Electroconvulsive Therapy

Number: 0445

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses electroconvulsive therapy.

  1. Medical Necessity

    Aetna considers electroconvulsive therapy (ECT) medically necessary for members diagnosed with any of the following conditions:

    1. Catatonia; or
    2. Certain acute schizophrenic exacerbations; or
    3. Major depressive disorder (unipolar disorder); or
    4. Bipolar disorder; or
    5. Mania.

    Note: More than 20 sessions of ECT in a treatment series is rarely medically necessary to achieve remission; however additional, less frequent sessions may continue as prophylaxis, sometimes indefinitely.

  2. Experimental and Investigational

    Aetna considers the following interventions experimental and investigational because the effectiveness of these approaches has not been established:

    1. Multiple monitored ECT; 
    2. Ultrabrief bilateral ECT;
    3. Adjunctive ketamine in ECT;
    4. ECT for the treatment of the following indications (not an all-inclusive list):

      1. Addictive disorders (e.g., methamphetamine dependence)
      2. Autism spectrum disorders
      3. Autoimmune encephalitis (e.g., anti-N-methyl-D-aspartate (NMDA) receptor encephalitis)
      4. Body dysmorphic disorder
      5. Complex regional pain syndrome
      6. Delirium
      7. Dementia-associated agitation and aggression
      8. Drug-resistant epilepsy
      9. Eating disorders
      10. Lennox-Gastaut syndrome
      11. Motor symptoms associated with Parkinson’s disease
      12. Neuropsychiatric complications of COVID-19
      13. Obsessive-compulsive disorder
      14. Post-traumatic stress disorder
      15. Refractory status epilepticus
      16. Self-injurious behaviors
      17. Somatic symptom disorder
      18. Tardive dyskinesias/tardive syndromes
      19. Tourette syndrome (tic disorders)
      20. Treatment-resistant schizophrenia;
    5. Functional magnetic resonance imaging (MRI) of fronto-temporal connectivity for prediction of ECT outcome in major depression;
    6. Measurement of plasma brain-derived neurotrophic factor (BDNF) as an indicator of treatment response following ECT;
    7. The use of ketamine, liothyronine, melatonin, opioid receptor agonists, piracetam, and prophylactic cognitive enhancers (e.g., cholinesterase inhibitors and memantine) for improvement of cognitive function in persons undergoing ECT;
    8. The use of electroencephalography (EEG) for predicting clinical response to ECT in individuals with major depression.

  3. Related Policies 

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

CPT codes covered if selection criteria are met:
00104 Anesthesia for electroconvulsive therapy
90870 Electroconvulsive therapy (includes necessary monitoring) [not covered for ultrabrief bilateral electroconvulsive therapy]

CPT codes not covered for indications listed in the CPB:
70554 Magnetic resonance imaging, brain, functional MRI; including test selection and administration of repetitive body part movement and/or visual stimulation, not requiring physician or psychologist administration
70555 Magnetic resonance imaging, brain, functional MRI; requiring physician or psychologist administration of entire neurofunctional testing

ICD-10 codes covered if selection criteria are met:
F06.1 Catatonic disorder due to known physiological condition
F20.0 - F20.9 Schizophrenia [covered for acute exacerbations only]
F25.0 – F25.9 Schizoaffective disorder
F30.10 - F30.9 Manic episode
F31.0 - F31.9 Bipolar disorder
F32.0 - F33.9 Major depressive disorder
F34.1 Dysthymic disorder

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
F01.50 - F03.C4 Dementia
F06.70 - F06.71 Mild neurocognitive disorder due to known physiological condition
F10.10 - F19.99 Mental and behavioral disorders due to psychoactive substance use [addictive disorders]
F40.00 - F48.9 Anxiety, dissociative, stress-related, somatoform and other non-psychotic disorders
F50.00 - F50.9 Eating disorders
F60.0 - F60.9 Specific personality disorders
F84.0 - F84.9 Pervasive developmental disorders
F95.0 - F95.9 Tic disorder
G04.81 Other encephalitis and encephalomyelitis [autoimmune encephalitis (e.g., anti-N-methyl-D-aspartate (NMDA) receptor encephalitis)]
G20 Parkinson's disease
G24.01 Drug induced subacute dyskinesia
G24.4 Idiopathic orofacial dystonia
G40.001 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, with status epilepticus [refractory]
G40.011 Localization-related (focal) (partial) idiopathic epilepsy and epileptic onset, intractable, with status epilepticus [refractory]
G40.101 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, with status epilepticus [refractory]
G40.111 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, with status epilepticus [refractory]
G40.210 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, with status epilepticus [refractory]
G40.211 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, with status epilepticus [refractory]
G40.301 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus [refractory]
G40.311 Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status epilepticus [refractory]
G40.A01, G40.A11 Absence epileptic syndrome, not intractable/intractable, with status epilepticus [refractory]
G40.B01, G40.B11 Juvenile myoclonic epilepsy, not intractable/intractable, with status epilepticus [refractory]
G40.401 Other generalized epilepsy and epileptic syndromes, not intractable, with status epilepticus [refractory]
G40.411 Other generalized epilepsy and epileptic syndromes, intractable, with status epilepticus [refractory]
G40.501 Epileptic seizures related to external causes, not intractable, with status epilepticus [refractory]
G40.801, G40.803 Other epilepsy, not intractable/intractable, with status epilepticus [refractory]
G40.811 - G40.814 Lennox-Gastaut syndrome, not intractable/intractable, with status epilepticus [refractory]
G40.821, G40.823 Epileptic spasms, not intractable/intractable, with status epilepticus [refractory]
G40.901, G40.911 Epilepsy, unspecified, not intractable/intractable, with status epilepticus [refractory]
G90.50 - G90.59 Complex regional pain syndrome I (CRPS I)
Numerous options Alcohol and drug, abuse, dependence and use [Codes not listed due to expanded specificity]
R25.0 - R25.9 Abnormal involuntary movements
R41.0 Disorientation, unspecified
U07.1 COVID-19 [neuropsychiatric complications of COVID-19]
Z91.51 - Z91.52 Personal history of self-harm

Background

Electroconvulsive therapy (ECT, also known as electroshock therapy) involves the intentional induction of generalized seizures by administering electrical impulses to the anesthetized patient.  Treatments are typically administered by a psychiatrist and an anesthesiologist or anesthetist.

Electroconvulsive therapy is generally administered in an inpatient setting, but can be administered on an outpatient basis in a facility with treatment and recovery rooms.  It is usually administered 2 or 3 times a week, although ECT may be administered daily if tolerated.

The primary indication for ECT is major depressive disorder.  Electroconvulsive therapy is usually considered when medications fail, can not be tolerated, or may be dangerous, but it is a first-line treatment for severely depressed patients who require a rapid response because of a high suicide or homicide risk, extreme agitation, life-threatening inanition, psychosis, or stupor.  The average course of treatment for depression is 6 to 12 treatments, but some patients may require as many as 20 treatments.

Electroconvulsive therapy has been found to be as or more effective than lithium in the treatment of manic episodes and is also a potential treatment for patients experiencing mixed episodes.  It is generally reserved for those patients with bipolar disorder who are unable to safely wait until a medication becomes effective, who are not responsive to or unable to safely tolerate one of the effective medications, is preferred by the patient in consultation with the psychiatrist, or who have had a good response to ECT in the past.  The number of ECT treatments reported to be effective for mania has ranged from 8 to 20.

Electroconvulsive therapy is not effective for chronic schizophrenia.  However, ECT may be effective for psychotic schizophrenic exacerbations when affective symptomatology is prominent, in catatonic schizophrenia, and when there is a history of a prior favorable response to ECT.  Schizophrenia may require 17 or more ECT treatments.

A small number of ECT treatments often reverse catatonia, a nonspecific symptom that can occur in mood disorders, schizophrenia, cognitive disorders, and medical and neurological illnesses.  Up to 12 treatments may be required in some patients.

There is very limited evidence that ECT is effective for delirium.  In addition, there may be considerable risks with ECT in medically unstable patients.  For these reasons, the American Psychiatric Association (APA) (1999) concluded that ECT “has not been shown to be an effective treatment for general cases of delirium.”  The APA recommends that ECT be “considered only rarely for patients with delirium due to specific etiologies such as neuroleptic malignant syndrome and should not be considered initially as a substitute for more conservative and conventional treatments.”

A few clinicians have reported the successful use of ECT in severe obsessive-compulsive disorder (OCD), anorexia nervosa, atypical psychosis, cycloid psychosis, epilepsy with alternating psychosis, and chronic pain disorder, but those disorders are not usually considered indications for ECT.  Electroconvulsive therapy is not an effective treatment for body dysmorphic disoder, dysthymic disorder, neuroses, dissociative disorders, hypochondriasis, conversion disorder, substance-related disorders, and personality disorders.  Dell'Osso and colleagues (2005) noted that in addition to pharmacological, behavioral, and neurosurgical interventions, different brain stimulation methods such as transcranial magnetic stimulation, deep brain stimulation, as well as ECT have been examined in treatment-resistant patients with OCD.  However, available data about the use of these techniques in OCD treatment are quite limited in terms of sample size and study design, given the difficulty in conducting standard blinded trials for these procedures.  Furthermore, none of the mentioned treatments has received approval for the treatment of OCD from the Food and Drug Administration.  This is in agreement with the observation of Schruers et al (2005) who stated that serotonin reuptake inhibitors augmentation strategies with a variety of drugs and ECT have demonstrated results in individual cases, but no conclusive evidence has been found in placebo-controlled trials.  In addition, the National Institute for Health and Clinical Excellence (NICE, 2006) guidelines on OCD stated that there is insufficient evidence on which to base a recommendation for the use of ECT in the treatment of OCD, especially given potential associated risks with ECT.  Furthermore, the NICE report stated that there is no evidence that ECT or psychosurgery is beneficial in treating patients with body dysmorphic disorder.

Clinical experience suggests that ECT be continued until the patient has shown a maximal response; there is no evidence that administering 1 or 2 additional treatments results in a better outcome.  Indeed, increased confusion from additional treatments may produce clinical deterioration.  Electroconvulsive therapy is discontinued in patients who have had a partial but substantial improvement but show no change after 2 more treatments and in patients who have not responded at all after 6 to 10 treatments.

Prophylactic ECT may be needed for patients who do not tolerate or respond to prophylactic medications or who respond better to ECT.  After remission, prophylactic ECT treatments are initially administered at weekly intervals, and the frequency of treatments is usually decreased gradually to once a month or less.  Treatment has been continued for periods of 4 or 6 months to five years or longer; some patients apparently require indefinite prophylactic ECT.

Relative contraindications to ECT include space-occupying lesions of the brain, high intracranial pressure, intracerebral bleeding, recent myocardial infarction, retinal detachment, pheochromocytoma, high anesthesia risk, adolescents and children, or a significant medical illness in which risk outweighs potential benefit.

In multiple monitored electroconvulsive therapy (MMECT), a patient undergoes ECT in the usual manner, but before regaining consciousness, undergoes another session of ECT designed to elicit a second (or additional) seizure.  The effectiveness of MMECT has not been established.  The National Institutes of Health 1985 Consensus Development Conference Statement on ECT states that “Multiple monitored ECT (several seizures during a single treatment session) has not been demonstrated to be sufficiently effective to be recommended…”.

Oudman (2012) noted that depression is one of the most frequently diagnosed psychiatric disorders in patients with dementia with a prevalence of up to 50 %.  The detrimental effects of depression in dementia include disability in daily living, worse quality of life, and faster cognitive decline.  Although ECT is a well-established and effective treatment for depression in the elderly, it is currently an over-looked treatment option in the elderly with dementia and depression.  The aim of this review was to provide a critical analysis of the safety and effectiveness of ECT in depression super-imposed on dementia by reviewing the current literature on this topic.  Current evidence suggests that ECT is an effective treatment for depression in dementia, although the relatively small number of controlled studies hampers the comparison of effectiveness between healthy non-geriatric patients and those with dementia.  Moreover, the systematic reports on cognitive side effects are very limited in number and currently only apply to moderately mild or mild dementia of non-vascular origin.  Some studies do suggest that cognitive side effects are likely in later stages of dementia and in patients with vascular dementia.  The author concluded that it is therefore of crucial relevance to prospectively study effects of ECT in different types and phases of dementia in controlled trials.

Loo and colleagues (2012) noted that the effect of shortening the pulse width of the electrical stimulus when administering ECT has recently been systematically studied with promising results.  These investigators examined outcomes from 3 randomized controlled trials that compared ultrabrief (less than or equal to 0.3 ms) with brief (0.5 to 1.5 ms) pulse width ECT, and other recent clinical trials of ultrabrief pulse width ECT.  The emerging evidence for ultrabrief pulse right unilateral (RUL) ECT suggested clinically meaningful efficacy and substantially reduced neuropsychological side effects compared with standard (brief) pulse ECT; this may represent a generational advance in the ECT technique.  However, it is unclear if patients receiving ultrabrief pulse RUL ECT may have a slower speed of response and require additional treatments compared with brief pulse ECT.  Therefore, until further data are available, clinicians may be well advised to use brief pulse ECT in situations requiring an urgent clinical response.  The authors concluded that the evidence base for ultrabrief bilateral ECT is limited, with findings that efficacy may be reduced compared with brief pulse width ECT.  They stated that ultrabrief bilateral ECT should not be used outside the research setting.

Lima et al (2013) reviewed the recent and classical aspects regarding ECT use in adolescents.  These researchers performed a systematic review that conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.  From the 212 retrieved articles, only 39 were included in the final sample.  The reviewed studies brought indications of ECT use in adolescents, evaluated the efficiency of this therapy regarding remission, and explored the potential risks and complications of the procedure.  The authors concluded that the use of ECT in adolescents is considered a highly efficient option for treating several psychiatric disorders, achieving high remission rates, and presenting few and relatively benign adverse effects.  Risks can be mitigated by the correct use of the technique and are considered minimal when compared to the efficiency of ECT in treating psychopathologies.

Leiknes et al (2015) explored practice, use, and risk of ECT in pregnancy.  These investigators performed a systematic search using the databases Medline, Embase, PsycINFO, SveMed and CINAHL (EBSCO).  Only primary data-based studies reporting ECT undertaken during pregnancy were included.  Two reviewers independently checked study titles and abstracts according to inclusion criteria and extracted detailed use, practice, and adverse effects data from full text retrieved articles.  Studies and extracted data were sorted according to before and after year 1970, due to changes in ECT administration over time.  A total of 67 case reports were included and studies from all continents represented.  Altogether, 169 pregnant women were identified, treated during pregnancy with a mean number of 9.4 ECTs, at mean age of 29 years.  Most women received ECT during the 2nd trimester and many were Para I.  Main diagnostic indication in years 1970 to 2013 was depression/bipolar disorder (including psychotic depression).  Missing data on fetus/child was 12 %.  Electroconvulsive therapy parameter report was often sparse.  Both bilateral and unilateral electrode placement was used and thiopental was the main anesthetic agent.  Adverse events such as fetal heart rate reduction, uterine contractions, and premature labor (born between 29 and 37 gestation weeks) were reported for nearly 1/3 (29 %) of the cases.  The overall child mortality rate was 7.1 %.  Lethal outcomes for the fetus and/or baby had diverse associations.  The authors concluded that ECT during pregnancy is advised only as last resort treatment under very stringent diagnostic and clinical indications.

The American Academy of Neurology’s evidence-based guideline on “Treatment of tardive syndromes” (Bhidayasiri et al, 2013) stated that “Data are insufficient to determine the efficacy of electroconvulsive therapy for TDD [tardive dyskinesias] treatment”.

The National Collaborating Centre for Mental Health’s clinical guideline on “Bipolar disorder: The assessment and management of bipolar disorder in adults, children and young people in primary and secondary care” (NICE, 2014) recommended ECT for the treatment of severe mania that has not responded to other interventions (e.g., anti-convulsants, anti-psychotics, and lithium).

Termine et al (2013) stated that Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor/phonic tics and a wide spectrum of behavioral problems (e.g., complex tic-like symptoms, attention deficit hyperactivity disorder, and obsessive-compulsive disorder).  Tourette syndrome can be a challenging condition even for the specialists, because of the complexity of the clinical picture and the potential adverse effects of the most commonly prescribed medications.  Expert opinions and consensus guidelines on the assessment and treatment of tic disorders have recently been published in Europe and Canada.  All pharmacological treatment options are mere symptomatic treatments that alleviate, but do not cure, the tics.  There is still a lack evidence of their effects on the natural long-term course and on the prognosis of TS and how these treatments may influence the natural course of brain development.  The most commonly prescribed drugs are dopamine antagonists, such as typical (e.g., haloperidol, pimozide) and atypical neuroleptics (e.g., aripiprazole, risperidone), and alpha-2-adrenoreceptor agonists (e.g., clonidine).  However, several studies have investigated the efficacy and tolerability of alternative pharmacological agents that may be effective, including the newest atypical antipsychotic agents (e.g., paliperidone, sertindole), tetrabenazine, drugs that modulate acetylcholine (e.g., nicotine) and GABA (e.g., baclofen, levetiracetam), tetrahydrocannabinol, botulinum toxin injections, anti-convulsant drugs (e.g., carbamazepine, topiramate), naloxone, lithium, norepinephrine, steroid 5-alpha reductase, and other neuroactive agents (buspirone, metoclopramide, phytostigmine, and spiradoline mesylate).  As regards non-pharmacological interventions, some of the more recent treatments that have been studied included ECT and repetitive transcranial magnetic stimulation.  The authors noted that their review focused primarily on the safety and effectiveness of these emerging treatment strategies in TS.

Furthermore, an UpToDate review on “Tourette syndrome” (Jankovic, 2015) does not mention EXT as a therapeutic option.

Roshanaei-Moghaddam and Pauly (2014) reviewed the literature to explore whether the use of ECT for the treatment of methamphetamine dependence can be justified by scientific rationale and/or evidence.  These investigators reviewed the literature on the use of ECT in addictive disorders.  They described a patient with methamphetamine dependence treated with ECT; and then offered a historical review of the moral and ethical difficulties encountered in the treatment of addictive disorders.  These researchers proposed a dynamic understanding as to why clinicians might deploy such brutal actions in the face of hopeless and emotionally intense encounters.  They found no scientific evidence or justification for ECT as a treatment of methamphetamine dependence or as the first-line treatment for methamphetamine-induced psychiatric co-morbidities.  The authors concluded that the current available evidence does not support using ECT for the treatment of addictive disorders, and hence is unethical, unacceptable and inhumane and warrants immediate social and political attention.

Okazaki et al (2015) stated that autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders that are reportedly characterized by aberrant neural networks.  Recently developed multi-scale entropy (MSE) analysis can characterize the complexity inherent in electroencephalography (EEG) dynamics over multiple temporal scales in the dynamics of neural networks.  These researchers encountered an 18-year old man with ASD whose refractory catatonic obsessive-compulsive symptoms were improved dramatically after ECT.  In this clinical case study, these investigators attempted to clarify the neurophysiological mechanism of ECT in ASD by assessing EEG complexity using MSE analysis.  Along with ECT, the fronto-central region showed decreased EEG complexity at higher temporal scales, whereas the occipital region expressed an increase at lower temporal scales.  Furthermore, these changes were associated with clinical improvement associated with the elevation of brain-derived neurotrophic factor, which is a molecular hypothesis of ECT, playing key roles in ASD pathogenesis.  Changes in EEG complexity in a region-specific and temporal scale-specific manner that were found might reflect atypical EEG dynamics in ASD.  The authors concluded that although MSE analysis is not a direct approach to measuring neural connectivity and the results were from only a single case, they might reflect specific aberrant neural network activity and the therapeutic neurophysiological mechanism of ECT in ASD.  Well-designed studies are needed to ascertain the clinical value of ECT, if any, for the treatment of ASD.

Adjunctive Ketamine in Electroconvulsive Therapy

Fond et al (2014) stated that ketamine's effectiveness in depressive disorders has been established in several controlled trials.  These researchers determined whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in ECT for resistant depression (ECT studies).  Secondary outcomes were the duration of ketamine's effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment.  Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials (RCTs), intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale.  These investigators calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study.  They used fixed and random effects models.  Heterogeneity was assessed using the I2 statistic.  The authors included 9 non-ECT studies in their quantitative analysis (192 patients with MDD and 34 patients with bipolar depression).  Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = -0.99; 95 % CI: -1.23 to -0.75; p < 0.01).  Ketamine's efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD = -0.91; 95 % CI -1.19,-0.64; p < 0.01), in bipolar depression (SMD = -1.34; 95 % CI -1.94 to -0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in the quantitative analysis.  A total of 103 patients were diagnosed with MDD and 15 with bipolar depression.  Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = -0.56; 95 % CI: -1.10 to -0.02; p = 0.04; I2 = 52.4 %).  The duration of ketamine's effects was assessed in only 2 non-ECT studies and seemed to persist for 2 to 3 days; this result needs to be confirmed; 3 of 4 studies found significant decrease of suicidal thoughts and 1 found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine's use should remain cautious in patients with a cardiovascular history.  The authors concluded that the present meta-analysis confirmed ketamine's efficacy in depressive disorders in non-ECT studies, as well as in ECT studies.  They stated that the results of this first meta-analysis were encouraging, and further studies are needed to detail efficacy in bipolar disorders and other specific depressed populations; middle- and long-term safety and effectiveness have yet to be explored.  They also noted that extrapolation should be cautious since patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.

Naughton et al (2014)
  1. reviewed the clinical literature on low-dose ketamine as a rapid-acting anti-depressant in affective disorders,
  2. provided a critical overview of the limitations of ketamine and research attempts to overcome these,
  3. discussed the proposed mechanisms of action of ketamine, and
  4. pointed towards future research directions. 
The electronic database PubMed, Web of Science and sciencedirect were searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action.  The literature demonstrated evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in MDD, in bipolar depression and in depression with suicidal ideation.  There were mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing ECT.  Ketamine's limiting factors are the transient nature of its anti-depressant effect and concerns regarding abuse, and research efforts to overcome these were reviewed.  The authors concluded that current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmitter system to learn more about the pathophysiology of depression and develop more specific rapid-acting anti-depressant treatments.

McGirr et al (2015) noted that ECT remains one of the most effective tools in the psychiatric treatment armamentarium, particularly for refractory depression.  Yet, there remains a subset of patients who do not respond to ECT or for whom clinically adequate seizures cannot be elicited, for whom ketamine has emerged as a putative augmentation agent.  These investigators searched EMBASE, PsycINFO, CENTRAL, and MEDLINE from 1962 to April 2014 to identify RCTs evaluating ketamine in ECT.  Clinical remission, response, and change in depressive symptom scores were extracted by 2 independent raters.  Adverse events were recorded.  Drop-outs were assessed as a proxy for acceptability.  Meta-analyses employed a random effects model.  Data were synthesized from 5 RCTs, representing a total of 182 patients with major depressive episodes (n = 165 MDD, n = 17 bipolar disorder).  Electroconvulsive therapy with ketamine augmentation was not associated with higher rates of clinical remission (Risk Difference (RD) = 0.00; 95 % CI: -0.08 to 0.10), response (RD = -0.01; 95 % CI: -0.11 to 0.08), or improvements in depressive symptoms (SMD = 0.38; 95 % CI: -0.41 to 1.17).  Ketamine augmentation was associated with higher rates of confusion/disorientation/prolonged delirium (odds ratio [OR] = 6.59, 95 % CI: 1.28 to 33.82, number needed to harm [NNH] = 3), but not agitation, hypertension or affective switches.  The authors concluded that the findings of this meta-analysis of RCTs of ketamine augmentation in the ECT setting suggested a lack of clinical effectiveness, and an increased likelihood of confusion.  Individuals for whom adequate seizures or therapeutic response cannot be obtained have not been studied using randomized controlled designs.  They stated that additional research needed to address the role of ketamine in this population.

Erdil et al (2015) evaluated the effects of a sub-anesthetic dose of ketamine, which was administered as an adjunct to sevoflurane, on duration of seizure activity, hemodynamic profile, and recovery times during ECT in patients with major depression.  Patients were randomly allocated to a group receiving either sevoflurane-ketamine (group SK) or sevoflurane-saline (group SS).  Sevoflurane was initiated in both groups at 8 % for anesthesia induction until loss of consciousness was achieved, at which point it was discontinued.  After loss of consciousness, ketamine was administered to the group SK in the form of a 0.5 mg/kg intravenous bolus; patients in the group SS received saline in the same manner.  Mean arterial pressure (MAP) and heart rate were recorded before anesthetic induction (T1); after anesthetic induction (T2); as well as 0, 1, 3, and 10 minutes after the seizure had ended (T3, T4, T5, and T6, respectively).  Motor and EEG seizure durations were recorded.  Motor and EEG seizure durations in the group SS were similar to those observed for the group SK.  The heart rate increased significantly during T2 to T6 in both group SS and group SK compared with the baseline.  The MAP increased in the group SS during the period between T3 and T6 as well as in the group SK during the same period compared with the baseline.  The MAP increased more in the group SK, in comparison with the group SS, during T2 (p < 0.05).  The authors concluded that the addition of ketamine at sub-anesthetic doses, for the purposes of anesthetic induction with sevoflurane, yielded results similar to those in the control group in terms of both seizure duration and hemodynamic stability.

Furthermore, an UpToDate review on “Overview of electroconvulsive therapy (ECT) for adults” (Kellner, 2015) does not mention ketamine as an adjunctive therapy.

Fernie and colleagues (2017) stated that ketamine has recently become an agent of interest as an acute treatment for severe depression and as the anesthetic for ECT.  Subanesthetic doses result in an acute reduction in depression severity while evidence is equivocal for this antidepressant effect with anesthetic or adjuvant doses.  Recent systematic reviews call for high-quality evidence from further RCTs.  To establish if ketamine as the anesthetic for ECT results in fewer ECT treatments, improvements in depression severity ratings and less memory impairment than the standard anesthetic, a double-blind, parallel-design, RCT of intravenous ketamine (up to 2 mg/kg) with an active comparator, intravenous propofol (up to 2.5 mg/kg), as the anesthetic for ECT in patients receiving ECT for major depression on an informal basis was carried out.  No significant differences were found on any outcome measure during, at the end of or 1 month following the ECT course.  The authors concluded that ketamine as an anesthetic did not enhance the effectiveness of ECT.

Refractory Status Epilepticus

In a systematic review, Zeiler and associates (2016) examined the literature on the use of ECT for refractory status epilepticus (RSE). Articles from MEDLINE, BIOSIS, EMBASE, Healthstar, Global Health, Scopus, Cochrane Library, the International Clinical Trials Registry Platform, clinicaltrials.gov (inception to August 2015), reference lists of relevant articles, and gray literature were searched.  The strength of evidence was adjudicated using both the Oxford and GRADE methodology by 2 independent reviewers.  These researchers identified 14 original articles with a total of 19 patients receiving ECT for RSE.  Of the 19 patients, 15 were adult, and 4 were pediatric.  All studies were retrospective in nature.  Seizure reduction/control with the application of ECT occurred in 11 of the 19 patients (57.9 %), with 4 (21.0 %) and 7 (36.8 %) displaying partial and complete responses, respectively.  Seizures control lasted for variable duration, with the most commonly quoted duration ranging from 2 weeks to 3 months.  Data on patient functional outcome was available in 13 patients, with 10 patients falling into the categories of dead or severely disabled.  All studies were an Oxford level 4, GRADE D level of evidence.  The authors concluded that Oxford level 4, GRADE D evidence exists to suggest an improvement in seizure control with ECT application for RSE.  However, they stated that routine use of ECT cannot be recommended at this time; further prospective study of this therapy is needed in order to determine its effectiveness in this setting.

Treatment-Resistant Schizophrenia

In a systematic review and meta-analysis, Wang and co-workers (2015) assessed the safety and effectiveness of the combined treatment of anti-psychotic medications and ECT for refractory schizophrenia. English and Chinese databases were searched for studies published prior to May 20, 2015 regarding the safety and effectiveness of the combined treatment of refractory schizophrenia with anti-psychotic medications and ECT.  Two researchers selected and evaluated studies independently using pre-defined criteria.  Review Manager 5.3 software was used for data analysis.  A total of 22 RCTs, 18 of which were conducted in mainland China, were included in the analysis.  Meta-analysis of data from 18 of the 22 studies with a pooled sample of 1,394 individuals found that compared to treatment with anti-psychotic medications alone, combined treatment with anti-psychotic medications and ECT had significantly higher rates of achieving study-specific criteria of “clinical improvement” (relative risk [RR] = 1.25, 95 % CI: 1.14 to 1.37).  Based on the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria, the quality of evidence for this assessment of effectiveness was “moderate".  However, the proportion of participants who experienced headache during the treatment was significantly higher in the combined treatment group (RR = 9.10, 95 % CI: 3.97 to 20.86, based on a pooled sample of 517 from 8 studies) and the proportion who experienced memory impairment was also higher in the combined treatment group (RR = 6.48, 95 % CI: 3.54 to 11.87, based on a pooled sample of 577 from 7 studies).  The quality of evidence about these adverse events was rated as “very low”.  The authors concluded that there are very few high quality RCTs regarding the combination of anti-psychotic medications and ECT in the treatment of refractory schizophrenia.  This meta-analysis found that the combination of anti-psychotic medications and ECT could improve psychiatric symptoms in patients with refractory schizophrenia, but the incomplete methodological information provided for most of the studies, publication bias (favoring studies with better outcomes in the combined treatment group), and the low quality of evidence about adverse outcomes, cognitive impairment, and overall functioning raised questions about the validity of the results.

In a systematic review and meta-analysis, Lally and colleagues (2016) evaluated the proportion of patients with treatment-resistant schizophrenia (TRS) that respond to ECT augmentation of clozapine (C+ECT). These investigators searched major electronic databases from 1980 to July 2015.  They conducted a random effects meta-analysis reporting the proportion of responders to C+ECT in RCTs and open-label trials.  A total of 5 clinical trials met the eligibility criteria, allowing data from 71 people with TRS who underwent C+ ECT across 4 open label trials (n = 32) and 1 RCT (n = 39) to be pooled.  The overall pooled proportion of response to C+ECT was 54 %, (95 % CI: 21.8 to 83.6 %) with some heterogeneity evident (I(2) = 69 %).  With data from retrospective chart reviews, case series and case reports, 192 people treated with C+ECT were included.  All studies together demonstrated an overall response to C+ECT of 66 % (95 % CI: 57.5 to 74.3 %) (83 out of 126 patients responded to C+ECT).  The mean number of ECT treatments used to augment clozapine was 11.3; and 32 % of cases (20 out of 62 patients) with follow-up data (range of follow up: 3 to 468 weeks) relapsed following cessation of ECT.  Adverse events were reported in 14 % of identified cases (24 out of 166 patients).  There is a paucity of controlled studies in the literature, with only 1 single-blinded RCT located, and the predominance of open label trials used in the meta-analysis is a limitation.  The authors concluded that these findings suggested that ECT may be a safe and effective clozapine-augmentation strategy in TRS.  Moreover, they stated that a higher number of ECT treatments may be required than is standard for other clinical indications; further research is needed before ECT can be included in standard TRS treatment algorithms.

Sanghani and associates (2018) reviewed recent studies of the use of ECT in the treatment of schizophrenia.  These researchers performed an electronic database search for articles on ECT and schizophrenia, published in 2017.  The main themes of these articles were: epidemiological data on ECT use from various countries; retrospective studies, prospective studies and meta-analyses focusing on efficacy and cognitive side-effects of ECT in schizophrenia; ECT technical parameters and potential biomarkers.  The authors concluded that there is growing evidence to support the use of ECT for augmentation of anti-psychotic response in the treatment of schizophrenia.  Cognitive side-effects were generally mild and transient.  In fact, many studies showed improvement in cognition, possibly related to the improvement in symptoms.  There is wide variation among countries in the use of ECT for the treatment of schizophrenia.  There are also variations in the choice of ECT electrode placement, parameters and schedules.  These technical differences are likely minor and should not interfere with the treatment being offered to patients.  Moreover, they stated that further long-term studies are needed to optimize ECT treatment parameters, to examine the effect of maintenance ECT and to investigate neuroimaging/biomarkers to understand the mechanism of action and identify potential response predictors to ECT.

In a Cochrane review, Sinclair and colleagues (2019) examined the effects (benefits and harms) of ECT for people with treatment-resistant schizophrenia; secondary objectives were to examine if ECT produces a differential response in people: who were treated with unilateral compared to bilateral ECT; who have had a long (more than 12 sessions) or a short course of ECT; who were given continuation or maintenance ECT; who were diagnosed with well-defined treatment-resistant schizophrenia as opposed to less rigorously defined treatment-resistant schizophrenia (who would be expected to have a greater affective component to their illness).  These investigators searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including clinical trial registries on September 9, 2015 and August 4, 2017.  There were no limitations on language, date, document type, or publication status for the inclusion of records in the register.  They also inspected references of all the included records to identify further relevant studies; RCTs investigating the effects of ECT in people with treatment-resistant schizophrenia were selected for analysis.  Two review authors independently extracted data.  For binary outcomes, they calculated the RR and its 95 % CIs, on an intention-to-treat (ITT) basis.  For continuous data, these researchers estimated the MD between the groups and its 95 % CIs.  They employed the fixed-effect model for all analyses; and assessed risk of bias for the included studies and created “Summary of findings” tables using the GRADE framework.  These researchers included 15 studies involving 1,285 subjects (1,264 completers with an average age of 18 to 46 years) with treatment-resistant schizophrenia.  They rated most studies (14/15, 93.3 %) as at high risk of bias due to issues related to the blinding of subjects and personnel.  The main outcomes of interest were: clinically important response to treatment; clinically important change in cognitive functioning; leaving the study early; clinically important change in general mental state; clinically important change in general functioning; number hospitalized; and death.  No trial reported data on death.  The included trials reported useable data for 4 comparisons: ECT plus standard care compared with sham-ECT added to standard care; ECT plus standard care compared with anti-psychotic added to standard care; ECT plus standard care compared with standard care; and ECT alone compared with anti-psychotic alone.  For the comparison ECT plus standard care versus sham-ECT plus standard care, only average end-point BPRS (Brief Psychiatric Rating Scale) scores from 1 study were available for mental state; no clear difference between groups was observed (short-term; MD 3.60, 95 % CI: -3.69 to 10.89; subjects = 25; studies = 1; very low-quality evidence).  One study reported data for service use, measured as number readmitted; there was a clear difference favoring the ECT group (short-term; RR 0.29, 95 % CI: 0.10 to 0.85; subjects = 25; studies = 1; low-quality evidence).  When ECT plus standard care was compared with anti-psychotics (clozapine) plus standard care, data from 1 study showed no clear difference for clinically important response to treatment (medium-term; RR 1.23, 95 % CI: 0.95 to 1.58; subjects = 162; studies = 1; low-quality evidence).  Clinically important change in mental state data were not available, but average end-point BPRS scores were reported.  A positive effect for the ECT group was found (short-term BPRS; MD -5.20, 95 % CI: -7.93 to -2.47; subjects = 162; studies = 1; very low-quality evidence).  When ECT plus standard care was compared with standard care, more subjects in the ECT group had a clinically important response (medium-term; RR 2.06, 95 % CI: 1.75 to 2.42; subjects = 819; studies = 9; moderate-quality evidence).  Data on clinically important change in cognitive functioning were not available, but data for memory deterioration were reported.  Results showed that adding ECT to standard care may increase the risk of memory deterioration (short-term; RR 27.00, 95 % CI: 1.67 to 437.68; subjects = 72; studies = 1; very low-quality evidence).  There were no clear differences between groups in satisfaction and acceptability of treatment, measured as leaving the study early (medium-term; RR 1.18, 95 % CI: 0.38 to 3.63; subjects = 354; studies = 3; very low-quality evidence).  Only average end-point scale scores were available for mental state (BPRS) and general functioning (Global Assessment of Functioning).  There were clear differences in scores, favoring ECT group for mental state (medium-term; MD -11.18, 95 % CI: -12.61 to -9.76; subjects = 345; studies = 2; low-quality evidence) and general functioning (medium-term; MD 10.66, 95 % CI: 6.98 to 14.34; subjects = 97; studies = 2; very low-quality evidence).  For the comparison ECT alone versus anti-psychotics (flupenthixol) alone, only average end-point scale scores were available for mental state and general functioning.  Mental state scores were similar between groups (medium-term BPRS; MD -0.93, 95 % CI: -6.95 to 5.09; subjects = 30; studies = 1; very low-quality evidence); general functioning scores were also similar between groups (medium-term Global Assessment of Functioning; MD -0.66, 95 % CI: -3.60 to 2.28; subjects = 30; studies = 1; very low-quality evidence).  The authors concluded that moderate-quality evidence indicated that relative to standard care, ECT had a positive effect on medium-term clinical response for people with treatment-resistant schizophrenia.  However, there is no clear and convincing advantage or disadvantage for adding ECT to standard care for other outcomes.  The available evidence was also too weak to indicate whether adding ECT to standard care was superior or inferior to adding sham-ECT or other anti-psychotics to standard care, and there was insufficient evidence to support or refute the use of ECT alone.  These researchers stated that more good-quality evidence is needed before firm conclusions could be made.

Dementia-Associated Agitation and Aggression

Ujkaj et al (2012) examined the safety and effectiveness of ECT for agitation and aggression in dementia patients.  A total of 16 patients with a diagnosis of dementia treated with ECT for agitation/aggression during 2004 to 2007 were included in this analysis.  Clinical charts were rated on the Pittsburgh Agitation Scale as the primary outcome; the Clinical Global Impression scale and the Global Assessment of Functioning pre- and post-ECT were also used.  Patients of mean age 66.6 +/- 8.3 years were studied.  Their average overall and pre-ECT lengths of stay were 59.7 +/- 39.7 days and 23 +/- 15.7 days, respectively.  Patients received a mean of 9 ECT treatments, mostly bilateral.  Patients showed significant reductions in their total Pittsburgh Agitation Scale scores from baseline after ECT (from 11.0 +/- 5.0 to 3.9 +/- 4.3 [F = 30.33, df = 1, 15, p < 0.001]).  Clinical Global Impression scale decreased significantly (from 6.0 +/- 0.6 pre-ECT to 2.1 +/- 1.6 post-ECT [F = 112.97, df = 1, 15, p < 0.001]).  Global Assessment of Functioning change was not significant (from 23.0 +/- 4.9 to 26.9 +/- 6.9 [F = 5.73, df = 1, 13, p = 0.32]).  Only 1 patient, in whom ECT was discontinued following 11 bilateral treatments, showed no improvement; 8 patients showed transient postictal confusion, which typically resolved within 48 hours.  Two patients showed more severe postictal confusion that required modification of treatment.  The authors concluded that these results suggested that ECT is an effective and safe treatment for agitation and aggression in dementia.  Moreover, they stated that further prospective studies are warranted.

Glass and colleagues (2017) provided a systematic review of published literature regarding the effectiveness of ECT for the treatment of agitation in patients with dementia (major neurocognitive disorder).  These investigators searched PubMed, Medline, Google Scholar, UpToDate, Embase, and Cochrane for literature concerning ECT for treating agitation in dementia using the title search terms "ECT agitation dementia", "ECT aggression dementia", "ECT behavior and psychological symptoms of dementia" and "ECT BPSD".  The term "dementia" was also interchanged with "major neurocognitive disorder".  No time frame restriction was placed.  These researchers attempted to include all publications that were found to ensure a comprehensive review.  They found 11 papers, with a total of 216 patients.  Limited to case reports, case series, retrospective chart review, retrospective case-control, and an open label prospective study, ECT has demonstrated promising results in decreasing agitation in patients with dementia.  Patients who relapsed were found to benefit from maintenance ECT.  The authors concluded that available studies are often limited by concomitant psychotropic medications, inconsistent use of objective rating scales, short follow-up, lack of a control group, small sample sizes, and publication bias.  A future RCT will pose ethical and methodological challenges; a RCT must carefully consider the definition of usual care as a comparison group.  These researchers stated that well-documented prospective studies and/or additional case series with explicit selection criteria, a wide range of outcome measures, and less selection bias of the study sample that may favor treatment response, is needed.  They noted that ECT may be a promising option for the treatment of aggression and agitation in patients with severe dementia who are refractory to other therapeutic options, but the limitations of available studies suggest that a cautious approach to future RCTs is needed.

van den Berg and colleagues (2018) noted that many patients with dementia develop agitation or aggression in the course of their disease.  In some severe cases, behavioral, environmental, and pharmacological interventions are not sufficient to alleviate these potentially life-threatening symptoms.  It has been suggested that in those cases, ECT could be an option.  These investigators summarized the scientific literature on ECT for agitation and aggression in dementia.  They performed a systematic review in accordance with PRISMA guidelines.  A search was conducted in Ovid Medline, Embase, and PsycINFO; 2 reviewers extracted the following data from the retrieved articles: number of patients and their age, gender, diagnoses, types of problem behavior, treatments tried before ECT, specifications of the ECT treatment, use of rating scales, treatment results, follow-up data, and adverse effects.  The initial search yielded 264 articles, 17 of which fulfilled the inclusion criteria.  Of these studies, 1 was a prospective cohort study, 1 was a case-control study, and the others were retrospective chart reviews, case series, or case reports.  Clinically significant improvement was observed in the majority (88 %) of the 122 patients described, often early in the treatment course.  Adverse effects were most commonly mild, transient, or not reported.  The authors concluded that the reviewed articles suggested that ECT could be an effective treatment for severe and treatment-refractory agitation and aggression in dementia, with few adverse consequences.  Moreover, they stated that because of the substantial risk of selection bias, the designs of the studies reviewed, and their small number, further prospective studies are needed to substantiate these preliminary positive results.

Post-Traumatic Stress Disorder

In an open, prospective study, Margoob et al (2010) examined the effects of ECT in the treatment of patients with chronic, severe, antidepressant- and congitive behavioral therapy (CBT)-refractory post-traumatic stress disorder (PTSD).  A total of 20 consenting adults were prospectively treated with a fixed course of 6 bilateral ECT treatments administered on an outpatient basis at a twice-weekly frequency.  The primary outcome measure was improvement on the Clinician-Administered Post-traumatic Stress Disorder Scale (CAPS).  Baseline refractoriness was defined as a failure to respond to an adequate course of at least 4 different antidepressant drugs along with 12 sessions of CBT.  Response to ECT was defined as at least 30 % attenuation of CAPS ratings, and remission as an end point CAPS score of 20 or less.  After ECT, patients were prescribed sertraline (100 to 150 mg/day) or mirtazapine (15 to 30 mg/day).  All but 3 patients completed the ECT course.  An intent-to-treat analysis (n = 20) showed statistically and clinically significant improvement in the sample as a whole: CAPS scores decreased by a mean of 34.4 %, and depression scores by a mean of 51.1 %.  Most of the improvement in CAPS and depression ratings developed by the third ECT; that is, by day 10 of treatment, itself.  The improvement in CAPS ratings was independent of the improvement in depression ratings; and improvement in CAPS did not differ significantly between patients with less severe versus more severe baseline depression.  The response rate was 70 %; no patient remitted.  In the completer analysis (n = 17), mean improvements were 40 % and 57 % for CAPS and depression ratings, respectively, and the response rate was 82 %.  Treatment gains were maintained at a 4 to 6 month follow-up.  The authors concluded that ECT may improve the core symptoms of PTSD independently of improvement in depression, and may therefore be a useful treatment option for patients with severe, chronic, medication- and CBT-refractory PTSD.  The findings of this small study need to be validated by well-designed studies.

Youssef and colleagues (2017) reviewed data on whether ECT is effective in the treatment of PTSD.  These researchers performed a systematic literature review from 1958 through August 2016 for clinical studies and case reports published in English examining the effectiveness of ECT in improving PTSD symptoms.  The literature search generated 3 retrospective studies, 1 prospective uncontrolled clinical trial, and 5 case reports.  It is not clear, given the small sample size and lack of a large randomized trial, whether favorable outcomes were attributed to improvement in depression (as opposed to core PTSD symptoms).  The authors concluded that current effectiveness data do not separate conclusively the effects of ECT on PTSD symptoms from those on depression.  They stated that RCTs are needed to examine the use of ECT in medication-refractory PTSD patients with and without co-morbid depression.  Subsequent studies may address response in PTSD subtypes, and the use of novel techniques, such as memory reactivation, before ECT.

Autoimmune Encephalitis (e.g., Anti-N-Methyl-D-Aspartate Receptor Encephalitis)

Coffey and Cooper (2016) stated that there is a growing scientific literature describing the neuropsychiatric symptoms of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, including the use of ECT to treat those symptoms.  These researchers consolidated this literature into a review that highlighted its relevance to ECT practitioners.  They performed a PubMed search using the terms electroconvulsive therapy and encephalitis, autoimmune encephalitis, or anti-NMDA receptor encephalitis.  They reviewed all relevant studies in detail, cross-referenced all bibliographies, and collected key clinical information related to the practice of ECT.  These investigators identified 6 studies offering patient-level descriptions of the use of ECT in patients with anti-NMDA receptor encephalitis.  In all cases ECT was used to target symptoms of catatonia; ECT was delivered safely and effectively irrespective of the timing of diagnosis, tumor removal, or immunotherapy.  The authors concluded that there are no controlled data on the use of ECT in anti-NMDA receptor encephalitis; further investigation is needed to determine whether ECT has a disease-modifying effect on this form of autoimmune encephalitis.

Gough and colleagues (2016) noted that autoimmune encephalitis is a poorly understood condition that can present with a combination of neurological and psychiatric symptoms, either of which may predominate.  There are many autoantibodies associated with a variety of clinical syndromes -- anti-N-Methyl-D-Aspartate receptor (NMDAR) is the commonest.  Currently, the most widely used therapy is prompt plasmapheresis and steroid treatment (and tumor resection if indicated), followed by 2nd line immunosuppression if this fails.  Given the growing awareness of autoimmune encephalitis as an entity, it is increasingly important that clinicians consider it as a potential diagnosis in order to provide timely, effective treatment.  These investigators discussed several previously published case reports and 1 new case.  These reports examined the effects of ECT on patients with autoimmune encephalitis, particularly those in whom psychiatric symptoms were especially debilitating and refractory to standard treatment.  They also discussed factors predicting good outcome and possible mechanisms by which ECT may be effective.  Numerous cases, such as those presented by Wingfield, Tsutsui, Florance, Sansing, Braakman and Matsumoto, demonstrated effective use of ECT in anti-NMDAR encephalitis patients with severe psychiatric symptoms such as catatonia, psychosis, narcolepsy and stupor who had failed to respond to standard treatments alone.  These researchers also presented a new case of a 71-year old female who presented to a psychiatric unit initially with depression, which escalated to catatonia, delusions, nihilism and auditory hallucinations.  After anti-NMDAR antibodies were isolated, she was treated by the neurology team with plasmapheresis and steroids, with a partial response.  She received multiple sessions of ECT and her psychiatric symptoms completely resolved and she returned to her pre-morbid state.  The authors concluded that in view of several case studies demonstrating the role in autoimmune encephalitis, ECT may be emerging as a viable alternative or adjunct to immunomodulatory therapies, particularly in those with prevailing psychiatric symptoms.  Moreover, they stated that further studies are needed to establish its role either alone or in combination with other treatments.

Lennox-Gastaut Syndrome and Drug-Resistant Epilepsy

Asadi-Pooya and colleagues (2016) noted that Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy, characterized by drug-resistant multiple seizure types.  In a pilot study, these researchers examined if the adjunctive use of ECT in patients with LGS and drug-resistant epilepsy is effective in decreasing their seizure frequency and also examined its safety and tolerability.  This was an open-label study with convenience sampling from 1 center.  Bi-temporal electrode placement was selected; ECT was administered 3 times per week for 4 weeks (considered as the induction phase), and then once-weekly for 2 months (considered as the maintenance phase).  Follow-up visits were scheduled at 2, 3, 4, and 6 months to determine the seizure types and counts and also to determine the safety and tolerability of adjunctive use of ECT in these patients.  All patients and/or their caregivers consented in writing to their participation.  A total of 7 patients were studied; just 1 patient experienced more than 50 % reduction in seizure frequency; 1 patient experienced more than 50 % seizure increase with ECT.  In 3 patients, there was an increase in aggressive behavior after receiving ECT; 2 patients experienced mild and transient ataxia with ECT; 1 patient experienced mutism with ECT, which was transient and resolved with the termination of the procedure.  The authors concluded that in this small (n = 7) pilot study, adjunctive use of an intensive ECT program in patients with LGS was not effective in decreasing their seizure frequency.  However, the safety profile was acceptable, and patients tolerated the adjunctive use of ECT very well; these findings can pave the road for future investigations.

Somatic Symptom Disorder

Borisovskaya and Augsburger (2017) noted that somatic symptom disorder (SSD) is a challenging condition to treat with chronic pain, a common and disabling symptom.  These investigators presented the case of a patient who received ECT for SSD with significant improvement in pain and gastro-intestinal symptoms.  They also presented a brief literature review of similar cases treated with ECT.  These researchers stated that preliminary evidence suggested that ECT should be considered for treatment of SSD co-morbid with major depressive disorder, when standard treatments fail.  Moreover, they concluded that further research is needed to clarify whether ECT can be used for SSD without associated depression.

Agitation in Schizophrenia

Gu and co-workers (2017) noted that agitation poses a significant challenge in the treatment of schizophrenia; ECT is a safe and effective treatment for a variety of psychiatric disorders, but no meta-analysis of ECT treatment for agitation in schizophrenia has yet been reported.  In a meta-analysis, these researchers systematically evaluated the safety and efficacy of ECT alone or ECT-antipsychotics (APs) combination for agitation in schizophrenia.  Systematic literature search of RCTs was performed; 2 independent evaluators selected studies, extracted data about outcomes and safety with available data, conducted quality assessment and data synthesis.  The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to judge the level of the overall evidence of main outcomes.  A total of 7 RCTs from China, including ECT alone (4 RCTs with 5 treatment arms, n = 240) and ECT-APs combination (3 RCTs, n = 240), were identified.  Participants in the studies were on average 34.3 (4.5) years of age and lasted an average of 4.3 (3.1) weeks of treatment duration.  All 7 RCTs were non-blinded, and were rated as low quality based on Jadad scale.  Meta-analysis of the pooled sample found no significant difference in the improvement of the agitation sub-score of the Positive and Negative Syndrome Scale (PANSS) when ECT alone (weighted mean difference [WMD] = -0.90, (95 % CI: -2.91 to 1.11), p = 0.38) or ECT-APs combination (WMD = -1.34, (95 %CI: -4.07 to 1.39), p = 0.33) compared with APs monotherapy.  However, ECT alone was superior to APs monotherapy regarding PANSS total score (WMD = -7.13, I2 = 0 %, p = 0.004) and its excitement sub-score (WMD = -1.97, p < 0.0001) as well as the PANSS total score at 14 days (WMD = -7.13, I2  = 0 %, p = 0.004) and its excitement sub-score at 7 and 14 days (WMD= -1.97 to -1.92, p = 0.002 to 0.0001) after ECT.  The ECT-APs combination was superior to APs monotherapy with respect to the PANSS total score at treatment endpoint (WMD = -10.40, p = 0.03) and 7 days (WMD = -5.01, p = 0.02).  Headache (number-needed-to-harm (NNH) = 3, 95 % CI: 2 to 4) was more frequent in the ECT alone group compared to AP monotherapy.  According to the GRADE approach, the evidence levels of main outcomes were rated as ''very low'' (37.5 %) and "low" (50 %).  The authors concluded that pooling of the data based on 7 RCTs from China found no advantage of ECT alone or ECT-APs combination in the treatment of agitation related outcomes in schizophrenia patients.  However, ECT alone or ECT-APs combination were associated with significant reduction in the PANSS total score.  They stated that high-quality RCTs are needed to confirm the current interpretations.

Obsessive-Compulsive Disorder / Self-Injurious Behaviors / Tic Disorders

Dos Santos-Ribeiro and colleagues (2018) examined the efficacy of ECT in DSM-5 obsessive-compulsive-related disorders (OCRDs) and conditions subsumed under an "extended" OCD spectrum, including tic disorders and self-injurious behaviors.  These researchers carried out a systematic search of the Medline, Web of Science, Scopus, and LILACS databases and other sources between June 6 and July 2, 2017.  Search terms included (Autis*) and (ECT or electroconvulsive), (Self-injur*) and (ECT or electroconvulsive), (Tic* or Tourette) and (ECT or electroconvulsive), (Body Dysmorphic Disorder or Dysmorphophobi*) and (ECT or electroconvulsive), (Hoard*) and (ECT or electroconvulsive), (Trichotillomani*) and (ECT or electroconvulsive), (Skin Picking or Excoriation) and (ECT or electroconvulsive), (Grooming) and (ECT or electroconvulsive), (Kleptomani*) and (ECT or electroconvulsive), and (Pyromani*) and (ECT or electroconvulsive).  No search restrictions (i.e., date, language, or document type) were used.  A total of 52 records that described the individual responses of OCRDs to ECT (involving 69 patients) were selected.  Clinical data and responses of individual cases were recorded; data from responders were compared to non-responders.  All records were case reports or case series; there were no RCTs.  Of the 69 OCRD subjects who had undergone ECT, a positive response was reported in 73.4 % of the cases (including 44.0 % of the BDD, 74.1 % of the tic disorder, and 85.7 % of the self-injurious behavior patients).  At follow-up, the majority of responders who had abstained from further ECT had experienced relapse.  However, a positive response was obtained in all subjects who received a new course of ECT.  Patients who responded positively to ECT were likely to report previous unsuccessful treatment with anti-psychotics (p < 0.001) and anti-depressants (p = 0.007).  The authors concluded that the finding that more than 70 % of the reviewed cases showed some response to ECT should not be considered unequivocal evidence of its efficacy in OCRDs.  They stated that the available evidence suggested that a RCT of ECT in OCRDs may be warranted, especially in severe tic disorders and self-injurious behaviors.

Fronto-Temporal Connectivity for Prediction of ECT Outcome in Major Depression

Leaver and colleagues (2018) stated that ECT is arguably the most effective available treatment for severe depression.  Recent studies have used MRI data to predict clinical outcome to ECT and other anti-depressant therapies.  One challenge facing such studies is selecting from among the many available metrics, which characterize complementary and sometimes non-overlapping aspects of brain function and connectomics.  These investigators examined the ability of aggregated, functional MRI metrics of basal brain activity and connectivity to predict anti-depressant response to ECT using machine learning.  A radial support vector machine was trained using arterial spin labeling (ASL) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) metrics from n = 46 (26 women, mean age of 42 years) depressed patients prior to ECT (majority right-unilateral stimulation).  Image pre-processing was applied using standard procedures, and metrics included cerebral blood flow in ASL, and regional homogeneity, fractional amplitude of low-frequency modulations, and graph theory metrics (strength, local efficiency, and clustering) in BOLD data.  A 5-repeated 5-fold cross-validation procedure with nested feature-selection validated model performance.  Linear regressions were applied post-hoc to aid interpretation of discriminative features.  The range of balanced accuracy in models performing statistically above chance was 58 to 68 %.  Prediction of non-responders was slightly higher than for responders (maximum performance 74 and 64 %, respectively).  Several features were consistently selected across cross-validation folds, mostly within frontal and temporal regions.  Among these were connectivity strength among: a fronto-parietal network [including left dorsolateral pre-frontal cortex (DLPFC)], motor and temporal networks (near ECT electrodes), and/or subgenual anterior cingulate cortex (sgACC).  The authors concluded that these findings indicated that pattern classification of multi-modal fMRI metrics could successfully predict ECT outcome, especially for individuals who would not respond to treatment.  Notably, connectivity with networks highly relevant to ECT and depression were consistently selected as important predictive features.  These included the left DLPFC and the sgACC, which were both targets of other neurostimulation therapies for depression, as well as connectivity between motor and right temporal cortices near electrode sites.  These researchers stated that future studies that probe additional functional and structural MRI metrics and other patient characteristics may further improve the predictive power of these and similar models.  They stated that going forward, multi-site studies with larger and varied cohorts, targeting responsibly pre-processed MRI and other data will be in an even better position to determine the extent to which these kinds of analyses could further elucidate the mechanisms of ECT and perhaps be used to make more accuracy prospective prediction of successful anti-depressant response to ECT.

Electroconvulsive Therapy for the Treatment of Eating Disorders

Pacilio and colleagues (2020) examined the safety and effectiveness of ECT in the treatment of eating disorders (EDs) in patients with and without co-morbid psychiatric disorders.  These investigators carried out a review of the literature pertaining to the use of ECT in patients with EDs through PubMed, PsycINFO, and Medline.  Search terms included "electroconvulsive therapy", "ECT," and "electroshock" each combined with "anorexia nervosa", "bulimia nervosa", "binge eating disorder", "eating disorder", "EDNOS" and "OSFED".  Additionally, a case in which ECT was used in the treatment of a patient with anorexia nervosa was presented.  A total of 89 articles were reviewed, and 11 were selected for inclusion.  These articles detailed 14 patients with active EDs who received ECT during their course of treatment.  Of these patients, 13 were noted to have improved in disordered eating after receiving ECT, and no adverse medical outcomes were reported.  The case presented by these researchers detailed an additional patient who benefitted from ECT.  The authors concluded that there were limited data supporting the use of ECT in treating EDs; however, there was evidence to support that ECT was safe in this population and has been effective in cases of patients with AN with and without psychiatric co-morbidities as well as binge eating disorder.  These researchers stated that more research is needed for treatment guidelines.

Measurement of Plasma Brain-Derived Neurotrophic Factor

Sorri and associates (2018) stated that brain-derived neurotrophic factor (BDNF) has been associated with depression and its treatment response.  These researchers examined the effect of ECT on serum and plasma BDNF levels and change of Montgomery-Asberg Depression Rating Scale (MADRS) and their associations in patients with MDD.  This trial included 30 patients suffering from MDD; their serum and plasma BDNF levels were examined before ECT (baseline) and after the 1st, 5th, and last ECT session.  The severity of the depression and the response to ECT were measured with MADRS.  Electroconvulsive therapy caused no significant changes in serum BDNF levels.  Plasma BDNF levels decreased during the 5th ECT session between the baseline and the 2-hour samples (p = 0.019).  No associations were found between serum or plasma BDNF levels and remission.  The correlations between plasma and serum BDNF levels in each measurement varied between 0.187 and 0.636.  The authors concluded that neither serum nor plasma BDNF levels were systematically associated with the clinical remission; however, the plasma BDNF levels somewhat varied during the ECT series.  Thus, the predictive value of BDNF for effects of ECT appeared to be at least modest.

Luan and colleagues (2020) noted that some evidence indicated that ECT could increase the level of BDNF in depressive patients.  However, there are some disagreements.  In a systematic review and meta-analysis, these investigators examined BDNF levels after ECT in patients with MDD.  Two independent researchers searched published articles in the Cochrane Library, PubMed, Medline, Embase and WanFang Data, from January 1990 to March 2019.  The following key words were used: "depression" or "depressive disorder", "major depressive disorder", "unipolar depression", "brain-derived neurotrophic factor" or "BDNF", and "electroconvulsive" or "ECT".  A total of 22 studies met the inclusion criteria of the meta-analysis and were included into the analysis.  BDNF levels were increased among patients with MDD after ECT (p = 0.000) in plasma samples; the SMD was 0.695 (95 % CI: 0.402 to 0.988).  These researchers also found BDNF levels increased at 1 week and 1 month following ECT (SMD = 0.491, 95 % CI: 0.150 to 0.833, p = 0.005; and SMD = 0.812, 95 % CI: 0.326 to 1.298, p = 0.001, respectively).  The authors concluded that the main finding of this study was that neither serum nor plasma BDNF levels was associated with remission following ECT in MDD.  However, plasma BDNF levels decreased after the 5th ECT session.  Thus, predictive value of BDNF for effects of ECT remains uncertain.  Also, the serum and plasma BDNF levels did not appear to be consistent with each other suggesting thus the separate methods are not comparable.

The authors stated that this study had several drawbacks.  First, using data on BDNF levels in blood samples from original studies carried a bias risk given the controversial opinions on how BDNF is peripherally restored as well as the seasonal variation of serum BDNF levels.  Moreover, there were limitations in the clinical studies on the brain BDNF levels in MDD patients.  Furthermore, these researchers did not separate the patients into subgroups according to age, gender, ethnicity and type of depression due to limitations in the original data.  They also could not analyze the long-term BDNF levels in MDD patients after ECT due to the observation limitations in the original studies and didn’t examine further on the responders and non-responders.

Meshkat et al (2022) noted that multiple lines of evidence have implicated BDNF in treatment-resistant depression (TRD).  In a systematic review and meta-analysis, these investigators examined the impact of TRD treatments on peripheral BDNF levels; and examined if these changes were associated with anti-depressant effects.  A total of 36 studies entailing 1,198 patients with TRD were included in this study.  Electroconvulsive therapy, ketamine, and repetitive transcranial magnetic stimulation (rTMS) were the most common TRD treatments investigated.  Serum BDNF levels significantly increased in 6, 2, 4 and 1 studies following ECT, ketamine, rTMS and atypical anti-psychotics, respectively.  The estimated mean baseline serum BDNF concentration in TRD patients ± 95 % CI was 15.5 ± 4.34 ng/ml.  Peripheral BDNF levels significantly increased overall (Hedges' g ± 95 % CI = 0.336 ± 0.302; p < 0.05), but no association with depressive symptoms was found (p ≥ 0.05).  The authors concluded that these findings showed that peripheral measurements of total BDNF (i.e., mature and precursor forms of BDNF) were inadequate predictors of treatment response in TRD patients.

Pelosof et al (2023) stated that studies have suggested BDNF increase following ECT although they were methodologically limited and enrolled small sample sizes.  These researchers updated a systematic review and meta-analysis to examine BDNF changes following ECT for the treatment of depression.  PubMed, PsycInfo, Embase and Global health were searched (March, 2021).  Clinical trials that measured BDNF in the blood before and after ECT in adults (18 years of age or older) with depression (MDD or bipolar disorder) were eligible.  Data were pooled through random-effects meta-analyses.  A total of 28 studies entailing 778 subjects were included.  Meta-analysis showed a significant increase in BDNF levels after ECT (Hedges' g = 0.28; 95 % CI: 0.10 to 0.46) while there was evidence of significant heterogeneity (I2 = 67.64 %) but not publication bias/small-study effect.  Subgroup analyses and meta-regressions were under-powered to detect significant differences.  Meta-analysis of depression severity scores demonstrated a considerable larger treatment effect in reducing depressive symptoms after ECT (Hedge's g = -3.72; 95 % CI: -4.23 to -3.21).  The authors concluded that this updated review showed that BDNF blood levels increased after ECT treatment.  However, there was still evidence of substantial heterogeneity and there were limited sample sizes to examine factors driving the variability of effects across studies.  More importantly, the increase in BDNF levels was substantially smaller than the observed in depressive symptomatology, which could be indicative that the former was independent than the latter.  These researchers stated that additional studies with larger sample sizes are currently required.

Gliwinska et al (2023) noted that BDNF belongs to the family of neurotrophins, which are growth factors with trophic effects on neurons.  BDNF is the most widely distributed neurotrophin in the central nervous system (CNS) and is highly expressed in the prefrontal cortex (PFC) and hippocampus.  Its distribution outside the CNS has also been demonstrated; however, most studies have focused on its effects in neuropsychiatric disorders.  Despite the advances in medicine in recent decades, neurological and psychiatric diseases are still characterized by high drug resistance.  These researchers focused on the use of BDNF in the developmental assessment, treatment monitoring, and pharmacotherapy of selected diseases, with a particular emphasis on epilepsy, depression, anorexia, obesity, schizophrenia, and Alzheimer's disease.  The authors highlighted the limitations of using a molecule with such a wide distribution range and inconsistent method of determination.  Moreover, these researchers stated that in the near future, it may turn out that the most significant benefit that comes from evaluating concentration of BDNF is related to the prediction of the course of the disease and the effectiveness of its treatment.

Prophylactic Cognitive Enhancers for Improvement of Cognitive Function in Persons Undergoing Electroconvulsive Therapy

Niu and colleagues (2020) noted that cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effect for reducing post-ECT cognitive side effects is unclear.  In a systematic review and meta-analysis, these researchers examined the effectiveness of cognitive enhancers in the prevention of cognitive side effects due to ECT.  They identified relevant studies by searching electronic databases (e.g., PubMed, Embase, Web of Science, Cochrane Library).  Only studies published up to October 2019 comparing cognitive enhancer versus placebo for cognitive function after ECT were included.  The primary outcome extracted from the studies was cognitive function score.  A total of 5 studies with 202 subjects were included in this study.  The cognitive enhancer group (CEG) had a significantly higher cognitive function score.  Moreover, sensitivity analysis showed that no individual study had a significant impact on the overall results.  The authors concluded that this meta-analysis revealed that cognitive enhancers might improve cognitive function and reduce ECT-induced cognitive side effects.  Moreover, these researchers stated that these findings should be regarded as promising, emphasizing the need to further explore the potential treatment benefits of cognitive enhancers for ECT-induced cognitive side effects in order to expand the evidence supporting their usefulness; more high-quality RCTs with long-term follow-up are needed to make the final conclusion.

The authors stated that this review had several drawbacks.  First, the main drawback of this study, as with other reviews, was that the subject population, the cognitive enhancer's kind and the outcome definitions were not the same across studies.  Second, variations in electrode placement and stimulus dosing have large effects on cognitive changes from ECT, particularly on retrograde memory, but they were not mentioned in those articles, a notable omission.  Third, different age determines different recovery rates of cognition, thus, these investigators believed that age played a significant role in reducing ECT-induced cognitive side effects.  Unfortunately, this point was ignored in most of the studies.  It followed that the results might not be applicable to patients of all ages.  Fourth, RCTs did not evaluate enough patients or did not follow patients for a sufficient duration to allow a definitive conclusion that rendered generalization difficult.  Fifth, the assessment of the clinical relevance of the results of the reviewed studies was still challengeable due to the imperfection of post-ECT cognitive assessment.  Finally, when beginning this review, these researchers planned to find a mass of RCTs that would allow them to determine the safety and effectiveness of cognitive enhancers for ECT-induced cognitive impairment.  However, their extensive literature searches only identified 5 studies, thus, this review may not be considered broadly representative because of the small number of relevant studies included in the analysis.  Although all results pointed to the same direction: Cognitive enhancers provided a significantly better post-ECT cognitive performance during ECT.  The results may appear limited due to the imperfections in the studies.

Electroconvulsive Therapy for the Treatment of Motor Symptoms Associated with Parkinson's Disease

Volkaerts and associates (2020) stated that in patients with a deep brain stimulator (DBS), ECT has proven to be a safe and effective therapeutic option after several medication failures in major depression, especially in the presence of psychotic symptoms.  To-date, there have been no reports on the effect of ECT on motor function in Parkinson's disease (PD) patients with an implanted DBS.  These investigators presented the case of a woman with DBS as a treatment for PD, safely treated with ECT for a psychotic depression.  Depression severity and motor changes were evaluated on a weekly basis using the Montgomery-Asberg Depression Rating Scale and the Unified Parkinson's Disease Rating Scale (UPDRS).  During the course of ECT, the Montgomery-Asberg Depression Rating Scale score declined from 34 to 13, and the UPDRS motor score from 44 to 12 with positive impact on rigidity.  The authors concluded that considering the positive impact of ECT on the motor function in this patient, new research should examine ECT as an augmentation strategy in motor dysfunction in patients treated with DBS for PD.

Takamiya and colleagues (2021) noted that ECT is a well-established treatment for psychiatric disorders, including depression and psychosis; and ECT has been reported to be effective in treating such psychiatric symptoms in patients with PD and has been also reported to be effective in treating motor symptoms.  In a systematic review and meta-analysis, these researchers summarized previous clinical studies examining the effectiveness of ECT for symptoms in patients with PD.  These investigators included any study that examined motor and/or non-motor symptoms in patients with PD before and after ECT.  Co-primary outcomes were set as motor manifestations evaluated by means of the UPDRS or other rating scales, and non-motor symptoms included depression and psychosis.  Secondary outcomes were wearing-off phenomenon and cognitive function.  The impact of ECT on those symptoms was examined by comparing the severity of the symptoms before and after ECT using a random effect model and was expressed in SMD.  Of 1,219 identified citations, 14 studies (n = 129; 1 RCT, 9 prospective observational studies, and 4 retrospective studies) were analyzed.  The findings were as follows: ECT significantly improved motor manifestations in patients with PD, and the improvement was significant in the subpopulation without psychiatric symptoms; ECT significantly improved depression and psychosis; and ECT significantly relieved wearing-off phenomenon and did not worsen cognitive functioning.  The authors concluded that the findings of this meta-analysis suggested the potential benefit of ECT on motor and non-motor symptoms in presumably complicated and difficult-to-treat subgroups.

Lithium Therapy for the Prevention of Post-ECT Depressive Relapse

Lambrichts and colleagues (2021) noted that the risk of relapse following successful anti-depressant treatment, including ECT, is substantial.  Lithium has been suggested to effectively prevent relapse, yet data remain limited and inconclusive.  In a systematic review and meta-analysis, these investigators examined the efficacy of continuation treatment with lithium in preventing relapse following a successful acute course of ECT in patients with major depression, in comparison to continuation treatment without lithium.  They also examined the role of several study characteristics, possibly impacting the treatment effect.  These researchers carried out a systematic literature search, using the PubMed, Embase, Web of Science, and Cochrane Library databases (up to June 2020) for prospective and retrospective studies, including patients with unipolar or bipolar depression, that evaluated the efficacy of lithium for post-ECT depressive relapse prevention.  Of 2,556 records screened, 14 articles reporting on 9,748 participants who received continuation treatment either with (n = 1,571) or without lithium (n = 8,177) were included in the meta-analysis.  Patients receiving lithium were less likely to experience depressive relapse after a successful acute course of ECT, compared to patients receiving post-ECT prophylaxis without lithium (weighted OR = 0.53, 95 % CI: 0.34 to 0.82), with a number needed to treat (NNT) of 7 (95 % CI: 4 to 21).  These investigators found limited evidence that older patients may benefit more from continuation treatment with lithium, compared to younger patients.  Using the GRADE criteria, the quality of evidence for the outcome measure (i.e., relapse rate) was rated as very low.  The authors concluded that continuation treatment with lithium may have superior efficacy in reducing the risk of relapse after a successful acute ECT course for major depression, in comparison to continuation treatment without lithium.  Moreover, these researchers stated that high-quality studies are needed to confirm this finding.

Schizophrenia and Schizoaffective Disorder

Cicek and colleagues (2021) stated that 70 % of patients with treatment-resistant schizophrenia do not respond to clozapine; ECT could potentially offer significant benefit in clozapine-resistant patients.  However, cognitive side effects can occur with ECT and are a function of stimulus parameters and electrode placements.  These researchers systematically reviewed published clinical trials related to the effect of ECT stimulus parameters and electrode placements on cognitive side effects.  They carried out a systematic review of the literature up to July of 2020 for clinical studies published in English or German examining the effect of ECT stimulus parameters and/or electrode placement on cognitive side effects in patients with schizophrenia or schizoaffective disorder.  The literature search retrieved 3 randomized, double-blind, clinical trials, 1 randomized, non-blinded trial, and 1 retrospective study.  There are mixed findings regarding whether pulse width and stimulus dose impact on cognitive side effects.  One study showed less cognitive side effect for right unilateral (RUL) than bi-temporal (BT) electrode placement, and 2 studies showed a cognitive advantage for bi-frontal (BF) compared with BT ECT.  Only 1 retrospective study measured global cognition and showed post-ECT cognitive improvement with all treatment modalities using Montreal Cognitive Assessment in comparison to pre-ECT Montreal Cognitive Assessment scores.  Current data are limited; but evolving.  The authors concluded that available evidence suggested that RUL or BF ECT have more favorable cognitive outcomes than BT ECT.  These researchers stated that definitive larger clinical trials are needed to optimize parameter and electrode placement selection to minimize adverse cognitive effects.

Electroconvulsive Therapy for Treatment-Resistant Mood Disorders in Children and Adolescents

Castaneda-Ramirez and colleagues (2022) stated that ECT is a well-established treatment for adults with mood disorders; however, its use in child and adolescent populations is less common.  Furthermore, approximately 60 % of child and adolescent patients do not respond satisfactorily to 1st-line treatments for mood disorders.  Given the need for effective treatments for severe mood disorders in adolescents and the low use rate of ECT, these researchers examined the available evidence on the effectiveness and adverse effect profile of ECT when used for treatment-resistant mood disorders in children and adolescents.  Searches were conducted in Medline, Embase, and PsycInfo using search terms related to children and adolescents; mood disorders; and ECT.  Searches identified 1,715 unique articles.  The full text of 71 selected articles were reviewed, leading to 41 studies included in the study.  A standardized data extraction tool was used to collect key information from each study (i.e., author and publication year, objectives, subjects and setting, design, measures, clinical outcomes, and side effects).  As most of the studies found were case series, the Joanna Briggs Institute Case Series Critical Appraisal tool was used to evaluate quality.  Studies were summarized qualitatively by comparing findings across key study parameters.  This review identified 41 studies for inclusion – 20 were case-series studies, 2 were case-control studies, and 19 were case reports.  Overall treatment response rates ranged from 51 % to 92 %, with patients receiving an average of 12 treatments.  Among studies with n of less than 30, response rates were largely 70 % to 82 % for depression and 87 % to 90 % for mania; 7 studies used the Mini-Mental State Exam and found no evidence of significant post-treatment cognitive impairment.  The majority of side effects were minor and transient.  Tardive seizure was reported in 4 (0.6 %) patients; and ECT was discontinued early due to side effects in 11 (1.5 %) cases; no deaths were reported.  The authors concluded that these findings suggested that ECT was safe and effective for the treatment of mood disorders in child and adolescent populations; and should be considered in severe and treatment-refractory cases.  Moreover, these researchers stated that controlled studies with objective measures and long-term follow-up are needed to advance the evidence base.

Lithium for the Treatment of Electroconvulsive Therapy-Emergent Hypomania and Mania

Cloutier and colleagues (2021) noted that ECT-emergent hypomania/mania is a clinically significant problem that has lacked evidence-based guidelines for effective management.  In a systematic review, these investigators compiled the current published literature on the treatment of ECT-emergent hypomania/mania to help guide treatment course in patients with unipolar and bipolar depression.  They searched Medline/PubMed for studies published from 1980 through August 2020 that examined the treatment of ECT-emergent hypomania/mania.  Search terms included Boolean combinations of the following: mania, hypomania, ECT, ECT induced mania, and ECT induced hypomania.  There were 1,662 articles reviewed, and all published studies detailing the treatment of ECT-emergent hypomania/mania written in English that met inclusion criteria were included.  Due to the limited number of articles, there were no restrictions.  Two reviewers extracted relevant articles and assessed each study based on inclusion criteria.  The literature review identified 12 articles that described the treatment course of ECT-emergent hypomania/mania in 17 patients.  There were 9 patients who had no known history of manic or hypomanic episodes and were diagnosed with unipolar depression and 8 patients diagnosed with bipolar disorder.  There were 4 primary treatment courses identified: continuing ECT alone, continuing ECT in conjunction with lithium, discontinuing ECT with no medication treatment, or discontinuing ECT and starting a medication.  The authors concluded that available data are insufficient to support definitive conclusions; however, potential treatment guidelines were suggested within the review to providers based on the limited data available.

Pharmacological Interventions for Diminishing Cognitive Side Effects of Electroconvulsive Therapy

In a systematic review and meta-analysis, Verdijk and colleagues (2022) examined the use of pharmacological interventions to diminish cognitive side effects of ECT.  These investigators searched electronic databases of PubMed, PsycInfo, Embase and Scopus from inception through April 1, 2021, using terms for ECT (e.g., electroconvulsive therapy), cognitive outcome (e.g., cogni*) and pharmacological intervention (e.g., calcium channel blocker and general terms, like protein).  Original studies with humans receiving ECT were included, which applied pharmacological interventions in comparison with placebo or no additive intervention to diminish cognitive side effects.  Data quality was evaluated using Risk of Bias and GRADE.  Random-effects models were used.  Qualitative synthesis (systematic review) showed 52 studies reporting 16 pharmacological intervention-types.  Quantitative synthesis (meta-analysis) included 26 studies (1,387 patients) describing 12 pharmacological intervention-types.  Low-quality evidence of effectiveness was established for memantine (large effect size) and liothyronine (medium effect size).  Very low-quality evidence showed effect of acetylcholine inhibitors, piracetam and melatonin in some cognitive domains.  Evidence of no effectiveness was revealed for ketamine (very low-quality), herbal preparations with anti-inflammatory properties (very low to low-quality) and opioid receptor agonists (low-quality).  The authors concluded that memantine and liothyronine are promising for further research and future application.  Quality of evidence was low because of differences in ECT techniques, study populations and cognitive measurements.  These findings provided a guide for rational choices of potential pharmacological intervention research targets to decrease the burden of cognitive side effects of ECT.  These investigators stated that future research should be more uniform in design and attempt to clarify pathophysiological mechanisms of cognitive side effects of ECT.

Electroencephalography (EEG) for Predicting Clinical Response to Electroconvulsive Therapy in Patients with Major Depression

Min and associates (2020) stated that ECT has strong effectiveness in patients with treatment refractory schizophrenia; however, access to ECT has been limited by high costs, professional labor, treatment duration, and significant adverse effects.  To provide support for the decision to perform ECT, these researchers predicted individual responses to ECT among patients with schizophrenia using machine learning analysis of resting-state electroencephalography (EEG).  A total of 47 patients diagnosed with schizophrenia or schizoaffective disorder with EEG recordings before the course of ECT were treated at Seoul National University Hospital.  Among these patients, 29 were responders who showed scores of 3 or less on the Clinical Global Impression Severity scale following the course of ECT.  Transfer entropy (TE), which represents information flow, was extracted from baseline EEG data and used as a feature.  Feature selection was carried out with 4 methods, including Random Subset Feature Selection (RSFS).  The random forest classifier was used to predict individual ECT responses.  The averaged TE, especially in frontal regions, was higher in ECT responders than in non-responders.  A predictive model using the RSFS method classified ECT responders and non-responders with 85.3 % balanced accuracy, 85.2 % accuracy, 88.7 % sensitivity, and 81.8 % specificity.  The positive predictive value (PPV) was 82.6 %, and the negative predictive value (NPV) was 88.2 %.  The authors concluded that this study provided the 1st evidence of individual prediction of ECT responses in patients with schizophrenia using TE in resting-state EEG.  Although predicting patients who would benefit from ECT in clinical practice will need rigorous follow-up studies, routinely assessing resting-state EEG before treatment, which is easier to apply and more affordable, might help to provide valuable guidance to psychiatrists and patients in deciding to perform ECT.  Moreover, these researchers stated that future biomarker studies for predicting the ECT response would be helpful for reducing unnecessary adverse effects and health-care costs and for elucidating the pathophysiology and recovery mechanism of brain disconnections in patients with schizophrenia.

The authors stated that this study had several drawbacks.  First, the EEG data used in this study were recorded for clinical use to determine the presence of epileptic discharge or slow waves; therefore, the quality of data could not be guaranteed to the level of data acquired for well-controlled study purposes.  However, by showing that EEG data acquired in a clinical setting could also accurately predict the ECT response, the results of this study suggested that the use of TE in resting-state EEG in real-world clinical practice may also be valuably used for precision medicine.  Second, because the study design was not a prospective RCT, several confounding factors, such as the number of ECT sessions, medication adjustment, and baseline symptomatic severity, were present.  Furthermore, standardized diagnostic instruments such as the Structured Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Axis I Disorders (SCID-I) were not used.  Nevertheless, with this naturalistic design, these investigators found that the ECT response could be predicted by resting-state EEG, which could also be a favorable result for real-world applications.  Third, the outcome of the ECT was not blinded to the researchers; therefore, a cautious interpretation should be made with regard to potential bias caused by the lack of the blinded condition.  Fourth, because there is no gold standard for calculation parameters for TE, the parameters could be adjusted based on the characteristics of raw data, study design, and study objectives.  In the current study, these researchers iterated several parameters for optimized classification performances by using a heuristic approach.  They stated that future studies with a more controlled design and a hypothesis-driven approach will provide an integrative interpretation of the role of TE in the mechanism of the ECT response in patients with schizophrenia based on the findings of this study.

Kirsten and co-workers (2020) stated that MDD is a common and potentially lethal disorder affecting up to 14 % of all persons worldwide; however, 1/3 to 2/3 of patients are non-responders to 1st-line therapy.  Even ECT (as the option of choice in treatment-refractory MDD) still showed a high proportion of non-responders.  In case of a predicted non-response to ECT (e.g., by means of EEG parameters), other therapies of MDD (e.g., augmentation, polypharmacy etc.) could be chosen.  In a retrospective study, these researchers analyzed 2-min resting state EEGs from patients with MDD who underwent ECT (6 to 12 sessions with 3 sessions/week) between 2006 and 2015 at the University Hospital of Zurich.  Following several lines of evidence, these investigators hypothesized altered linear EEG connectivity within the alpha band being predictive for treatment outcome.  They used a network-based statistics (NBS) approach to compare connectivity measures between responders and non-responders.  Source estimates and connectivity measures were mapped using low-resolution brain tomography (LORETA).  As the main outcome parameter served the retrospectively assessed efficacy index (CGI-E) from the Clinical Global Impression (CGI) rating scale.  Responders in comparison with non-responders showed a significant lower linear lagged connectivity in widespread cortical areas within the EEG alpha 2 band.  In addition, there were strong correlations between CGI ratings and connectivity strength mainly within frontal cortices.  The authors concluded that pre-treatment EEG-connectivity within the alpha 2 band had a predictive value for the effectiveness of ECT treatment.  Moreover, these researchers stated that prospective, multi-center studies are needed to facilitate the way toward routine usage of EEG in psychiatry.

The authors stated that the main drawback of this study was that the CGI-E score was performed retrospectively and without direct patient contact.  Although the judgment was based on 2 independent raters’ opinions and on the unformalized daily records of symptom change, future studies should take into account scores based on face-to-face scorings or more detailed self-questionnaires.  A 2nd drawback was that the MDD scores have been examined only at a global level using CGI, a retrospective more detailed analysis of the population under study has not been possible due to the lack of more sophisticated symptom focused and disorder specific questionnaires in most patients.  However, the CGI can be seen as a measure that correlates very well with clinical symptom improvement.  A response by means of the CGI has been associated with an improvement of depression specific clinical rating scales such as the Hamilton Depression Rating Scale (HDRS).  In detail, the response and remission criteria have been found to correspond 47 % decrease in HDRS-21 or cut-off of less than or equal to 7 for remission (when conducted in a face-to-face contact).  In light of the relatively good validity of the CGI the results appeared reliable despite the missing of more diagnosis specific measures.  Although the retrospective CGI assessment was carried out by 2 independent raters based on the daily clinical records from the medical staff; therefore, most probably reflecting the changes related to ECT sessions, it could not be fully excluded, that the CGI-E measure however reflected in some cases a more unspecific improvement of symptoms than intended.  A 3rd drawback of the study was that all patients were under medication with several psycho-pharmacological drugs, resembling a real-world setting in contrast to a well-defined, medication-free sample.  Although the fact that most patients received medication lessened the interpretability of the findings in light of possible neurophysiological mechanisms (due to the complex interactions of medication with connectivity measures), the results pointed toward a possible clinical usage of the used measures.  This held true even more, since there were no differences of medication between the groups (i.e., responders versus non-responders).  Still, an impact of drugs on connectivity measures at baseline could not be completely ruled out.

Simon and colleagues (2021) noted that an important approach to improve the therapeutic effect of ECT may be to early characterize patients who are more likely to respond.  These researchers examined if baseline EEG settings before the beginning of ECT treatment can predict future clinical response to ECT in patients with depressive disorder.  They carried out a systematic search in the Medline, Embase, PsycINFO, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases to identify studies using EEG in adults with depressive disorder treated by ECT.  To examine the predictive value of baseline EEG on clinical outcomes of ECT, these researchers extracted from the retrieved studies and qualitatively described the association between the baseline EEG markers characteristics and the rates of future responders and/or remitters to ECT.  The primary search yielded 2,531 potentially relevant citations, and 12 articles were selected according to inclusion criteria.  Most of the studies were prospective studies with small sample size.  Socio-demographic and clinical characteristics of patients, ECT settings, EEG settings, and outcomes were heterogeneous.  Event-related potential (ERP) paradigms were used in 3 studies, polysomnography (PSG) was used in 3 studies, and the remaining 6 studies used EEG to measure cerebral connectivity and activity.  The authors concluded that P300 amplitude, coherence, and connectivity measures were correlated with remission in patients with depression treated by ECT.  Sleep EEG recordings appeared not to be correlated with remission following ECT.  These investigators stated that further prospective studies with large sample size and more reproducible design are needed to determine optimal EEG parameters associated with clinical response to ECT in depressive disorder.

The authors stated that the main drawback of this review was the heterogeneity across studies that increased the risk of confounding factors.  There was also a high risk of publication bias, limiting the generalization of these findings.  These investigators retrieved studies examining both sleep-related EEG, EEG-evoked potentials, and EEG with measures reflecting connectivity and activity unbalance in depression.  By focusing on strict EEG baseline data, these researchers drastically limited other confounding factors and risk to consider epiphenomenon, not associated with direct ECT response.  The most promising outcomes were P300 amplitude in cortical regions (C3, Cz) measured during auditory task with oddball paradigm, delta coherence in pre-frontal and fronto-central regions or between hemispheres measured with eyes-closed EEG, and connectivity in widespread cortical areas within the alpha 2 band analyzed with LORETA.  Results on theta activity in the anterior cingulated cortex were contradictory with those observed in patients with depression.  Sleep EEG recordings appeared not to predict remission following ECT.  Clinical characteristics of depressed patients (i.e., unipolar or bipolar, single or recurrent episodes, with psychotic or melancholic features, baseline illness severity and co-morbidities, psychotropic drugs) and ECT settings (i.e., unilateral or bilateral, frequency, number of sessions) must be considered to not measure an effect driven by a confounding factor.  Moreover, more similarities in EEG settings and outcomes across studies would be necessary to have a potential marker available in current clinical practice.

Continuation and Maintenance Electroconvulsive Therapy for Depression

Rowland et al (2023) stated that ECT is a highly effective treatment for severe and treatment-resistant depression; however, relapse rates remain high despite maintenance pharmacotherapy.  Continuation or maintenance ECT (C/M-ECT) offers the potential to prevent relapses in the most unwell patients; however, there remains disagreement among guidelines regarding its effectiveness and tolerability.  In a systematic review, these investigators examined the available evidence on the effectiveness and tolerability of C/M- ECT for depression, including data from randomized and observational studies, which included an appropriate control group.  A total of 20 studies met the inclusion criteria.  There was evidence from 14 studies suggesting that relapse rates were reduced in those receiving C/M-ECT.  There was evidence from 6 studies suggesting that C/M-ECT had no effect on global cognitive function.  Detailed neuropsychological testing was limited, but within studies that evaluated specific cognitive domains, there was inconsistent evidence for deficits in C/M-ECT compared with the control group.  The certainty of evidence across outcomes was low or very low because of inclusion of observational studies, heterogeneity of study design, and patient populations.  The findings added further weight to evidence suggesting that C/M-ECT is a viable therapeutic option to prevent relapse in severe depression and provided clinicians with further evidence for the benefits and risks of C/M-ECT when discussing therapeutic options with patients.  The authors concluded that future research should focus on randomized or well-designed prospective studies with sufficient follow-up to determine longer-term outcomes, while including a standardized, detailed neurocognitive battery to examine potential adverse effects.

Delirium

Lupke et al (2022) stated that delirium is costly for patients, caretakers, and healthcare systems.  Furthermore, non-pharmacological and pharmacological management of delirium is challenging.  While ECT has been used as an anecdotal treatment of delirium in clinical practice, the safety and effectiveness of this approach are not well understood.  In a systematic review, these investigators examined the evidence relating to the safety and effectiveness of ECT as a treatment for delirium.  A systematic review was completed according to PRISMA guidelines using the PubMed, CINAHL, Cochrane Library, and PsycINFO databases.  Studies were eligible for inclusion if modified ECT was used to treat delirium symptoms.  ECT for delirium in patients with neuroleptic malignant syndrome, catatonia, or confusional states associated with acute primary psychiatric conditions were excluded.  All included records were first ranked using the hierarchy of evidence-based medicine; quality was then assessed using the Joanna Briggs critical appraisal checklists.  Pooled data across the cases identified were analyzed using descriptive statistics.  Of 1,226 records screened, 10 studies met inclusion criteria: 6 case reports, 3 case series, and 1 quasi-experimental study.  The literature base was of mixed quality.  A single quasi-experimental study was assessed to be of “fair” quality, the remainder of the case series and case reports were rated as “poor” to “fair” quality.  A total of only 40 individuals with delirium who were treated with ECT were identified.  In 33/40 cases, the etiology of delirium was substance withdrawal.  The number of ECT treatments administered ranged from 1 to 13.  ECT was reported to positively contribute towards treatment of delirium in all cases, although objective measures of improvement were reported in only 6/13 patient cases from case reports and case series (46 %).  The singular quasi-experimental study reported a statistically significant decrease in duration of delirium, time spent in physical restraint, and in benzodiazepine requirement when ECT was used as an adjunct in benzodiazepine withdrawal delirium.  When adverse events (AEs) were described these included mild confusion and memory deficits; all were reported as time limited and reversible.  Considerable limitations in the quality of the evidence base were identified, including the risk of selection, publication and reporting bias.  Much data reporting on safety and effectiveness of ECT in delirium was missing.  The authors concluded that there was insufficient evidence to support modified ECT as a clinical treatment for delirium.  The few studies identified were generally of weak evidence lacking important data on safety and objective outcome measures, and not including populations with broad delirium etiologies.  These researchers stated that extreme caution is needed in considering the relevance of these findings in guiding clinical practice, given the limited empirical data, poor methodological quality and low-level evidence.  Thus, based on this review, these investigators could not conclude that ECT is an evidence-based or safe practice for treating delirium; they stated that further research using more robust methodologies and broader populations (age, etiology) of patients with delirium treated with ECT is needed.

Neuropsychiatric Complications of COVID-19

Austgen et al (2022) noted that there is a significant prevalence of new onset neuropsychiatric symptoms (NPS), some severe and persistent, in patients with coronavirus disease 2019 (COVID-19).  These investigators reported on the use of ECT for the treatment of NPS associated with COVID-19.  They reviewed the literature pertaining to the use of ECT in patients with COVID-19 and NPS via PubMed, PsycINFO, and Medline.  Search terms included "Electroconvulsive Therapy" and "ECT" combined with "COVID-19" and "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2)".  Furthermore, these researchers presented a case in which ECT was used to achieve complete remission in a patient who developed new onset, treatment-resistant depression, psychosis, and catatonia, associated with COVID-19.  A total of 67 articles were reviewed with 3 selected for inclusion.  These studies detailed 3 case reports of patients with new onset NPS (mania, psychosis and suicidality, and catatonia) that developed in the context of active COVID-19 and were treated successfully with ECT.  The authors concluded that ECT has been demonstrated in this case report and others, to be safe and effective for NPS associated with COVID-19.  These researchers stated that although they only identified 3 other cases in the literature, they believed that the probable anti-inflammatory mechanism of ECT, its safety and tolerability, and the faster time to symptom remission support the need for more research.

The authors noted that limitations were found in this study.  The methods of COVID-19 diagnosis used in the identified case reports were inconsistent.  One did not clearly specify the method of diagnosis.  In another, the patient was diagnosed clinically, and this was later confirmed with a positive IgG.

Appendix

Selection Criteria for ECT

  1. Member has one of the qualifying psychiatric conditions listed in the policy section above; and
  2. Member is at least 12 years of age; and 
  3. One of the following criteria is met:
     
    • Member is unresponsive to effective medications, given for adequate dose and duration, that are indicated for the member's condition (e.g., anti-depressants, anti-psychotics, etc., as appropriate); or   
    • Member is unable to tolerate effective medications or has a medical condition for which medication is contraindicated; or 
    • Member has had favorable responses to ECT in the past, or 
    • Member is unable to safely wait until medication is effective (e.g., due to life-threatening inanition, psychosis, stupor, extreme agitation, high suicide or homicide risk, etc.); or  
    • Member is experiencing severe mania or depression during pregnancy; or
    • Member prefers ECT as a treatment option in consultation with the psychiatrist.

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Adjunctive Ketamine in Electroconvulsive Therapy

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  2. Fernie G, Currie J, Perrin JS, et al. Ketamine as the anaesthetic for electroconvulsive therapy: The KANECT randomised controlled trial. Br J Psychiatry. 2017;210(6):422-428.
  3. Fond G, Loundou A, Rabu C, et al. Ketamine administration in depressive disorders: A systematic review and meta-analysis. Psychopharmacology (Berl). 2014;231(18):3663-3676.
  4. Kellner C. Overview of electroconvulsive therapy (ECT) for adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2015.
  5. McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: Efficacy and tolerability. J Psychiatr Res. 2015;62C:23-30.
  6. Naughton M, Clarke G, O'Leary OF, et al. A review of ketamine in affective disorders: Current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord. 2014;156:24-35.