions. Current research is elucidating treatment strategies to prevent relapse of depression after ECT. Another common problem is memory impairment. Current ECT research is evaluating alternative electrode placements to lessen ECT-induced cognitive adverse effects. For example, the bifrontal placement allows the electrical current to be concentrated in the frontal lobes, where clinical efficacy may be most important, but bypasses the mesial temporal lobes, areas thought to be most critical for memory impairment. An exciting area of ECT research involves the use of sophisticated brain imaging (eg, positron emission tomog-

4 Mayo Clin Proc, June 2002, Vol 77 Treatment of Medication-Refractory Mental Illness 555 raphy and single-photon emission computed tomography) and computerized EEG technology to elucidate the mechanism of action of ECT and even the neurobiological basis of depressive illness. As mentioned previously, successful courses of ECT produce sharp (although reversible) reductions of cerebral blood flow in the frontal lobes as well as induction of delta and theta EEG activity in the same region. 4,5 Additionally, computer analysis of the EEG during ECT seizures is helping to distinguish therapeutic from nontherapeutic treatments. 7 This line of inquiry should help us understand brain mechanisms in the action of ECT and may help lead to other treatment technologies. FUTURE DIRECTIONS Because ECT involves repeated administrations of general anesthesia, some risk of medical complications, and memory impairment, less invasive neuropsychiatric treatments are needed. The 2 emerging technologies that appear promising are transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS). A novel and safe method of brain stimulation first used in 1985, TMS consists of applying magnetic fields to the brain through a metal coil placed over the cranium. 8 During a typical TMS session, the patient sits comfortably awake throughout the whole procedure. It was first used clinically to stimulate the motor cortex to record electromyographic activity in certain muscle groups to test the integrity of the motor pathways, analogous to the use of evoked potentials to test the integrity of sensory pathways. Transcranial magnetic stimulation can be used to study cortical neurophysiology or as a possible therapeutic intervention for psychiatric disorders. In recent years, much excitement has developed regarding the possibility that TMS can treat depression. 8 In contrast to ECT, TMS requires no anesthesia, does not induce seizures, and does not appear to cause cognitive deficits. Studies directly comparing ECT to TMS are limited thus far but suggest comparable antidepressant efficacy. 9 At publication of this article, TMS has not been approved for the treatment of depression. Based on early work in animals showing that electrical stimulation of the vagus nerve stopped seizures in dogs, an implantable device capable of stimulating the vagus nerve in humans was developed and studied. Vagus nerve stimulation involves implantation of an electrical generator (about the size and shape of a cardiac pacemaker) into the left chest wall. This is connected to a wire, which in turn is connected to the vagus nerve in the neck. An implantable vagus nerve stimulator (NeuroCybernetic prosthesis [Cyberonics, Inc, Houston, Tex]) is now commercially available, has been approved by the Food and Drug Administration for medication-refractory partial-onset epilepsy, and has been implanted in thousands of humans. The function of the electrical generator, including modification of the intensity of electrical stimulation to the vagus, is monitored and modified by a portable wand connected to a computer and held over the generator site above the skin noninvasively. Long-term safety has been established. This stimulator has been successful in patients with refractory epilepsy and has been found to be safe and effective by the American Academy of Neurology. 10 Based on apparent antidepressant activity in epileptic patients and effects of VNS on cortical blood flow and neurochemistry that are similar to the effects of antidepressant treatments, a preliminary open trial of VNS in patients with medicationrefractory depression was undertaken, and it was found to be successful in a substantial proportion. 11 At publication of this article, the NeuroCybernetic prosthesis has not been approved by the Food and Drug Administration for the treatment of depression. CONCLUSION Despite advances in modern neuropharmacological treatment, refractory psychiatric illness is common. Electroconvulsive therapy remains the most potent modality currently available for the treatment of depressive illness as well as for mania and some psychotic disorders. It has been used worldwide for more than 6 decades and has a proven record of safety and efficacy, even in patients with advanced concurrent medical or neurologic illness. However, ECT involves the use of general anesthesia, has potent cognitive adverse effects, and is not universally effective. Thus, there is a need for newer techniques with the same excellent clinical benefits as ECT but with fewer adverse effects. Two emerging technologies, TMS and VNS, may become part of the neuropsychiatric therapeutic armamentarium. REFERENCES 1. Abrams R. Electroconvulsive Therapy. 3rd ed. New York, NY: Oxford University Press; Sackeim HA, Prudic J, Devanand DP, et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med. 1993;328: American Psychiatric Association Committee on Electroconvulsive Therapy. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging. 2nd ed. Washington, DC: American Psychiatric Association; Nobler MS, Sackeim HA, Solomou M, Luber B, Devanand DP, Prudic J. EEG manifestations during ECT: effects of electrode placement and stimulus intensity. Biol Psychiatry. 1993;34: Nobler MS, Sackeim HA, Prohovnik I, et al. Regional cerebral blood flow in mood disorders, III: treatment and clinical response. Arch Gen Psychiatry. 1994;51: Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285:

5 Krystal AD, Holsinger J, Weiner RD, Coffey CE. Prediction of the utility of a switch from unilateral to bilateral ECT in the elderly using treatment 2 ictal EEG indices. J ECT. 2000;16: George MS, Lisanby SH, Sackeim HA. Transcranial magnetic stimulation: applications in neuropsychiatry. Arch Gen Psychiatry. 1999;56: Grunhaus L, Dannon PN, Schreiber S, et al. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Biol Psychiatry. 2000;47: Fisher RS, Handforth A. Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1999;53: George MS, Sackeim HA, Marangell LB, et al. Vagus nerve stimulation: a potential therapy for resistant depression? Psychiatr Clin North Am. 2000;23: Questions About Treatment of Medication-Refractory Mental Illness 1. Which one of the following most likely indicates further medical investigation before clearance for ECT? a. Patient complains of sore throat b. Electrocardiogram shows nonspecific T-wave abnormalities c. Patient complains of exertional chest tightness d. Patient has mildly elevated liver function test results e. Patient has long-standing headaches 2. Which one of the following most appropriately indicates referral for ECT? a. Patient with poorly compensated congestive heart failure who is depressed but still functional at work b. Patient with Parkinson disease whose depression is refractory to 2 medication trials and who is becoming increasingly suicidal c. Epileptic patient with pronounced anxiety d. Agitated patient with Alzheimer disease e. Patient with obsessive-compulsive disorder that is highly refractory to medication and who has poorly controlled hypertension 3. Which one of the following is not true regarding the memory disturbances caused by ECT? a. Immediate posttreatment confusion usually clears within a few hours b. Anterograde amnesia is reversible c. Patient forgets something that happened a few weeks before treatments were initiated d. Retrograde amnesia can be permanent e. Modification of electrode placements and electrical doses probably has no bearing on memory disturbance 4. Which one of the following is true about TMS? a. Involves general anesthesia b. Causes about the same memory impairment as ECT c. Was first used clinically to test integrity of motor pathways d. Is commonly used for depression in clinical care e. Is commonly used to elicit seizures 5. Which one of the following is true regarding VNS? a. Is approved for use in refractory partial-onset epilepsy b. Has been shown to be superior to ECT in clinical trials c. Has been shown to have the greatest efficacy for anxiety disorders d. Involves electrical stimulation of vagal efferents as the intended mechanism e. Rarely causes hoarseness Correct answers: 1. c, 2. b, 3. e, 4. c, 5. a