1. 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

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

3. 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

4. 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

5. 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

6. 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)

7. 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

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

9. 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

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

11. 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

12. DOPAMINE PATHWAYS IN THE BRAIN

13. 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

14. 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)

15. FEEDBACK ADAPTIVE MECHANISM

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

17. 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.

18. TARDIVE DYSKINESIA

19. TARDIVE DYSKINESIA DA
ACh DA
ACh DA
ACh DA
ACh

20. 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

21. 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%

22. 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.

23. 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

24. 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

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

26. 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.

27. 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.

28. 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

29. 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

30. 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.

31. 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.

32. 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.

33. * 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