Psychopharmacology: Anti-psychotic Medications

1. Psychopharmacology: Anti-psychotic Medications Brian Ladds, M.D.

2. Outline • Role of dopamine in psychosis • Dopamine pathways • Dopamine receptors • Anti-psychotic medication • Mechanism of action • Classification • Side effects

3. Schizophrenia: The Dopamine Hypothesis • Chance discovery: • Chlorpromazine (Thorazine) reduced psychosis • It was found to block the effects of dopamine • The “dopamine hypothesis” posits that the development of schizophrenia involves an overactive dopamine system in the brain

4. Dopamine • One of the key neurotransmitters in the brain, together with: • other ‘monoamine’ neurotransmitters: • norepinephrine, serotonin, acetylcholine • and the commonest neurotransmitters: • glutamate, GABA • Dopamine is released by a relatively small number of neurons, but serves important regulatory functions

6. Dopamine Pathways • Several different dopamine pathways • all originate in the mid-brain • 2 of the main clusters of nuclei are: • Ventral Tegmental Area (VTA) • meso-limbic/meso-cortical pathway • Substantia nigra • nigro-striatal pathway

7. Dopamine Pathways • VTA (ventral tegmental area): • Mesolimbic & mesocortical pathways • projects to limbic system and to the pre-frontal cortex • primary path for production of psychosis • target for anti-psychotic medications • blockade of the post-synaptic dopamine receptors

8. Dopamine Pathways • Substantia nigra: • Nigro-striatal pathway • projects to the striatum (caudate and putamen) • anti-psychotic medications block the post-synaptic dopamine receptor in the striatum causing motoric side effects (e.g., rigidity and tremors)

9. Dopamine Pathways • Arcuate and peri-ventricular nuclei: • Tubero-infindibular pathway • project to the pituitary • inhibits prolactin release • some anti-psychotic medications cause increased prolactin release (by blocking dopamine) and cause galactorrhea

10. Dopamine Receptors • D-2 receptors • main site of action for the anti-psychotic effect of many medications • clinical potency for many of the older conventional anti-psychotic medications correlates with their affinity for the post-synaptic D-2 receptor

11. Dopamine Receptors • D-3 and D4 receptors • May also be involved in the actions of some of the newer “atypical” anti-psychotic medications • These receptors are present more in limbic areas than in striatum • Therefore there are less motoric side effects with the newer “atypical” medications

12. Anti-psychotic Medication: Mechanism of Action • Anti-psychotic medications all involve blockade of the post-synaptic D-2 dopamine receptor • The therapeutic actions of the newer “atypical” anti-psychotic medications: • May also involve blockade of other types of dopamine receptors, and, • blockade of certain post-synaptic serotonin receptors

13. Anti-psychotic Medication: Classification • Conventional (typical) medications • vs. “atypical” anti-psychotic medications • Affinity for the D-2 receptor is related to clinical potency (especially for the conventional meds) • high affinity -> low dose • e.g., haloperidol (Haldol), fluphenazine (Prolixen) • low affinity -> high dose • e.g., chlorpromazine (Thorazine), thioridazine (Mellaril)

14. Side Effects • Low potency anti-psychotic medication (e.g., chlorpromazine) cause more of the non-motoric side effects • sedation (H-1 blockade) • hypotension (alpha-adrenergic blockade) • anti-cholinergic

15. Anti-cholinergic Side Effects • Blurred vision • Urinary retention • Constipation • Dry mouth • (Confusion)

16. Side Effects • High potency anti-psychotic medication (e.g., haloperidol) cause more of the neurological and motoric side effects • EPS • TD • NMS

17. Extra-pyramidal Symptoms Parkinsonian-like symptoms • “Parkinson’s Disease” = too little dopamine • due to degeneration of dopaminergic neurons • bradykinesia • rigidity • shuffling gait • tremor

18. EPS cont.’ • Dystonia: sudden spasms of head/neck muscles • Akathisia: restlessness • subjective and/or objective

19. EPS: Causes and Treatment • Nigro-striatal pathway finely regulates initiation and coordination of movements • DA inhibits acetycholine release in the striatum • Anti-psychotic medications block DA in striatum causing too much Ach there and thus EPS

20. EPS: Treatment • Treatment with anti-cholinergic medication decreases EPS • benztropine (Cogentin) • diphenhydramine (Benadryl)

21. Tardive Dyskinesia • Involuntary choreo-athetoid movements of mouth, tongue, and other muscles • generally irreversible • after chronic use (> 3 months) of anti-psychotic • 10-20% of patients on conventional AP after 1 year get TD • usually mild, but can be severe • elderly and women at highest risk • etiology: upregulation of striatal D-2 receptor

22. Neuroleptic Malignant Syndrome • NMS • fever • muscular rigidity • autonomic instability • tachycardia • increased blood pressure • fluctuating levels of consciousness • Rare, but has 20% mortality • Males and younger people are at higher risk

23. “Atypical” Anti-psychotic Meds • Clozapine (Clozaril) • Risperidone (Risperidal) • Olanzapine (Zyprexa) • Quetiapine (Seroquel) • Ziprasidone (Geodon)

24. “Atypical” Anti-psychotic Meds • Efficacy: • Generally comparable to conventional meds • May have some superior effects • Clozapine helps where conventional meds fail • They may help more with “negative symptoms” • Side effect profile: • Superior to conventional meds • Little EPS, less TD, less sedation, less anti-cholinergic • Some may cause EKG changes, weight gain, or increase in serum glucose

25. “Atypical” Anti-psychotic Meds • May have different mechanism of action • ? more DA blockade in mesolimbic pathway • including more D-3 and D-4 ? • ? weak D-2 antagonists, esp. in striatum • Minimal EPS • ?? Increases DA in frontal cortex ?? • ? Improves negative symptoms

26. Clozapine • Clozapine • agranulocytosis 1% • weekly cbc tests • approved only for treatment-refractory schizophrenia seizure risk 3-5%, dose-dependant