Electroconvulsive Therapy (ECT)

Definition

History

Indications

• Severe, treatment-resistant major depression (most common indication; ~100,000 patients/year in the USA)
• Catatonia
• Severe suicidality (where rapid response is needed)
• Mania unresponsive to medications
• Bipolar depression
• Life-threatening inanition (inability to eat due to psychiatric illness)

Pre-ECT Evaluation

• CBC, serum electrolytes, urinalysis, LFTs
• ECG (cardiovascular assessment)
• Comprehensive medical history and physical examination
• Spinal X-ray not routinely required due to use of modern muscle relaxants
• Informed consent

Technique

1. Anesthesia - patient receives general anesthesia (commonly methohexital or propofol) + muscle relaxant (succinylcholine) to prevent physical injury during seizure
2. Oxygenation - ventilated by mask
3. Electrode placement:
   • Bilateral (bitemporal) - most effective, but more cognitive side effects
   • Right unilateral - fewer cognitive effects, but dose must be adequately suprathreshold
   • Bifrontal - intermediate option
4. Stimulus - brief-pulse or ultrabrief-pulse square wave current; dose measured in millicoulombs (charge). Only ~20% of applied charge enters the skull because bone has high impedance.
5. Seizure duration goal - approximately 25-60 seconds (both motor and EEG)
6. Sessions - typically 3 times per week for 2-4 weeks (total: 6-12 treatments in an acute course)

Mechanism of Action

• Bilateral generalized seizure is necessary - subconvulsive stimulation is ineffective
• Neurotransmitter effects: downregulation of post-synaptic β-adrenergic receptors (same as antidepressants); effects on serotonin, dopamine, muscarinic/cholinergic systems
• Anticonvulsant effect: raises seizure threshold progressively over the course
• Metabolic changes: during seizure - increased cerebral blood flow, glucose, O2 use, and blood-brain barrier permeability; after seizure - decreased metabolism in frontal lobes (degree correlates with therapeutic response)
• Neuroplasticity: ECT triggers neurogenesis and structural changes, particularly in the hippocampus
• EEG: postictal suppression (60-90 seconds), followed by delta/theta waves, returning to baseline ~30 min later

Adverse Effects

Efficacy

• Response rates of 60-80% in treatment-resistant depression
• Faster onset than antidepressants (days, not weeks) - key advantage for suicidal or severely ill patients
• ECT remains the most effective treatment for major depression
• Nobel laureate Paul Greengard proposed renaming it "electrocortical therapy" to reduce stigma around the word "convulsion"

Continuation After ECT

• Continuation pharmacotherapy - combination of nortriptyline + lithium is superior to either alone (landmark 2001 trial)
• Maintenance ECT (monthly or more frequent sessions) for patients who relapse on medications

Electron Transport Chain (ETC)

Location

Overview

The Four Complexes

• Coenzyme Q (CoQ / ubiquinone) - lipid-soluble, free to diffuse in membrane; links Complexes I and II to Complex III
• Cytochrome c - small protein in the intermembrane space; shuttles electrons from Complex III to Complex IV

Step-by-Step Electron Flow

NADH → Complex I → CoQ ↘
                         → Complex III → Cytochrome c → Complex IV → ½O2 → H2O
FADH2 → Complex II → CoQ ↗

1. NADH donates a hydride ion (H-) to Complex I; electrons pass through FMN and Fe-S centers to CoQ. NAD+ is regenerated.
2. FADH2 (from succinate dehydrogenase, Complex II) donates electrons directly to CoQ. Since Complex I is bypassed, fewer H+ are pumped (lower ATP yield).
3. CoQH2 carries electrons to Complex III, where they pass through cytochrome b, Fe-S center, and cytochrome c1, then to cytochrome c.
4. Cytochrome c (in intermembrane space) ferries electrons to Complex IV.
5. Complex IV transfers electrons to the final acceptor: O2, reducing it to H2O. The iron in cytochromes alternates between Fe3+ (ferric) and Fe2+ (ferrous) with each electron transfer.

Chemiosmosis and ATP Synthesis (Complex V)

• Proton pumping at Complexes I, III, and IV creates an electrochemical proton gradient (high H+ in intermembrane space, low in matrix)
• H+ flow back into the matrix through ATP synthase (F0F1-ATPase, Complex V)
• This drives rotation of the F1 subunit, causing conformational changes in the three αβ subunit pairs (binding change mechanism), synthesizing ATP from ADP + Pi
• The energy-requiring step is actually ATP release from the synthase, not the phosphorylation itself
• ~3 H+ are needed per ATP synthesized

ATP Yield

• Energy released from NADH oxidation: ~53 kcal/mol
• Energy released from FADH2 oxidation: ~41 kcal/mol
• Only ~30% is captured as ATP; the rest is released as heat (this is the body's major source of heat)

Reactive Oxygen Species (ROS)

• Superoxide (O2-)
• Hydrogen peroxide (H2O2)
• Hydroxyl radicals (OH-)

Cytoplasmic NADH - Shuttle Systems

Inhibitors Summary

Clinical Relevance

• Ischemia/MI: Lack of O2 halts Complex IV → no H+ pumping → no ATP → mitochondrial swelling → irreversible cell death (necrosis)
• Cyanide poisoning: Blocks Complex IV; cells cannot use O2; treated with hydroxocobalamin or nitrites (form methemoglobin which scavenges CN-)
• Doxorubicin cardiotoxicity: Binds cardiolipin in the inner membrane; inhibits succinate oxidation, inactivates cytochrome oxidase, inhibits ATP synthase → reduced ATP in cardiomyocytes
• Mitochondrial diseases (MELAS, Leigh, MERRF): Mutations in mitochondrial DNA encoding ETC subunits