Neuroscience 18C - Antidepressant Drugs

Neuroscience 18c - Antidepressant Drugs Anil Chopra

1. Definitions & classification 2. Monoamine theory of depression 3. Types of antidepressant drugs a. Tricyclic antidepressants (TCAs) b. Monoamine oxidase inhibitors (MAOIs) c. Selective 5-HT re-uptake inhibitors (SSRIs) d. ‘Atypical’ antidepressants 4. Lithium 5. Electroconvulsive therapy (ECT)

Unipolar Depression  Characterised by mood swings in the same direction.  Is late in onset.  Reactive Depression o Related to a stressful event o Non familial.  Endogenous depression o Not related to a stressful event o Familial.

Bipolar Depression  Also known as manic depression  Characterised by oscillating depression.  Early adult onset  Strong hereditary tendency

Monoamine theory of Depression: this is the theory that depression is caused by deficits in monoamine production (dopamine, noradrenaline, serotonin). The theory is supported by the fact that: - Monoamine oxidase inhibitors (reduce catabolism of monoamines) improve mood. - Tri-cyclic antidepressants (block uptake of noradrenaline) improve mood. - Reserpine (depletes amines) causes depression in animals. - Methyldopa (reduces noradrenaline synthesis) causes depression. It does not however explain why: - Amphetamines, cocaine, and L-dopa (all increase monoamines) do not affect mood - Atypical antidepressants (iprindole) work without affecting monoamine systems. - There is a delay of 2 weeks between when therapy starts and when the effects take place. Tricyclic Antidepressants Names Amitriptyline, desipramine, imipramine, protriptyline, clomipramine.

Usage Chronic & bipolar depression. Neuropathic pain Nocturnal eneuresis ADHD

Mode of Action They block monoamine uptake (mainly noradrenaline and serotonin) from the synaptic cleft hence increase transmission.

Side Effects - Orally administered - Metabolised by liver and excreted in kidney - Long duration of action (1-3 days) They also have actions at muscarinic receptors: (anti-muscarinic effects) . Dry mouth and nose (salivary secretion is affected) . Blurred vision (accommodation in the eye is affected) . Decreased gastro-intestinal motility and secretion. This may lead to constipation . Urinary retention or difficulty with urination . Hyperthermia . Sedation . Postural hypotension . DANGER IF OVERSOSE  Seizures  Cardiac dysrhythmias.  Coma  Respiratory depression . Drug interactions  Increased action by aspirin, phenytoin, neuroleptic, OCP. Also reacts with CNS depressants and antihypertensive drugs. Monoamine Oxidase Inhibitors

Names Iproniazid, toloxatine, deprenyl

Usage Depression

Mode of Action Irreversibly block the action of mono-amine oxidase which causes decrease in breakdown of: - Noradrenaline (Monoamine oxidase A) - serotonin (Monoamine oxidase A) - dopamine (Monoamine oxidase B) Most are non-selective so will inhibit both of them and cause an increase in cytoplasmic NA and 5-HT (serotonin).

Side Effects and Pharmacokinetics - Orally administered - Long duration of action (2 weeks) - Metabolised in the liver and excreted in the urine. Side effects include:  Postural hypotension  Tremors  Insomnia  Siezures  Sedation  Weight gain  Liver damage  Has many drug interactions o ‘Cheese reaction’: Tyramine-containing foods + MAOI causes hypertensive crisis (throbbing headache, increase in blood pressure and risk of intracranial haemorrhage) o With TCA’s can cause hypertension o Can react with Pethidine to produce hyperpyrexia, restlessness, coma & hypotension

Selective Serotonin Reuptake Inhibitor

Name Fluoxetine (Prozac)

Usage Clinical depression

Mode of Action Works in the same way as MAOI – inhibits the uptake of serotonin only resulting in a less pronounced effect than MAOIs. Side Effects and Pharmacokinetics - Orally administered - Long duration of action (1-3 days) - Delayed onset of action (2 weeks) Interacts with tri-cyclic antidepressants. Side effects include:  Nausea,  Anorexia,  Insomnia  Loss of libido

Atypical Antidepressants

Names – maprotiline, venlafaxine, trazodone, mianserin, bupropion

Usage – Clinical depression

Mode of Action – generally unknown although some act as MAOIs.

Side Effects – rare.

Name – lithium

Usage – clinical depression & mania/bipolar depression

Mode of Action – inorganic ion taken as lithium carbonate. Not properly understood but has numerous effects on neurotransmitter systems such as interference with IP3 an cAMP formation (secondary messenger in dopamine receptors)

Side Effects and Pharmacokinetics - Taken orally as lithium carbonate. - Long plasma halflife and narrow therapeutic window. Interacts with diuretics (enhances action) Side effects include:  Nausea  Headache  Hypothyroidism  Tremor  Weakness  Mental confusion  Polyuria  Thirst  Acute overdose can lead to confusions, convulsions and dysrhythmias Electroconvulsive Therapy ECT

This is a treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. It is used as a treatment for severe major depression which has not responded to other treatment, and is also used in the treatment of mania (often in bipolar disorder), catatonia, schizophrenia and other disorders.