Pharmacology of antidepressants and mood stabilisers Dr Caroline Stewart c.a.stewart@dundee.ac.uk

Learning Outcomes List the main classes of antidepressant drug Describe the effects of antidepressant drugs on synaptic monoamine levels Describe the principal adverse effects of each drug class Define the term “mood stabiliser” and give examples

Core Clinical Problems Altered Mood Anxiety Arrested Intellectual Development Behavioural Problems in Adults Deliberate Self Harm Eating Disorders Medically Unexplained Symptoms Memory Problems Misusing Drugs or Alcohol Psychological Responses to Trauma Psychosis

CNS pharmacology Synaptic transmission (chemical) Formation, storage, release, action, inactivation of neurotransmitters Variety and distribution of neurotransmitters and receptor subtypes Access of drugs to the brain (BBB) see “Neuropharmacology introduction” on Blackboard

Antidepressant drugs Monoamine oxidase inhibitors Monoamine reuptake inhibitors Tricyclics & related selective serotonin reuptake inhibitors other non-selective reuptake inhibitors Atypical drugs (post-synaptic receptor effects) Most of the drug used have a similar efficacy but different profile of side effects.

The monoamine hypothesis Depression results from a functional deficit of monoamine transmitters (Schildkraut 1965) particularly: noradrenaline and serotonin (5-HT) Drugs that deplete stores of monoamines (e.g. reserpine) can induce low mood CSF from depressed patients have reduced levels of monoamines or metabolites Most drugs that treat depression act to increase monoaminergic transmission CH – CH2 – NH2 HO OH H — N HO CH2 – CH2 – NH2 Monoamine transmitters contain a single amine (green) group.

Noradrenaline pathways in human brain Cingulate Gyrus Frontal Cortex Thalamus Locus coeruleus LC → forebrain, brain stem, spinal cord control of arousal, sleep-wake cycle, anxiety Hippocampus A Locus coeruleus Amygdala Lateral tegmental area Brain stem anterior → limbic structures; posterior → brain stem, spinal cord role unclear

The noradrenergic synapse Tyrosine hydroxylase Reserpine L-AA decarboxylase X tyr VMAT metabolites DOPA MAOA dopamine 2 DA ß-hydroxylase noradrenaline NET COMT PLC 1 2 AC Gq Gi Gs  (-) (+) ion channels IP3, DAG, Ca2+ cAMP cellular responses

Serotonin pathways in human brain arousal sleep stress attention sexual behaviour mood regulation (e.g. aggression) processing of sensory information in cerebral cortex Cingulate Gyrus Frontal Cortex Thalamus Hippocampus Rostral Amygdala Caudal Raphe

The serotonergic synapse Reserpine tryptophan hydroxylase X tryp metabolites VMAT L-AA decarboxylase MAOB 5-OHTryp 5HT1D serotonin SERT MAO PLC AC 5HT1A Gi Gs 5HT2C/D Gq 5HT3 (-) (+) 5HT4,5,6 ion channels cAMP IP3, DAG, Ca2+ cellular responses

Monoamine oxidase inhibitors MAOA (expressed in NA neurones) – selective for NA, 5-HT MAOB (expressed in 5-HT neurones) – selective for -phenylethylamine, benzylamine Both – DA, tyramine, tryptamine MAOA inhibition – clorgyline, tranylcypromine, phenelzine, isocarboxazid MAOB inhibition – selegiline , tranylcypromine, phenelzine, isocarboxazid Meclobemide is reversible MAOA inhibitor

Monoamine oxidase inhibitors: site of action metabolites MAO inhibitor X precursor MAO neurotransmitter PLC AC Gq Gi Gs (-) (+) ion channels IP3, DAG, Ca2+ cAMP cellular responses

Monoamine oxidase inhibitors: adverse effects “Cheese reaction” caused by inhibition of MAO-A in gut (& liver). Irreversible inhibitors prevent breakdown of dietary tyramine – requires dietary restriction Drug preparations also containing amines should be avoided (e.g. pseudoephedrine) Potentiates the effects of tricyclic antidepressants e.g. on hypertension Potentiates effects of depressant drugs (e.g. barbiturates, morphine, ethanol) by decreasing their metabolism

Tricyclic & related antidepressants LIVER imipramine desmethylimipramine LIVER amitriptyline nortriptyline mianserin trazodone clomipramine

Tricyclic & related drugs: site of action metabolites precursor MAO neurotransmitter X Reuptake inhibitors PLC AC Gq Gi Gs (-) (+) ion channels IP3, DAG, Ca2+ cAMP cellular responses

Tricyclic antidepressants: adverse effects Improvement over MAOIs: No dietary control required Less severe drug interactions Adverse effects: muscarinic blockade sedation cardiac arrhythmias postural hypotension

Selective serotonin reuptake inhibitors citalopram escitalopram fluoxetine fluvoxamine maleate paroxetine sertraline

X SSRIs: site of action SSRIs tryp metabolites 5-HTryp serotonin MAO 5HT1D serotonin X SERT SSRIs PLC AC 5HT1A Gi Gs 5HT2C/D Gq 5HT3 (-) (+) 5HT4,5,6 ion channels cAMP IP3, DAG, Ca2+ cellular responses

SSRIs: adverse effects Improvements over MAOIs & tricyclics Non sedative Less cardiac effects Adverse effects: Nausea/diarrhoea Insomnia sexual dysfunction suicidal behaviour

Other monoamine reuptake inhibitors Dual reuptake inhibitors e.g venlafaxine Mode of action: Block the reuptake of monoamines (noradrenaline and/or 5-HT) into presynaptic terminals. Side effects: Lack major receptor-blocking actions so fewer side effects

Selective NA reuptake inhibitors? Atomoxetine inhibits NET and also DAT Reboxetine selective inhibitor of NET which was approved for major depression in 1997 Systematic review and meta-analysis (BMJ 341: c4737–c4737. doi:10.1136/bmj.c4737) has now determined no overall significant difference compared to control inferior response compared to SSRIs greater harm than placebo or SSRIs for adverse events

Selectivity of uptake inhibitors

Atypical antidepressant drugs Agomelatine: a melatonin receptor agonist and a selective serotonin-receptor antagonist Mirtazapine: mixed receptor effects (blocks 2, 5-HT2)

Efficacy of current antidepressants Most classes of drug have a similar clinical efficacy (40-70%) Side effect profiles differ Most have delayed onset of action (several weeks) How do they actually work? Long-term adaptation in receptor density/function? Alterations in corticosteroid receptors/HPA function?

Antidepressant drugs: clinical uses Moderate to severe depression Dysthymia Generalised anxiety disorder Panic disorder, OCD, PTSD Premenstrual dysphoric disorder Bulimia nervosa Neuropathic pain

Bipolar affective disorder treatment Acute treatment of symptoms: antipsychotics for episodes of mania antidepressants for episodes of depression Stabilise mood and prevent recurrence (prophylaxis): lithium salts anticonvulsants

Lithium therapy Discovered accidentally: Normally given as lithium carbonate Mode of action: block of phosphatidylinositol pathway (second messenger system)? inhibition of glycogen synthase kinase-?

Inositol depletion hypothesis PLC AC Gq Gi Gs (-) (+) ion channels IP3, DAG, Ca2+ cAMP cellular responses PIP2 DAG IP3 IP Glucose I PLC Gq IMPase Li+

Side effects of lithium therapy nausea, vomiting, anorexia, diarrhoea, tremor, polydipsia, polyuria lithium toxicity (drowsiness, ataxia and confusion) Blood levels must be monitored

Anticonvulsants as mood stabilisers Drugs like carbamazepine and valproic acid are now being for prophylaxis in bipolar disorder Mode of action: very unclear, perhaps block overactive pathways (kindling model of bipolar disorder) Side effects: carbamazepine: drowsiness, ataxia, cardiovascular effects, induces liver enzymes valproate: liver failure, teratogenicity (neural tube defects)

The End