Practical Points of Antipsychotics

and Antidepressants

Thanompong Sathienluckana Pharm. D., BCP, BCPP

Assistant Professor, Faculty of Pharmacy, Siam University
 Outlines
• Practical points of antipsychotics

• Practical points of antidepressants

• Role of pharmacist in psychiatric setting

• Case discussion

• Summary
 Practical Points of
Antipsychotic Drugs
Schizophrenia: “Progressive Neurodevelopmental Disoder”
The Four Domains of Psychopathology

Positive Symptoms Negative Symptoms

• hallucination • affective flattening
• delusion • impoverished speech
• paranoia • anhedonia
• though disorganization

Social and vocationally

disabilities

Mood Symptoms
Neurocognitive Symptoms
• depression
• distractibility
• anxiety
• executive function deficit
• agitation
• memory deficit
• aggression
• abstract thinking impairment
• suicidality
 Pathophysiology of Schizophrenia

• Dopaminergic hypothesis

- DA hyperactivity in mesolimbic tract and DA hypoactivity

in mesocortical tract

• Glutamatergic hypothesis

- NMDA receptor hypofunction

• Neuroinflammation / neuroimmune hypothesis

- Elevation of proinflammatory cytokines

Dopamine Tract
Pathophysiology of Schizophrenia and MOA of APs

Mesolimbic pathway Mesocortical pathway

Hyperserotonergic
SGAs
DA DA
5-HT2A
FGAs

Hyperdopaminergic Hypodopaminergic
D2 Limbic D1 PFCx

Negative symptoms
Positive symptoms
Cognitive symptoms
 First Generation Antipsychotics

• High potency FGAs

- low affinity for M1, H1, α1 receptor
- haloperidol, fluphenazine, trifluoperazine, pimozide,
flupenthixol
• Moderate potency FGAs
- perphenazine, zuclopenthixol
• Low potency FGAs
- high affinity for M1, H1, α1 receptor
- chlorpromazine, thioridazine
 Antipsychotics and D2 Dose-Response Curve of
Receptor Antagonist Antipsychotics
Effect
risk for EPS, cognitive
impairment and CV
mortality

Threshold for hyperprolactinemia

72

60-65

Dose-response effect

Subtherapeutic

Adapted from Pharmacotherapy: A Pathophysiologic Davis JM. J Clin Psychopharmacol 2004; 24: 192-208
Approach,7th edition, 2008
 Dosage Regimen of Antipsychotics in Schizophrenia
Antipsychotics Starting dose Dosing interval Target dose Target dose multi- Maximal dosage
(mg/day) FES (mg/day) episode (mg/day) (mg/day)
First generation antipsychotics (FGAs)
Chlorpromazine 50-150 2-4 300-500 300-1,000 1,000
Thioridazine 50-100 2-4 150-500 250-550 800
Perphenazine 4-24 2-4 6-36 12-64 64
Zuclopentixol 2-50 1-3 2-10 25-50 75
Haloperidol 1-10 2-3 1-4 3-15 30
Pimozide 1-4 2 1-4 2-12 16
Trifluoperazine 2-5 2 2-20 10-30 80
Flupenthixol 2-10 1-3 2-10 10-20 60
Second generation antipsychotics (SGAs)
Clozapine 25 2-4 100-250 300-600 900
Olanzapine 5-10 1 5-15 10-20 20
Risperidone 1-2 1-2 1-4 2-8 16
Quetiapine IR/XR 50 2/1 300-600 400-750 800
Ziprasidone 40 2 40-80 80-160 160
Aripiprazole 5-15 1 15 – (30) 15-30 30
Paliperidone 3-6 1 3-9 3-12 12
Amisulpride (positive sym) 200-800 2 200-800 400-800 1,200
Lurasidone 20-40 1 40-80 40-120 120
Efficacy/Adverse Effects Based-on Receptor Binding
Mechanism of action Clinical efficacy Adverse effects
D2 antagonist Relief positive symptom EPS, hyperprolactinemia
5-HT1A partial agonist Antidepressant and anxiolytic effect
Reduce negative and cognitive symptom
5-HT2A antagonist Reduce EPS and hyperprolactinemia Cardiometabolic adverse effect
Reduce negative and cognitive symptom
5-HT2C antagonist Antidepressant Cardiometabolic adverse effect
5-HT7 antagonist Antidepressant
Improve circadian rhythm
α1 antagonist Orthostatic hypotension,
sedation, dizziness, priapism
α2 antagonist increase noradrenergic and serotonergic Tachycardia, hypertension
(antidepressant)
H1 antagonist Sedation, weight gain
Muscarinic receptor Reduce EPS M1: cognitive impairment
antagonist M2: tachycardia
M3: insulin resistant, dry mouth,

constipation, blurred vision

M4 agonist: sialorrhea
 Receptor Profile of Antipsychotics
(expressed as equilibrium constant; Ki)
APZ LUR CLZ OLZ PLD RPD QTP AMP CPZ HAL PPZ
D2 ++++ ++++ + ++ +++ +++ + +++ +++ ++++ +++
(PA)
5-HT1A +++ +++ + + + + ++ - - - -
(norQTP)
5-HT2A ++ ++++ ++ +++ ++++ ++++ ++ - ++ ++ ++
5-HT2C ++ + +++ +++ ++ ++ + - +++ - +
5-HT7 ++ ++++ ++ + +++ +++ +(norQTP) ++ ++ - ++
α1 ++ ++ +++ ++ +++ +++ +++ - +++ ++ ++
α2 ++ +++(α2C) + + ++ +++ ++ - + + +
H1 ++ - ++++ ++++ ++ ++ +++ - ++++ + +++
M1 - - +++ +++ - - ++ - ++ - -
(norQTP)
M3 - - ++ + - - ++ - ++ - -
(norQTP)
M4 - - ++ + - - + - ++ - N/A

++++ very strong binding affinity (Ki < 1), +++ strong binding affinity (Ki 1-10), ++ moderate binding affinity (Ki 10-100),
+ weak binding affinity (Ki 100-1,000), - not binding or nelegible, PA = partial agonist, CLZ = clozapine, OLZ = olanzapine,
QTP = quetiapine, norQTP = norquetiapine (active metabolite), LUR = lurasidone, RPD = risperidone, APZ = aripiprazole,
PLD = paliperidone, AMP = amisulprise, HAL = haloperidol, PPZ = perphenazine, CPZ = chlorpromazine
 Adverse Effect of Antipsychotics
• D2-related adverse effects • Other adverse effects
- EPS - anticholinergic SE
- hyperprolactinemia - sedation
• Cardiovascular toxicity - ocular adverse effect
- orthostatic hypotension - skin photosensitivity
- tachycardia - sialorrhea
• Metabolic adverse effects • Serious adverse effects
- weight gain - NMS
- hyperglycemia - QTc prolongation
- dyslipidemia - seizure
- agranulocytosis:clozapine
 ADR of Antipsychotics
Antipsychotics Sedation EPS Akathisia Anticholinergic Orthostatic Weight gain Dyslipidemia/ Prolactin
hyperglycemia

First-generation antipsychotics
Chlorpromazine ++++ ++ ++ +++ ++++ ++ +++ +++
Fluphenazine + ++++ ++++ + + + + ++++
Haloperidol + ++++ ++++ + + + + ++++
Perphenazine ++ +++ +++ ++ + + + ++++
Thioridazine ++++ ++ ++ ++++ ++++ ++ +++ +++
Second-generation antipsychotics
Clozapine ++++ + + ++++ ++++ ++++ ++++ +
Olanzapine +++ + + ++ + ++++ ++++ +
Quetiapine +++ + + + ++ ++ ++ +
Risperidone + ++ ++ + ++ ++ + ++++
Ziprasidone ++ + ++ + + + + +
Aripiprazole + + ++ + + + + +
Paliperidone + ++ ++ + ++ ++ ++ ++++
Amisulpride + + / ++ + / ++ + + + + ++++
Lurasidone + ++ + / ++ + + + + +
Brexpiprazole + + + + + ++ + +
Cariprazine + ++ ++ + + + /+ + +

Adapted from 1. Pharmacotherapy: A Pathophysiologic Approach,10 h edition, 2017; 2. Solmi M. Ther Clin
Risk Manag 2017; 13: 757-77; 3. Leucht S. Lancet 2013; 382: 951-62; 4. Garnock-Jones KP. CNS Drugs15
2016; 30: 335-42; 5. Citrome L. Clin Schizophr Relat Psychoses 2016; 10: 109-19.
 Antipsychotics-Induced EPS

Tardive Dyskinesia

Pseudoparkinsonism

Akathisia

Acute
Dystonia

Start or 1 wk 2 wk 1 mo 3 mo
increase
dose of APs
 Medication used to treat EPS
Avoid in BPH, close-angle glaucoma, urinary retention

Block adrenergic effect in CNS: Lipophilic BBs

Holloman LC. Am J Health-Sys Pharm 1997;54:2461-77.
 Effect of Discontinuation of Anticholinergic
Use on Cognitive Function in Schizophrenia

• Gradual discontinuation of long term anticholinergic

drugs can improve cognitive function and subjective
QOL in schizophrenia
• Decrease trihexyphenidyl 2 mg q 2-4 week

Ogino S. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 78-83

• Gradual discontinuation of long term anticholinergic
drugs can improve cognitive function and subjective
QOL in schizophrenia
• Decrease trihexyphenidyl 2 mg q 2-4 week

Sathienluckana T. Integr Pharm Res Pract 2018; 7: 161-71.

 Antipsychotic-induced hyperprolactinemia

Henderson DC. J Clin Psychiatry 2008; 69: 32-44

Management of AP-Induced Hyperprolactinemia

• Decrease dose of antipsychotics

- should consider risk of relapse/recurrence

• Switch to prolactin-sparing antipsychotics

- quetiapine, clozapine, aripiprazole

• Add-on aripiprazole
• Add-on metformin
• Other strategies : hormone therapy, add-on DA rec
eptor agonists (not recommended)
 Metabolism Pathway of Antipsychotics
Antipsychotics 1A2 2D6 2C9 2C19 3A4 Other pathways
First generation antipsychotics (FGAs)
Chlorpromazine + +++ ++
Thioridazine ++ +++ +/-
Perphenazine + to ++ +++ ++ ++
Zuclopentixol +++
Haloperidol + +++ +++ UGT
Fluphenazine + +++
Pimozide ++ ++ +++
Trifluoperazine +++ UGT1A4
Second generation antipsychotics (SGAs)
Clozapine +++ + + to ++
Olanzapine +++ UGT1A4
Risperidone +++ ++
Quetiapine +++
Ziprasidone ++ Aldehyde oxidase
Aripiprazole +++ +++
Paliperidone +/- +/- P-gp
Amisulpride Renal
Lurasidone +++
Brexpiprazole +++ +++
Cariprazine + +++
Indication and C
ontraindication f
or Thioridazine
Therapy

CYP 2D6 inhibitors

- fluoxetine
- paroxetine
- bupropion
- duloxetine

Haddad PM. Drugs 2002; 62(11): 1649-71

 DI between Enzyme Inducing AEDs
with Antipsychotics

• Enzyme inducing AEDs (e.g. PHT, PB, and CBZ) redu

ce plasma level of many antipsychotics
- reduce haloperidol level 20-80%
- reduce ziprasidone and paliperidone level 30-35%
- reduce clozapine, olanzapine and risperidone level 50%
- reduce aripiprazole level 70%
- reduce quetiapine level > 80% (minimal reduction for
norquetiapine)
- reduce lurasidone level > 80%
DI between Quetiapine and CYP3A4 Ind
ucers

Grimm SW. Br J Clin Pharmacol 2005; 61: 58-69

 Practical Points of Haloperidol

• High potency D2 rec antagonist (EPS, ↑ prolactin)

• Low risk anticholinergic, seizure, metabolic side effects

• Safest for hepatotoxicity

• DI with CYP 2D6 / 3A4 (1A2) inhibitors / inducers

• Plateau dose about 10-12 mg/day

• Haloperidol injection [ √ ] IM [ Х ] IV
 Practical Points of Perphenazine

• Effective dose about 10-64 mg/day divided dose (in s

ome case may be used once daily based-on CATIE)

• Moderate potent D2 receptor antagonist

• ADR based-on receptor profile except CVS (bradycar

dia > tachycardia)

• In practice, use low dose perphenazine for anxiolytic

 Practical Points of Chlorpromazine

• Multifunctional drugs
- low dose: sedative agents
- high dose (> 300 mg/day): antipsychotic effect

• Safety concerns
- aware in patients with epilepsy, elderly, dementia
and hepatic impairment
Practical Points of
Antidepressants
 Clinical Presentation of Depression
• Emotional
- sad or depressed
- loss of interrest
• Physical
- chronic fatigue
- appetitie disturbances
- sleep disorder
• Cognitive
- poor memory, decreased ability to concentrate 30
 Pathophysiology of Depression

• Monoamine hypothesis

-  5-HT / NE / DA

• Neuroplasticity hypothesis

- neurogenesis and BDNF

• Neuroinflammation

 proinflammatory cytokines in CNS

31
Neuroplasticity Hypothesis of Depression
Abnormal of neuroplasticity (e.g. BDNF, ERK/MAPK pathway)

↑BDNF

32
Mechanism of Action of Antidepressants

BDNF : Brain-derived neurotrophic factor

33
Duman RS. Neuropsychopharmacology 2001; 25: 836-844
 Pattern of Antidepressant Response
Onset of action is delayed
• Initial clinical response: 1-2
weeks (physical symptom
improvement )
• Full therapeutic effect: 4-8
weeks (mood symptom
improvement)

Common Problem !!!!!!

Nonadherence in initial treatment
and maintenance phase

Wade A. Int Clin Psychopharmacol 2002; 17: 95-102

 Efficacy/Adverse Effect Profile Based-on Monoaminergic Activity
Pharmacologic action Efficacy/adverse effect
5-HT reuptake inhibition
NE reuptake inhibition
DA reuptake inhibition
α2 rec antagonist
α1 rec antagonist
H1 rec antagonist
Muscarinic rec antagonist
result
benefit Antidepressant and anxiolytic (via 5-HT1A rec
agonist )
risk Anxiety, agitation, insomnia and reduced REM
sleep, sexual dysfunction, hyponatremia, EPS (via
5-HT2A rec agonist)
Anxiety, anorexia (via 5-HT2C rec agonist)
Nausea/vomiting, GI problem (via 5-HT3,4 rec
agonist)
Benefit Antidepressant efficacy
risk Tremor, tachycardia, increased BP, sweating (via
α1 and β1 rec agonist)
benefit Antidepressant efficacy (via interaction in
rewardsystem)
risk Psychosis, euphoria (via D2 rec agonist in limbic
system)
benefit Antidepressant by increase noradrenergic (via
autorec) and serotonergic activity (via heterorec)
risk Tachycardia, increased BP
risk Orthostatic hypotension, dizziness, reflex
tachycardia
risk Sedation, weight gain
risk Confuse, cognitive impairment (via M1 rec )
Tachycardia (via M2 rec )
Dry mouth, constipation, urinary retention, insulin
resistant (via M3 rec )
 Primary Pharmacologic Actions of Antidep
ressants
Action TCAs SSRIs SNRIs SARIs bupropion mirtazapine agomelatine vortioxetine
/ mianserin

5-HT reuptake inhibition X X X X X

NE reuptake inhibition X X X
DA reuptake inhibition X
α2 receptor antagonist X X
5-HT1A receptor agonist X
5-HT2A receptor antagonist X X X
5-HT2C receptor antagonist X X
5-HT3 receptor antagonist X X
5-HT7 receptor antagonist X
α1 receptor antagonist X X X*
H1 receptor antagonist X X X
Muscarinic receptor X
antagonist

Melatonin receptor agonist X

* Only mianserin has α1 receptor blocking effect

Adapted from Pharmacotherapy Principles & Practice,4 th edition, 2016

 ADR of TCAs
• ADR (3o amines > 2o amines)
- inhibit M receptor → anticholinergic effect
- inhibit α1 receptor → orthostatic hypotension,
priapism
- inhibit H1 receptor → sedation, weight gain
- inhibit Na ch and Ikr (HERG) → cardiotoxicity
- reduce seizure threshold (clomipramine)
- weight gain (from antagonist effect of 5-HT2C/2A)
37
TCAs: Multifunctional Drugs

38
Relative Binding Affinities of Trazodone

• Sedative effect: low dose trazodone (25-100 mg/day)

• Antidepressant effect: high dose trazodone (150-300 mg/d)
39
Stahl SM. CNS Spectr 2009; 14: 536-46
Selective Serotonin Reuptake Inhibit
ors (SSRIs)

www.Preskorn.com 40
 ADR of SSRIs
• ADR of SSRIs mainly related to serotonergic activity
- 5-HT3 rec (in CTZ) → N/V
- 5-HT2A rec (in RAS and PPT) → insomnia and
reduced REM sleep
- 5-HT2A,2C rec (in ventromedial hypothalamus; VMH)
→ weight loss (long term may be vary effect)
- 5-HT2A rec (in SNc) → ↓DA → EPS
- 5-HT3, 4 rec (in GI tract) → diarrhea
- 5-HT2A rec (in spinal cord) → sexual dysfunction
- inhibition of 5-HT reuptake in platelet → risk for
bleeding 41
 SSRIs : Sexual Dysfunction
• Sexual dysfunction from SSRIs: dose-dependent
- anorgasm, delay orgasm/ delay ejaculation
- erectile dysfunction
• Management
♠ reduced dose but caution of exacerbate symptom
♠ Adjunctive therapy
- sildenafil 50-100 mg prn
- bupropion (most popular) as need or continue
- cyproheptadine 4-12 mg as need
42
♠ Change drugs : bupropion, mirtazapine, vortioxetin
 Pharmacist Workup: Fluoxetine

• Long t½ of norfluoxetine: 1-2 weeks

- use with caution in elderly
- when discontinuation of fluoxetine, consider washout
period before start other serotonergic antidepressants

• CYP inhibitors: 2D6 (strong), 2C9, 2C19, 3A4

- rapid onset and delay offset

• Most common ADR: serotonergic adverse effects

43
 CYP 450 Inhibitor
s of Antidepressa
nts

44
Preskorn SH. J Psychiatr Pract 2006; 12: 312-6
 Clinically Significant DI among Psychotropic an
d Cardiovascular Drugs

45
Pina IL. J Am Coll Cardiol 2018; 71: 2346-59
Pharmacist’s Role in Psychiatric Setting

• Assess the patients both before and after treatment

• Maximise the efficacy and safety of drug therapy in

depression

- promote adherence is the key !!!

- evidence-based pharmacotherapy in special

population and comorbidities

- safety consideration (ADR / DI)

46
Case Discussion
 Case Study

• Thai female 32 years, F/U in psychiatric hospital

• PMH: schizophrenia (3 years)
• MH: risperidone 6 mg/day + trihexyphenidyl 4 mg/day
• Right now patient can control psychotic symptom ver
y well about 2 years
• Before dispense medication, pharmacist ask patient
about menstrual cycle
• Pharmacist found the patient had amenorrhea about
6 months !!
 Guide to Management

• Check other causes of amenorrhea: NO

• Risperidone – induced hyperprolactinemia

• Management

- reduce dose

- switching to another antipsychotics

 Case Study

• Thai male 53 years, F/U in medical hospital

• PMH: cardioembolic stroke
• MH: warfarin 21 mg/week (previous INR stable abou
t 2-3), atorvastation, amlodipine
• Today, INR of patient about 4.5 !!
• Physician ask pharmacist for investigate the proble
m
• Pharmacist found patient received fluoxetine in psyc
hiatric hospital about depression 3 week ago
 Guide to Management

• Drug interaction between fluoxetine and warfarin

• Fluoxetine inhibit CYP2C9 and 3A4 resulting increas

e the level of warfarin
• Management

- reduce dose of warfarin

- switching to another antidepressants (e.g.

sertraline)
Thank you for
your attention

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