Drugs Used in Psychosis, Agitation & Extrapyramidal Symptoms

Dopamine pathways

1) Mesolimbic Pathway 2) Mesocortical Pathway 3) Nigrostriatal Pathway 4) Tuberofindibular Pathway

Phenothiazine

1. aliphatic side chain → *Chlorpromazine* 2. piperidine side chain → *Thioridazine* 3. piperazine side chain → *Trifluoperazine & Fluphenazine*

3) Nigrostriatal Pathway

Substantia nigra to Striatum (striatum = caudate + putamen) ‣ loss of neurons → Parkinson's Disease ‣ blockade of neurons from antipsychotics → Parkinsonian symptoms

4) Tuberofindibular Pathway

Tuberonfindibular pathway ‣ Hypothalamus to Pituitary → tonic inhibitory control over the release of prolactin from anterior pituitary → "man boobs" or "gynecomastia" ‣ *blockade from antipsychotic medication causes excessive prolactin → lactation*

2) Mesocortical Pathway

Ventral tegmentum (part of midbrain) to: ‣ Frontal cortex including prefrontal cortex ‣ *DIMINISHED tone associated with ↓ attention & cognition*

1) Mesolimbic Pathway

Ventral tegmentum (part of midbrain) to: ‣ Nucleus accumbens (part of ventral striatum [striatum = caudate + putamen] → essential endpoint for reward ‣ Amygdala → regulates emotional responsiveness ‣ Hippocampus → creates and process memories ‣ *EXCESSIVE dopaminergic tone associated with POSITIVE symptoms of psychosis → hallucinations, delusions*

EPS Treatment (Anticholinergics)

‣ *Benztropine (Cogentin) → M1 antagonist; least sedating, M/C used* ‣ *Trihexyphenideyl (Artane)* → M1 antagnoist ‣ *Diphenhydramine (Benadryl)* → antihistamine ‣ *Tx of choice for:* tremor, stiffness, drooling, dystonias ‣ not effective for akithisia, tardive dyskinesia ‣ *S/E:* fever, hot/flushed skin, constipation, blurred vision, urinary retention, dry mucous membrane

Medium potency

‣ *Drugs:* *Perphenazine*, Loxapine, Molindone ‣ *Mnemoni:* *M*edium *L*ethal *P*ills ‣ low-medium sedation, high EPS, low-medium AC

Electroconvulsive Therapy (ECT)

‣ *Uses:* *Depression (80%)*, Schizoaffective Disorder, Bipolar Disorder (not usually 1st-line Tx, should be considered for: Highly suicidal patients, depressed pregnant patients) ‣ *MOA:* place electrodes bilaterally on the head & electrocute you → 90% show some immediate improvement ‣ usually requires 5-10 treatments ‣ *S/E:* memory loss & headache common, returns to normal in several weeks ‣ *C/I:* ↑ cranial pressure

Clozapine

‣ *agranulocytosis*, seizure risks, diabetes/↑ lipids ‣ ↑ affinity for serotonin-receptors ‣ no EPS/TD, no sexual S/E

High potency

‣ *strong* affinity for Dopamine receptors → ↑ likelihood of extrapyramidal symptoms ‣ *less* affinity for other receptors (histamine & muscarinic/acetylcholinergic) → *less sedation & less anticholinergic effects* ‣ *Drugs:* *Fluphenazine*, Trifluoperizine, Thiothixene, *Haloperidol*, Pimozide ‣ *Mnemonic:* *F*ive *T*ruly *T*errible *H*arsh *P*ills ‣ medium-low sedation, *high EPS*, low AC

Low potency

‣ *weaker* affinity for Dopamine receptors → ↓ likelihood of EPS ‣ *more* affinity for other receptors → *more sedation & more AC effects* ‣ *Drugs:* *Chlorpromazine*, Mesoridazine, Thioridazine ‣ *Mnemonic:* *M*edications *C*reating *T*iredness ‣ medium-high sedation, low-medium EPS, high AC

Thioridazine

‣ Black Box ‣ QTc prolongation ‣ *S/E:* retrograde ejaculation & retinitis pigmentosa

Perphenazine

‣ CATIE trial supported equivalent to atypicals

Haloperidol

‣ DOC for delirium, agitation

Atypical/2nd generation Antipsychotics

‣ Dopamine & Serotonin blockade. ‣ Serotonin is like a "brake" to dopamine; block dopamine → S/E, BUT, block the "braking" of dopamine → ameliorate those effects ‣ it is like stopping the accelerator & the brake, so the car doesn't stop entirely

MOA of Typical/1st generation Antipsychotics

‣ Dopamine blockage ‣ α-adrenergic blockage (hypotension) ‣ anticholinergic effects ‣ blocks both NE re-uptake and serotonin & histamine receptors

Typical/1st generation Antipsychotics

‣ Phenothiazine ‣ Butyrophenones → *Haloperidol* ‣ Thioxanthenes → *Thiothixene* ‣ Other heterocyclics → *Pimozide & Loxapine*

Ziprasidone

‣ QTc prolongation ‣ inhibits 5-HT re-uptake ‣ acute agitation of psychosis mania ‣ given as intramuscular injection ‣ risk of morality in elderly with dementia

Which has stronger affinity for Dopamine receptors? Typical/1st Gen. or Atypical/2nd Gen. Antipsychotics?

‣ Typical/1st Gen. ‣ powerful blockers of Dopamine

Risperidone

‣ approved for aggression in Autism (Aripiprazole & Risperdal can also be used) ‣ like "typicals" at high doses ‣ dizzy, fatigue, dry mouth, tachycardia, HTN, EPS

Chlorpromazine

‣ heavily sedating ‣ approved for use in children

Olanzapine

‣ high likely diabetes/↑ lipids

What are Typical/1st Gen. broken down to?

‣ high potency ‣ medium potency ‣ low potency ‣ based on how *potent* or *strong* they bind to Dopamine receptors

What are extrapyramidal symptoms (EPS)?

‣ impairment in tracts that descend from the cortex, involved in motor control but not involving the pyramidal tracts (voluntary motor) ‣ *5 EPS:* Acute dystonia, Akathisia, Parkinsonism, Tardive Dyskinesia (TD) & Neuroleptic Malignant Syndrome (NMS)

Lurasidone

‣ may have less propensity for unwanted/negative effects on cognition

Aripiprazole

‣ nausea, akithisia, common S/E ‣ EPS rare ‣ partial agonist

EPS #5: Neuroleptic Malignant Syndrome (NMS)

‣ pipe-like rigidity, fever, tremor, altered level of consciousness ‣ hypotension, tachycardia ‣ *laboratory abnormalities → ↑ WBC & CK (Unique to this Dx)* ‣ mortality → 10-20% ‣ can occur any time in course of Tx ‣ SPECTRUM ‣ *Tx:* IV fluids, cooling blankets & stopping the Dopamine blockage (don't want to do a Dopamine agonist)

Uses of Atypical/2nd Gen

‣ schizophrenia and other psychotic disorders ‣ acute bipolar mania & maintenance ‣ augmentation of antidepressants & mood stabilizers ‣ aggression & impulsivity

EPS #4: Tardive Dyskinesia (TD) (3-6 months after medication)

‣ spastic facial distortion & tongue movement, pill-rolling *rhythmic small continuous movements* ‣ may extend to neck, trunk, & extremities (fingers & toes) ‣ delayed effect, usually beyond 6 months from starting medication ‣ ↑ risk with duration to exposure to antipsychotic, lithium, age, & other neurological diagnosis ‣ known to occur without antipsychotic therapy ‣ may be permanent, occur on discontinuation or resolve on own

EPS #1: Acute dystonia (AD) (1 week after medication)

‣ sustained muscular contraction of neck, eyes, throat ‣ generally occurs soon after starting medication ‣ *Question:* sense of what the diagnosis is from how long it took to develop, AD happens right away after start of medication

EPS #3: Parkinsonism (2-6 weeks after medication)

‣ tremor, muscle stiffness, slowed movement, drooling masked face ‣ generally occurs beyond 1 week after medication ‣ *Scenario:* gives a Parkinsonism symptom(s), ask which Dopaminergic pathway is impaired? *Nigrostiatal Pathway* or drug causing S/E? * Haloperidol (Haldol)*

EPS #2: Akathisia (10 weeks after medication)

‣ uncomfortable continuous motor restlessness ‣ can occur any time in Tx but generally in first week(s) ‣ easily misdiagnosed as the underlying psychiatric disorder ‣ *Tx:* β Blocker → Propranolol (must be lipid soluble because the brain is made up of lipids) ‣ *Scenario:* "Restless, urge to move"; "ants in their pants"; "internal restlessness"

Quetiapine

‣ very low EPS risk ‣ minimal AC, hypotension, drowsy, dry mouth, upset stomach ‣ very expensive

Uses of Typical/1st generation Antipsychotics

‣ ↓ psychotic symptoms → hallucinations, alterations of affect, ideas of reference, delusions