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 2012-2013 http://vyuka.lf3.cuni.cz

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

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

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

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

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. 1976 Nature 361: 717.) Downloaded from: StudentConsult (on 15 December 2012 09:54 AM) © 2005 Elsevier

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)

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

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.

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

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

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)

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

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

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

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

Antidepressive effects of antidepressants differ from those of placebo only in medium and severe depressions Kirsch I. a spol. PLoS Medicine 5 (2): 260-268,2008 www.plosmedicine.org

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

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