1. Pharmacology of antipsychotics, antidepressants and mood stabilizers
Charles University in Prague, Third Faculty of Medicine
Pharmacology of antipsychotics, antidepressants and mood stabilizers
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine
Ruská 87, Prague 10,
GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME
Module Neurobehavioral Science I.
Academic year

2. ANTIPSYCHOTICS Psychotic symptoms
Positive (hallucinations, delusions, thought disorder , abnormal behaviour)
Negative (social withdrawal, emotional flattening, anhedonia, reluctance to perform everyday tasks)
Aetiology and pathogenesis of schizophrenia
The cause of schizophrenia remains unclear but involves a combination of genetic factors (multiple genes may be responsible) and environmental factors (particularly maternal virus infections).
The main neurotransmitters involved in the pathogenesis of schizophrenia are dopamine and glutamate, serotonin.
Drugs with dopaminergic effects (e.g. amphetamine), activating serotonergic or glutamatergic receptors (e.g. LSD or ketamine, respectively) can produce psychotic symptoms.
Neurodegeneration, apoptosis and oxidative stress may also play role in the pathogenesis of schizophrenia

3. ANTIPSYCHOTICS
CLASSIFICATION
First-generation („typical“, conventional) antipsychotics
phenothiazines - chlorpromazine
butyrophenones - haloperidol
Second-generation („Atypical“) antipsychotics
MARTA* - clozapine, olanzapine
SDA** – risperidone
Other e.g. sulpiride, quetiapine, aripiprazole
*Multi Acting Receptor Targeted Agents
**Serotonin Dopamine Antagonists

4. ANTIPSYCHOTICS Main Effects
Therapeutic antipsychotic, sedative/tranqilizant/anxiolytic/hypnotic, antiemetic
Adverse extrapyramidal, hyperprolactinemia, drowsiness,hypotension, antimuscarinic, weight gain

5. Carlsson 1963, later Nobel prize
ANTIPSYCHOTICS
Mechanism of action:
All antipsychotics antagonize D2 receptors
antagonism of receptors:
dopamine (D1, D2), serotonine (5-HT2A),
acetylcholine (M1), alpha1-adrenergic, histamine (H1)
Carlsson 1963, later Nobel prize

6. Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs.
Figure 45.1 Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs. Clinical potency is expressed as the daily dose used in treating schizophrenia, and binding activity is expressed as the concentration needed to produce 50% inhibition of haloperidol binding. (From Seeman P et al Nature 361: 717.)
Downloaded from: StudentConsult (on 15 December :54 AM)
© 2005 Elsevier

7. MESOLIMBIC, MESOCORTICAL*
ANTIPSYCHOTICS by blocking dopaminergic receptors in … produce …
MESOLIMBIC, MESOCORTICAL*
DOPAMINERGIC SYSTEM
NIGROSTRIATAL
DOPAMINERGIC SYSTEM
TUBEROINFUNDIBULAR
DOPAMINERGIC SYSTEM
Antipsychotic effects
Extrapyramidal effects
Endocrine effects
Acute (reversible):
Parkinsonism (rigidity, bradykinesia, tremor, Akathisia (a feeling of motor restlessness), Acute dystonia (involuntary movements e.g. protruding tongue, fixed upward gaze, spasm of neck muscles)
Chronic (irreversible):
Tardive dyskinesia (involuntary movements of the face and limbs)
Hyperprolactinemia
Gynaecomastia (breast swelling, pain and lactation)

8. Antipsychotics D1 Notes ++ +++ + + + + ++ ± +++ PA
alfa1 H1
mAch
5-HT2A
Notes
1st generation
chlorpromazine ++
+++
+ +
EPS, increased prolactin, hypotension, antimuscarinic effects
haloperidol +
+ ++ -
As chlorpromazine but fewer antimuscarinic effects
2nd generation
(atypical)
clozapine
Risk of agranulocytosis! Regular blood counts required Weight gain No EPS
olanzapine
Weight gain Without risk of agranulocytosis, No EPS
risperidone
Weight gain Significant risk of EPS
sulpiride
Increased prolactin (gynaecomastia)
quetiapine
Weight gain. No EPS
aripiprazole
+++ PA
Fewer side effects [“Third generation?“- dopamine stabilizers]
EPS=extrapyramidal side effects, PA = partial agonist

9. Mechanism of action of antipsychotic drugs - summary
Antipsychotic drugs are antagonists or partial agonists at D2 dopamine receptors, but most also block a variety of other receptors.
Antipsychotic potency generally runs parallel to activity on D2 receptors, but activities at other receptors (e.g. 5- HT2A and muscarinic) may reduce extrapyramidal side effects.
Activity at muscarininc, H1 and α receptors may determine unwanted side effect profile.
Imaging studies suggest that therapeutic effect requires about 80% occupancy of D2 receptors.

10. metabotropic glutamate receptors
ANTIPSYCHOTICS: CURRENT AND FUTURE DEVELOPMENTS
Preclinical and preliminary clinical studies have provided encouraging evidence that drugs modifying activity of specific types of
metabotropic glutamate receptors
may improve positive and negative symptoms as well as cognitive function in schizophrenia

11. ANTIDEPRESSANTS Depression - symptoms Mechanism of action
Emotional depressive mood, suicide ideas, feelings of guilt, …
Biological sleep disturbance, fatigue, psychosomatization
Mechanism of action
the monoamine theory
stimulation of neurogenesis, trophic effects

12. inhibition of reuptake of monoamines (NA, 5-HT) IMAO
Mechanism of action
the monoamine theory
inhibition of reuptake of monoamines (NA, 5-HT)
IMAO
depletion of monoamines (reserpine)

13. NERVE ENDING (presynaptic) ↓ ELIMINATION by MAO moklobemid
MONOAMINE THEORY:
NERVE ENDING (presynaptic)
SYNAPTIC CLEFT
POSTSYNAPTIC NEURON
↓ REUPTAKE imipramin
↓ STORAGE reserpin
Almost all antidepressants increase supply of monoamine transmitters at postsynaptic receptors
↓ ELIMINATION by MAO moklobemid
↑RELEASE amfetamin

14. stimulation of neurogenesis, trophic effects
Mechanism of action
stimulation of neurogenesis, trophic effects
antidepressants increase production of BDNF („Brain-derived-neurotrophic-factor“)
preventing neurogenesis (e.g. by irradiation) prevents antidepressive effects of antidepressants
chronic stress, corticoids > neuronal loss

15. ANTIDEPRESSANTS Re-uptake inhibitors (RUI)
CLASSIFICATION
Re-uptake inhibitors (RUI)
tricyclic (TCA) - amitriptyline, imipramine
SSRI – fluoxetine, sertraline, citalopram, escitalopram, paroxetine …
Other e.g. SNRI venlafaxin …, St. John‘s wort
IMAO
irreversible
reversible (RIMA) – moclobemide

16. ANTIDEPRESSANTS Main Effects
Individual differences [SSRI = „sixty seven responding individuals“]
Main Effects
Therapeutic antidepressive, anxiolytic (GAD, panic attacks …)
Adverse
TCA: antimuscarinic (dry mouth,blurred vision,constipation,urinary retention) dangerous in acute overdose (cardiac dysrhytmias )
SSRI: sexual disorders, weight gain, inhibition of CYP2D6 (codeine), serotonin syndrome (tremor, aggitation, diarhoea, tachycardia)
IMAO: food („cheese reaction“) and drug interactions

17. Antidepressive effects of antidepressants differ from those of placebo only in medium and severe depressions
Kirsch I. a spol. PLoS Medicine 5 (2): ,

18. MOOD STABILIZERS
Prophylaxis and treatment of mania, bipolar and unipolar disorder
Lithium –dose must be adjusted according to plasma concentration! (narrow therapeutic window) !!!
Valproate
Carbamazepine

19. Thank you for your attention