THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGY “ The Pathogenesis of Adverse Events: Focus on Antidepressants and Antipsychotics” Vicente S. Cabuquit, MD, FPPA, FPCPsych, DPBP, DPM (Lond.) Professor, Department of Psychiatry, UERMMMC

TOPICS TO BE COVERED Adverse events of antidepressants Adverse events of antipsychotics Psychotropic Drug Alert System (PDAS)

ADVERSE EVENTS Usually sudden, apparently inexplicable reactions of patients on medications. 90% within one week of treatment 40% of patients 33% - CNS adverse events 36% - GIT adverse events

To Know The Receptors Is To Know The Adverse Events The actions of drugs on receptors determine the adverse events of drugs Drugs which act on many receptors can lead to numerous adverse events, some potentially fatal Conversely, drugs which act on just several receptors can cause less adverse events

ANTIDEPRESSANTS: MODES OF ACTION EFFECTS ON RECEPTORS TCAs SSRIs SNRIs NaSSA NE uptake inhibition yes no 5HT uptake inhibition 5HT2a blockade 5HT2c blockade 5HT3 blockade NE alpha2 blockade Ach blockade H1 blockade

MECHANISMS OF ANTIDEPRESSANTS Tricyclics (TCAs) – inhibit reuptake of 5HT, NE and other receptors plus fast Na channels SSRIs – selectively inhibit reuptake of 5HT SNRIs – inhibit reuptake of 5HT and NE NaSSA – blocks 5HT (5HT2a, 5HT2c, 5HT3) and NE (Ά2)

ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS TCAs – block Ach, NE, 5HT1, H1 presynaptically; stimulate 5HT, 5HT2, 5HT3 postsynaptically (built- in polypharmacy) Result in : dry mouth, blurred vision drowsiness, urinary retention constipation, dizziness and confusion (elderly) nausea/vomiting, tachycardia orthostatic hypotension, tremor sedation, sexual dysfunction, weight gain

ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS SSRIs – stimulate various 5HT subtypes Result in : 5HT3 – nausea/diarrhea, headache 5HT2a – nervousness/restlessness 5HT2c – nervousness/restlessness

ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS SNRIs – stimulate 5HT1, 5HT2, 5HT3 and noradrenergic receptors Result in: Similar to SSRIs - plus tachycardia, tremor, orthostatic hypotension, sedation

ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS NaSSA – blocks H1 and Ά2 receptors Result in: Sedation, weight gain, tremors

CLINICAL JUDGEMENTS Avoid using TCAs as first choice (built- in “polypharmacy”); receptor profile prone to adverse events; could be fatal in overdose (fast Na channels) First choice: either single receptor (SSRIs) or a dual receptor like NaSSA; safe in overdose Receptor profile favors NaSSA

DOPAMINE PATHWAYS IN THE BRAIN

CLINICAL IMPLICATIONS OF DOPAMINE PATHWAYS Nigrostriatal – controls movements; site of EPS events; site of typical antipsychotics Mesolimbic – involved in many behaviours (pleasure, hallucinations, delusions); site of atypicals

CLINICAL IMPLICATIONS OF DOPAMINE PATHWAYS Mesocortical – mediates + and – symptoms and cognitive side effects; site of typicals Tuberoinfundibular – controls prolactin; high levels cause galactorrhea, gynecomastia, amenorrhea, sexual dysfunction; site of typicals and some atypicals (risperidone)

FEEDBACK ADAPTIVE MECHANISM

SOME ADVERSE EVENTS OF ANTIPSYCHOTICS A normal extrapyramidal system requires a balance of dopamine and acetylcholine concentration. DA ACh

PSEUDO-PARKINSONISM ACh DA ACh DA ACh DA DA ACh Dopamine ↓ due to post-synaptic antagonism of dopamine receptors and degeneration of the NS dopaminergic pathway variations.

TARDIVE DYSKINESIA

TARDIVE DYSKINESIA DA ACh DA ACh DA ACh DA ACh

What Happens in TD? Chronic dopamine blockade causes reflex overactivity of dopamine in the basal ganglia Compensatory upregulation overcomes blockade; initially successful Later, compensation becomes inadequate; the balance between DA and Ach in the basal ganglia is disturbed. TD sets in

TARDIVE DYSKINESIA AND ACUTE EPS: A CAUTIONARY TALE Acute EPS is a risk factor in the appearance of TD (Chouinard, et al) Condition Start 10 years later End Parkinsonism 34% 70% Tardive Dyskinesia 21% 56% Both conditions 9% 39%

DYSTONIA: HYPER OR HYPO DOPAMINE ACTIVITY? Intake of antipsychotics  dopamine receptor blockade  dopamine depletion Based on Ach VS DA balance: DA, Ach  dystonia (?) With feedback loop mechanism: compensatory rapid  dopamine release  hyperdopaminergia DA, Ach  dystonia (?) Is dystonia a hypercholinergic or hypodopaminergic problem? CLUE: anticholinergics promptly relieve dystonia.

AKATHISIA: HYPO or HYPER DOPAMINE ACTIVITY? Could be due to hyperdopaminergic activity brought about by compensatory feedback system. But how come drugs which deplete dopamine also cause akathisia? Ex reserpine, tetrabenzene Nigrostriatal area: a chemical jungle

SITE OF AKATHISIA Site may be mesolimbic/mesocortical Here, DA exerts a tonic inhibitory action on locomotion  in mesocortical DA due to DA antagonism of antipsychotics  loss of tonic inhibition   purposeless activity, sense of inner restlessness  akathisia Anticholinergics  not effective β–adrenoreceptors  effective

D2 / 5HT2 BLOCKADES (PETscans) DRUG D2 blockade 5HT2 blockade Typicals 70 – 90% 20% Atypicals 40% 60% CLZ 30 – 60% 85 – 90%

ALSO, IN ATYPICALS When D2 is blocked in the NS pathway  5HT2 is also blocked  5HT2 blockade REVERSES the effects of D2 blockade (but ONLY in the NS pathway and NOT in the mesolimbic pathway). Clinical implication: EPS minimized, efficacy maintained.

FLUPHENAZINE AND THIORIDAZINE Both are dopamine receptor antagonists; fluphenazine more likely to cause EPS than thioridazine. Why? Thioridazine, unlike fluphenazine, is also a potent Ach antagonist (like procyclidine, an anti-parkinsonian agent). Giving thioridazine is like giving thioridazine PLUS procyclidine.

CLOZAPINE AND AGRANULOCYTOSIS Clozapine has 9 neurotransmitter receptors: one of them or several in combination may cause agranulocytosis. Exact cause: ? 5HT2, 5HT2c, 5HT3 D1, D2, D4 M1 H1 Ά1

ATYPICALS AND DIABETES Class effect, with olanzapine and clozapine more likely than others Weight gain a factor (olz and clz cause biggest gain); also hyperprolactinemia which disturbs insulin metabolism ( in risperidone) Philippine experience negligible, if at all

PSYCHOTROPIC DRUG ALERT SYSTEM (PDAS) Provides a road map to deal effectively with adverse events due to psychotropic drugs. Joint undertaking of the Philippine College of Psychopharmacology, of the Department of Health, and of the pharmaceutical companies.

MECHANISM OF REPORTAGE Levels of responses Level 1 – a patient with adverse event calls a telephone hotline manned by trained personnel who take details of the complaints. Emergency advice is given. Level 2 – data collected logged in central computer; psychiatrist of patient and company that manufactures the particular drug are informed.

MECHANISM OF REPORTAGE Level 3 – company communicates back with the psychiatrist and patient; psychiatrist discusses with the patient the problem and provides advice or treatment. Level 4 – company sends report to own monitoring body which may or may not act further on the reported adverse events.

* Cabuquit’s prayer against psychotropic adverse events “In the name of dopamine, serotonin, noradrenaline, and acetylcholine, and all the other neurotransmitters in the brain, may you remain stable in your systems, now and forever, amen.” * * Cabuquit’s prayer against psychotropic adverse events