Electroconvulsive Therapy (ECT) – Review of the Evidence and Summary of The RANZCP Guidelines

INDICATIONS FOR ECT

Mood disorders :

• Major depressive disorder
• Major depression with psychotic features
• Major depression with melancholic features
• Major depression with peripartum onset.
• Bipolar disorder (resistant mania and depression)
• Depressed patients who have not responded to adequate trials of medication and psychotherapy.
• Need for rapid clinical improvement.
• First-line treatment in severe depression when there is inadequate oral intake or high suicide risk or a high level of patient distress.

Psychoses:

• Acute and chronic treatment of schizophrenia
• Schizoaffective disorder
• Catatonia
• Acute psychosis
• Puerperal psychosis
• Neuroleptic malignant syndrome.

Other indications:

• May have a role in the treatment of severe or repetitive self-injurious behaviours in autism.
• Treatment of agitation and aggression in patients with dementia (second opinion with a psychiatrist with the expertise of the use of ECT in such indication).
• Treatment of severe parkinsonism not responsive to medication with on-off phenomenon.
• Parkinson’s disease for treatment of motor symptoms (including for those without psychiatric symptoms), depression and psychosis as co-morbidity. ECT also relives wearing off phenomenon without worsening cognitive functioning. [Takamiya et al., 2020]
• Intractable temporal lobe epilepsy.
• Patients with a previous positive response to ECT.

Factors influencing the choice of ECT as a treatment approach:

• Need for speed of response
• Urgency of the clinical situation
• Patient’s previous response
• Cognitive side effects

MECHANISM OF ACTION

It has been hypothesised that seizure-induced neurotrophic effects can ameliorate a range of neuropsychiatric symptoms. [Hellsten J, et al. 2002], [Wennstrom M et al., 2004], [Chen F et al., 2009]

Neuroimaging shows that the seizures increase the rate of neurogenesis and synaptogenesis in the hippocampus and the subgenual anterior cingulate cortex. [Liu Y et al., 2015]

Electrical impulses traverse the brain causing depolarised neurons to fire simultaneously, particularly in the cortex, sub-cortex, thalamus, basal ganglia, and limbic system. [Enev M et al., 2007]

Neurophysiological:

• Neuroimaging studies show that ECT causes changes to cerebral blood flow and regional glucose metabolism. [Takano H et al., 2007], [Takano H et al., 2011], [Suwa T et al.,2012]
• Further to this there are changes to electroencephalography (EEG) in specific brain regions and there is evidence that this can predict clinical response. Increased subgenual theta wave activity is associated with a decrease in psychotic symptoms. The antipsychotic effect of ECT is related to normalisation of subgenual ACC theta hypoactivity. [McCormick L et al., 2009]

Neurobiochemical:

• ECT has an effect on neurotransmission with significant changes to the expression and secretion of serotonin, dopamine, acetylcholine, epinephrine, and norepinephrine (e.g enhancement of serotonergic transmission and activation of the mesocorticolimbic dopamine system . [Baldinger P et al, 2014]
• ECT has also been proposed to change the level of neurotrophic factors (e.g. BDNF and GDNF) that have a neuroprotective and neuroproliferative effect. [Marano C et al., 2007], [Zhang X et al., 2009]

Neuroplastic:

• Studies have shown that ECT changes the volume of the whole brain but notably in the prefrontal cortex and limbic structures along with functional connectivity. [Abbott C et al., 2014], [Cano M et al., 2016]
  
• There are increases of grey matter volume in medial temporal lobes following ECT. [Ota M et al., 2015]
• ECT-induced neuroplasticity in the hippocampus and amygdala relates to improved clinical response and smaller hippocampal volumes at baseline predict a more robust clinical response. [Joshi S et al., 2016]

However, there are many inconsistent findings with much of the data often contradictory. Differences in research methodologies and study populations mean that it is difficult to confirm the precise mechanisms that underpin the therapeutic effects of ECT.

EFFICACY AND RESPONSE RATE OF ECT

The response rate to unilateral ECT patients with melancholic psychotic depression who have failed one or more medication trials are as high as 48%. [Prudic J et al., 1996]

A recent meta-analysis found remission rates with ECT of 48% for medication-refractory patients compared to 64.9% for patients who have not received pharmacological treatment.  [Heijnen W et al., 2010]

The ECT remission in psychotic versus nonpsychotic depressed patients (CORE Study) states:

The overall remission rate was 87% for study completers (N = 253 patients, nonpsychotic depression 176, psychotic 77).  Among these, patients with psychotic depression had a remission rate of 95% and those with nonpsychotic depression, 83%.  Improvement in symptomatology, measured by the HRSD, was more robust and appeared sooner in psychotic patients compared with nonpsychotic patients. [Petrides G et al., 2001]

In another study, patients were randomly assigned to BF, BT or RUL. Remission was reported to be similar: 61% with BF, 64% with BT, and 55% with RUL electrode placements. These remission rates were not affected by the presence of psychosis, the polarity of depressive illness, or severity of HAMD₂₄ scores. [Kellner C et al., 2010]

ECT can reduce a high HAMD₂₄ score for suicidal thoughts, actions, or gestures in 15% of patients after one ECT session, in 38% after three sessions, in 61% after six sessions, and 76% after nine sessions. [Kellner C et al., 2005]

ECT has the same effect on patients regardless of whether the patient is diagnosed with either unipolar depression or bipolar depression (78% vs 80%, respectively). [Bailine S et al., 2010]

ECT in Schizophrenia:

ECT may augment antipsychotic response in individuals with schizophrenia who have an inadequate response to antipsychotic medication. ECT, in combination with antipsychotics, may be effective for acute positive symptoms.

Depressive symptoms in schizophrenia may respond to ECT.

There is no evidence of negative symptom response to ECT.  The cognitive side effects are consistent with treatment in depression.

One study suggests that bifrontal ECT may be as effective or more effective than bitemporal ECT in people with schizophrenia with the added benefit of causing less cognitive impairment. [Phutane et al., 2013]

ECT ADMINISTRATION

The key considerations in ECT administration are the following:

DOSING (SEIZURE THERESHOLD)

The seizure threshold is the lowest electrical dose, which elicits seizure activity as seen on EEG or visible motor movement.

The three methods commonly used to estimate the seizure threshold are:

1. Empirical dose titration.
2. Age.
3. Half-age method.

The recommendation is that the stimulus should be determined on an individualised basis using a dose-titration method.

ELECTRODE PLACEMENT AND PULSE WIDTH

• Both Bitemporal (BT) and Right unilateral (RUL) ECT are effective treatments but require different doses. Cognitive side-effects are greater with BT placement and with higher stimulus doses.
• Doses up to 6 times threshold can maximise the efficacy of unilateral ECT, while for bilateral ECT, doses at 1.5 times seizure threshold are usually sufficient.
• The use of Bifrontal (BF) ECT is increasing and has a better side effect profile than BT ECT.
• BF has a lesser impact on cardiac rhythm and is considered the choice in treating patients who are at risk of arrhythmias.
• If treatment is considered unilaterally, consider switching from brief pulse unilaterally to brief pulse BF or BT ECT if there is no improvement after 4-6 treatments (note that individual patients respond at different times and in some cases 4 treatments may be early). Re-titration is recommended as the seizure threshold will be different with a different form of ECT is used.
• The number of ECT treatments required by a patient in the course of treatment should be guided by the patient’s progress and clinical improvement. Generally, a course of ECT involves 6–12 treatments. However, longer courses may be needed for some patients who respond slowly to ECT.
• Traditionally, ECT has been given with a ‘brief’ pulse width (0.5-2.0 ms). Recently, ultrabrief pulse width (0.25–0.3 ms) for RUL ECT has been introduced, which has markedly fewer cognitive side-effects.
• Ultrabrief pulse ECT may have slightly reduced efficacy compared to brief-pulse RUL ECT, including a slower rate of response. When compared with BT, 46% of patients were required to switch to BT ECT due to reports of poor seizure induction and inadequate response. [McCormick L  et al.,2009]
• Therefore, consider switching from ultrabrief RUL to brief-pulse RUL, BF, or BT ECT if there is no improvement after six to eight treatments.

ANAESTHETIC MANAGEMENT

Key principles:

• Ensure the seizure threshold is not excessively elevated by drugs or dosage used.  The most commonly used agents are thiopentone and propofol. Use the lowest effective dose.
• The addition of remifentanil or other short-acting opioids enables a reduction in dose of the induction agent and potentially lowers the seizure threshold.
• Muscle relaxants such as rocuronium or vecuronium may be administered before suxamethonium to minimise the suxamethonium-induced myalgia. Rocuronium needs to be considered in cases with a pseudocholinesterase deficiency where there is prolonged paralysis even with low doses of suxamethonium.
• Adequate oxygenation and ventilatory management are essential. Hyperventilation increases neuromuscular excitability and may enhance seizure production, improving treatment outcome and reducing acute cognitive adverse effects.
• Minimise cognitive impact in terms of drug and techniques used
• Use drugs and techniques to minimise respiratory depression
• Recognise the risk of cardiac arrhythmias
• Monitor appropriate physiological parameters during the procedure.
• Appropriate bite block after anaesthetic induction and before ECT stimulation to minimise the risk of dental injury.

Ketamine:

Ketamine has been used as an anaesthetic or in combination with remifentanil, thiopentone or propofol.  It has less effect on the seizure threshold, thereby enabling lower ECT stimulus dose to be administered.

If ketamine is used, it may prolong recovery time and may be associated with dissociative side effects, hallucinations or illusions.  Side effects of repeated dosing in ketamine also need to be monitored such as cystitis, LFT abnormalities, dependency and dissociative symptoms.

Appropriate standards and recommendations are documented in relevant Australian and New Zealand College of Anaesthetists (ANZCA) professional practice documents including: PS04 Recommendations for the Post-Anaesthesia Recovery Room; PS08 Statement on the Assistant for the Anaesthetist; PS09 Guidelines on Sedation and/or Analgesia for Diagnostic and Interventional Medical, Dental or Surgical Procedures; and PS55 Recommendations on Minimum Facilities for Safe Administration of Anaesthesia in Operating Suites and Other Anaesthetising Locations.

PRE-ECT ASSESSMENT AND INFORMED CONSENT

• Psychiatric assessment
• Physical assessment
• Baseline cognitive screen,
• Chest x-ray
• U&Es, FBE
• Anaesthetic review and a specialist medical review
• Informed consent

MONITORING DURING PROCEDURE

Time out procedure: ensure correct patient, correct electrode placement, correct dose and pulse width, correct anaesthetic drugs and doses as well as complete induction. The isolated limb technique is useful in monitoring for awareness.

Determining an adequate seizure:

• The clinical response
• An EEG seizure duration of 25 seconds or more
• A motor seizure with muscular activity noted
• Good post-ictal suppression (87 per cent has been suggested)
• The quality, amplitude and left-right synchronisation of the EEG recording

Causes of poor quality of seizures:

• Anticonvulsant drugs
• Poor baseline recording
• Poor conductive leads
• Movement artefacts
• Variation in anaesthetic technique

MONITORING DURING TREATMENT COURSE

EEG quality and cognitive side effects are the two main aspects to be monitored.

Weekly review to monitor progress and cognitive side effects.

A second opinion from a psychiatrist is recommended if more than 12 treatments required in an acute course.

Monitoring of depressive symptoms using the Montgomery Asberg depression rating scale (MADRS) to assess ongoing clinical condition including suicide risk.

Cognitive performance and clinical assessment carried out before the course of ECT as a baseline, during the course of treatment and end of the treatment course.

Monitoring cognitive side effects:

• Measurement of time to re-orientation after each ECT treatment is a simple, brief measure of retrograde memory function.
• Routine monitoring of re-orientation using a structured scale is recommended.
• Montreal Cognitive Assessment (MoCA) before and after ECT to evaluate cognitive outcomes
• Brief ECT cognitive screen (pre ECT and after one week) to monitor for the development of anterograde amnesia.
• Neuropsychological assessment if indicated

MAINTENANCE AND CONTINUATION OF ECT

Following a course of ECT, relapse rates within 12 months have been shown to be about 50% with the majority relapsing within the first six months despite maintenance pharmacotherapy or ECT. [Jelovac A et al., 2013]

To assist with reducing relapse, tapering of an index course of treatment is important as opposed to abruptly ceasing treatment.

In some cases, patients may require ongoing continuous maintenance ECT.  Continuation ECT consists of further treatment given in the first six months, for example, ECT given every week for three to four weeks or less often.

Current literature suggests that combined continuation ECT and pharmacotherapy is more effective than either alone in preventing relapse.

SIDE EFFECTS AND CONTRAINDICATIONS

• Side effects such as headache, myalgia, nausea, and drowsiness are common but subside with appropriate symptomatic or supportive therapy.
• Mortality is estimated at 2.1 per 100 000 treatments [Tørring N et al., 2017]
• Cardiovascular complications remain the leading cause of mortality and morbidity.
• Cerebrovascular complications are rare.

Contraindications:

• There are no absolute contraindications to ECT.

Relative contraindications

• Space-occupying lesions – increased CNS pressure
• Myocardial infarction
• Leaky/unstable aneurysm or AVM
• Recent intercerebral haemorrhage
• Retinal detachment
• Pheochromocytoma
• Situations associated with high anaesthetic risk
• Poor cardiac output
• Unstable arrhythmias.

COGNITIVE SIDE EFFECTS

ECT can cause retrograde and anterograde amnesia that can be persistent.

Post – ictal confusion:

• Initially, during recovery, postictal confusion can occur, which clears as the day progresses and patients regain full orientation.

Anterograde amnesia:

• Develops first and most rapidly (uneven memory loss of events that occur during and around index ECT) and resolves once ECT stops.
• Anterograde memory changes generally return to normal or maybe improved compared to pre-ECT levels within 2–4 weeks [Semkovska and McLoughlin, 2010]

Retrograde amnesia:

• Retrograde memory changes, including autobiographical impairment, are more likely with bilateral placement and develop more gradually and cumulatively.
• It can persist for weeks to months after ECT [Sackeim et al., 2007]. Permanent retrograde memory loss may occur in approx 12% of cases receiving bilateral ECT.

It is also possible that long-term autobiographical memory impairment may persist permanently  [Sackeim et al., 2007]. Patients should be advised that some people have significant cognitive side-effects after a course of ECT. This should be taken into account in terms of any plans to make major life decisions, and the ability to drive, particularly in the first month after ECT.

• The severity and risk of cognitive side effects are dependent on the ECT approach, the number of treatments, patient risk factors, and cannot always be predicted. BT ECT carries the highest risk of retrograde amnesia (therefore used in specific situations only e.g. need for rapid response).
• Advancing age, lower premorbid intellectual function, and female gender were associated with greater cognitive deficits.
• Objective measures of cognition may not correlate with subjective reports in patients with depression. In a recent Swedish national register-based study (n = 1212 patients), 26% reported subjective memory worsening after a course of ECT.
•  Risk seemed to be associated with female gender, younger age, fewer subjective memory problems before ECT, non-remission status and use of a brief pulse rather than ultrabrief pulse electrical stimulus. It is therefore difficult to predict which patients will develop cognitive impairment. [Brus et al., 2017]

To summarise the main risk factors are: [Porter et al, 2022].

• Bilateral (bitemporal/bifrontal) ECT
• Prolonged course of standard treatment or frequent maintenance treatment
• Existing cognitive difficulties (brain injury, intellectual disability, other existing brain disease)
• Elderly patients.
• Concomitant lithium prescription
• Females are more vulnerable to severe loss of autobiographical memory

The use of bifrontal ECT is increasing and has a better side effect profile than BT ECT.

Techniques to reduce cognitive side effects

• Use of RUL ECT
• Reducing the frequency of ECT three to two times a week
• Using ultra-brief pulse instead of brief pulse
• Focal electrically administered seizure therapy (FEAST) is a relatively new approach to ECT designed to reduce adverse cognitive effects.  It differs from ultra-brief pulse RUL ECT because it uses unidirectional rather than bidirectional current and novel non-symmetric electrode placement (a large posterior electrode in front of the right motor cortex and a small anterior electrode above the centre of the right eyebrow, over the right orbitofrontal cortex. [Sahlem G et al., 2016]
• Reducing the electrical stimulus pulse amplitude (usually fixed at 800–900 mA) to 500–700 mA, to reduce the size of the electric field induced by ECT, may reduce cognitive side effects,  although clinical effectiveness needs to be evaluated and optimised. [Abbott et al., 2021]

Monitoring of Cognitive side effects:

• Columbia University autobiographical memory interview (CUAMI) or the short form of this scale (CUAMI-SF) have been studied.
• Montreal Cognitive Assessment. (MoCA)

WHAT TO TELL PATIENTS AND FAMILIES ABOUT COGNITIVE SIDE EFFECTS OF ECT?

A committee of academic experts from Australia and New Zealand provided the following list of points to discuss with patients and families with regards to cognitive side effects. [Porter et al, 2022].

1. ECT may cause loss of memory for things that patients have learnt or experienced. Some patients find this distressing but some do not.
2. This memory loss is normally worse for the time immediately before ECT (3 months) – but sometimes extends back for up to 1 year and may occasionally extend beyond this.
3. Usually this memory loss will improve significantly by 6 months but depression may result in residual problems and some of the memories for things that have been experienced will not return.
4. Ability to learn new ‘things’ will be less for a short time after ECT – this is usually for a maximum of 2 weeks, at which point, this ability will be back to baseline. This may delay return to usual activities.
5. Ability to plan things, concentrate and attend to things may be improved because the depression has been treated.
6. Beyond possible effects of ECT on learning and memory, unfortunately severe depression itself is related to problems with learning and memory and for some people this does not improve completely even when the depression has considerably improved.

MEDICATIONS AND ECT

Tricyclic antidepressants (TCAs):

• TCAs can lower the seizure threshold and increase the risk of cardiac arrhythmia.  Nortriptyline has been shown to be relatively safe and may improve cognitive outcomes.

Lithium: 

• Lithium can increase the risk of post ECT delirium. High lithium levels are particularly associated with this risk (above 0.6) and low lithium levels are therefore recommended where it is essential to continue lithium during the course acute index ECT.
• This can be achieved by either lowering the lithium dose and withholding it the night before and the morning of treatment.

Benzodiazepines (BZDs) and Anticonvulsants (e.g Valproate, Lamotrigine, Carbamazepine):

• Consider ceasing benzodiazepine and anticonvulsants before ECT treatment. Benzodiazepines potentially shorten seizure duration and decrease treatment efficacy, particularly when administering RUL ECT.
• BZDs and Lamotrigine are associated with poor treatment efficacy when concurrently administered with ECT.
• Reduce dose and/or cease BZDs and anticonvulsants for better response and also to minimise cognitive side effects.

Antipsychotics (APs):

• APs have been shown to improve positive symptoms and work synergistically with ECT.  The combination of ECT and clozapine may be of particular benefit to people with an inadequate response to clozapine alone.

CONCLUSION

ECT is an effective treatment for treatment-resistant depression and may be more effective than additional pharmacological strategies when patients haven’t responded to several pharmacological interventions.

Consideration for ECT should include the severity of illness, patient factors, informed consent and side effects.

It is astonishing that, after more than 80 years, no other treatment for depression has been developed that is the equivalent of ECT. Despite this, ECT is difficult to access because of a combination of factors, including limited availability, lack of professional training in modern ECT techniques, misinformation campaigns, stigma and genuine concerns about effects on cognition. Another issue is that, like many effective medical treatments, the precise mechanism of ECT is not yet fully unravelled. Preclinical (including sham-controlled rodent and primate studies) and translational research increasingly support a central role for neuroplastic mechanisms in ECT. [Kirov et al., 2021]

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