Psychopharmacology: Anti-psychotic Medications

Brian Ladds, M.D.

Outline

• Role of dopamine in psychosis

• Dopamine pathways

• Dopamine receptors

• Anti-psychotic medication– Mechanism of action– Classification– Side effects

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

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

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

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

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)

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

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

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

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

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)

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

Anti-cholinergic Side Effects

• Blurred vision

• Urinary retention

• Constipation

• Dry mouth

• (Confusion)

Side Effects

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

Extra-pyramidal Symptoms

Parkinsonian-like symptoms – “Parkinson’s Disease” = too little dopamine

» due to degeneration of dopaminergic neurons

• bradykinesia

• rigidity – shuffling gait

• tremor

EPS cont.’

• Dystonia: sudden spasms of head/neck muscles

• Akathisia: restlessness– subjective and/or objective

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

EPS: Treatment

• Treatment with anti-cholinergic medication decreases EPS

• benztropine (Cogentin)• diphenhydramine (Benadryl)

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

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

“Atypical” Anti-psychotic Meds

• Clozapine (Clozaril)

• Risperidone (Risperidal)

• Olanzapine (Zyprexa)

• Quetiapine (Seroquel)

• Ziprasidone (Geodon)

“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

“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

Clozapine

• Clozapine– agranulocytosis 1%

• weekly cbc tests

• approved only for treatment-refractory schizophrenia seizure risk 3-5%, dose-dependant