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1

Define Psychoses

Mental disorders characterized by rifts in rational thought, inappropriate processing of sensory information, and disturbed views of reality and self. Psychotic symptoms are generally not recognized as such by the sufferer.

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Define Nueroses

Abnormal reaction to an external state that is generally recognized as abnormal by the sufferer.

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Psychotic markers, "positive" or overt symptoms

Delusions and/or paranoia, hallucinations (mostly auditory), Disordered thoughts/loose ideation, inappropriate emotional responses

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Psychoses in disease states

Schizophrenia, delirium in dementia, manic psychoses, secondary to severe depression, post-traumatic stress disorders, drug-induced

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Drug Induced psychoses

Amphetamine, steroid, LSD, ketamine, PCP, sedative/hypnotics

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Schizophrenia

Disease with psychotic symptoms affecting 1% of the population (men and women affected equally; there are multiple and varied subtypes)

Age of onset varies from 15-25 years (odd behaviors and other symptoms often precede onset of psychoses)

Clinical presentation and course are highly variable

High mortality (10%) with poor long term prognosis

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Negative or residual symptoms of schizophrenia

Flat affect; anhedonia and apathy; anxiety; lack of volition; social and emotional withdrawal; disorganized speech, thinking and behavior; impaired attention; poor self-care

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Etiology of schizophrenia

Neurodevelopmental disorder (cause unknown)

Genetic and environmental factors in causation (twin studies show a genetic predisposition, perinatal insults and traumatic early life events increase susceptibility)

Anatomic irregularities (enlarged cerebral ventricles, reduced cortical mass, hypofrontality)

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Hypofrontality

Reduced processing in the prefrontal cortex

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Treatment options for Schizophrenia

Frontal lobotomy (used in 40s and 50s, calmed patients but was permanently debilitating)

Psycotherapy (ineffective by itself)

Cognitive behavioral therapy (improves social skill, life skills and may improve ability to self-assess)

Self medication with nicotine

Antipsychotics

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Antipsychotic Agents

AKA Neuroleptics or major tranquilizers

Most effective means of treating psychotic symptoms with much less effect on emotional and social problems

Effective in 70% of psychotic patients (reduces frequency and obtrusiveness of hallucinations and delusions; reduces the 12 month relapse rate from 90% without drugs to 40% with drugs; additional affects included improved mood, reduced anxiety and improved sleep)

Not anesthetics but can supplement anesthesia

Do NOT cure schizophrenia and are usually life-long treatments

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Latency of effectiveness of anti-psychotics

Calming (tranquilizing) effects may be seen within minutes to hours

Diminished psychotic symptoms within 24-28 hours

Full antipsychotic effects evolve over 2-8 weeks

Improvement may continue for up to 6 months (fewer hallucinations, less paranoia and more rational thinking can significantly improve functioning)

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D2 Antagonism correlation with antipsychotic pharmacology

All antipsychotics are D2 dopamine receptor antagonists or weak partial agonists

Antipsychotic affinity for D2 receptors correlates wtih average clinical dose (an approximation of potency)

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Dopaminergic Pathways

Mesocortical (VTA to frontal and prefrontal cortex)

Mesolimbic (VTA to nucleus accumbens in limbic area)

Nigrostriatal (Substantia nigra to striatum in the basal ganglia)

Tuberoinfundibular (hypothalamus to pituitary)

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Dopamine Theory of Psychosis

Psychoses resulting from over-stimulated dopamine receptors in the cortex (reasoning) and limbic (emotional) areas

>drugs that increase dopamine levels (e.g. amphetamine) can induce or exacerbate psychoses
>drug that block dopamine release decrease psychoses (reserpine)

Dopamine "hypofrontality" refers to a hypothesized lack of dopamine in the mesocortical pathway

Positive symptoms seem to be a result of dopamine hyperactivity

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Serotonin signaling in psychosis

LSD is a serotonin partial agonist

Newer antipsychotics have higher affinity for serotonin 5HT2 receptors

Negative symptoms may be associated with dysfunction in the serotonin (and dopamine) systems

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Glutamate signaling in psychosis

NMDA receptors:

>Glutamate antagonists (Ketamine and PCP) can exacerbate or produce psychoses
>Potential new antipsychotics affecting glutamate signaling have not moved beyond Phase 3 clinical trials yet

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1st Generation Antipsychotics

Phenothiazines and related thioxanthines (Chlorpromazine - the grandparent of all antipsychotics, Thioridaine, Fluphenazine, Thiothixene)

Butyrophenones and related are more D2 selective (Haloperidol, Pimozide)

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2nd Generation Antipsychotics

Dibenzapines (Clozapine, Loxapine, Olanzapine, Quetiapine)

Others (Risperidone, Ziprasidone, Aripiprazole, Iloperidone, Paliperidone, Lurasidone, Asenapine, Brexpiprazole, Cariprazine)

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Side Effects: Nigrostriatal Pathway

Initiation and control of movement and muscle tone

Selectively degenerated in Parkinson's disease

Involved in obsessive and compulsive disorders

Antagonism of D2 receptors in the basal ganglia produces extrapyramidal side effects (EPS)

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Toxic Dose-Limiting Effects: EPS/Acute Dyskinesias

Akathisia (after a few months) - motor restlessness and distress compels constant movement

Dystonia (early on, within 1-2 doses) - spasms of neck and face muscles including grimacing, torticollus, ocular dysfunction; involuntary, often painful movements and bodily distortions

Respiratory disress - pharyngeal/laryngeal dysfunction

Pseudo-Parkinsonism (occurs around 6 months) - bradykinesia and rigidity, resting treomr of head and hands, flat affect)

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EPS or Motor Side Effects

Dose related - most common with high dose bolus or initial depo injection

Treat by decreasing dose, changing drugs, adding anti-Parkinson agent

Women more sensitive than men

Lead to irreversible tardive dyskinesias

Less selective antipsychotics (the dirty drugs) cause fewer EPS

In general, 2nd generation drugs cause less EPS than 1st generation drugs

23

Muscarinic Receptor Affinity and EPS

Inverse relationship

In order of increasing EPS frequency:
(Thioridazine < Clozapine < Chlorpromazine < Promazine < Thiothixene Fluphenazine < Haloperidol)

Haloperidol is often given in combination with benzotropine, a muscarinic antagonist, to reduce EPS

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Muscarinic antagonists in combo with dopamine antagonists (or as properties of dopamine antagonists) work by...

Helping to reset the motor output imbalance caused by D2 antagonists

25

Tardive Dyskinesias

Involuntary movement of the tongue, lips, head and neck (grimacing, tongue rolling, lip smacking, eye rolling)

Occurs in up to 50% of patients long-term (after a few years) of treatment with antipsychotics - resulting from increase of D2 receptors

Frequently irreversible

Severity is related to dose, duration of treatment, and gender

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Mechanism for Tardive Dyskinesias

Resulting from too many Dopamine (D2) receptors as a result of long term treatment with antipsychotics

Can occur short term

Treatment: Withdraw or reduce antipsychotic, consider a cholinomimetic; Vitamin B6 supplements (100mg pyridoxine/day) used as prevention

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Tuberoinfundibular Pathway SIde Effects

Pituitary D2 receptors normally inhibit prolactin

Blockade of D2 inhibition leads to increased prolactin (gynecomastia and increased lactation; disturbed thermal regulation; amennorhea, inretility and sexual dysfunction)

Prolactin levels above 100 ng/mL lead to prolactinomas and increased risk of breast cancer (usually don't see this in antipsychotics)

28

2nd Generation Antipsychotics (general)

Relative to FGAs, SGAs:

One average have a higher affinity for 5HT2 receptors

Have somewhat lower affinity for D2 dopamine receptors (by 5-50 fold)

Generally have lower incidence of EPS and endocrine side effects


Recommended as first line therapies (have other side effects)

29

Serotonergic CNS pathways/antipsychotic theory

Projection from the raphe to the pre-frontal cortex, hypothalamus, limbic areas, spinal reflex areas, and basal ganglia

5HT2 receptors modulate dopamine release

Theory is that there are fewer EPS with antipsychotics that combine 5HT2 antagonism with lower affinity D2 antagonism because 5HT modifies dopamine release in the basal ganglia

*the best possible drug is a DA/HT/muscarinic antagonist but is dirty in nature (blocking of 5HT2 heteroreceptors will result to increased dopamin in cleft with every signal)

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Autonomic Effects of antipsychotics

A1 adrenergic antagonism

Muscarinic cholinergic antagonism (blind, hot, dry, red, confusion/crazy and other anticholinergic effects)

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Sedation in Antipsychotics

H1 antagonism leads to drowsiness and sedation, weight gain, and anti-nausea effects on vestibular apparatus

Difficult for patients on prophylactic or chronic therapy

Very useful for acute treatment of florid psychoses with agitation

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Weight gain/metabolic disorder with antipsychotics

Serotonin, H1 and alpha1 adrenergic receptor blockade causes:

Increased appetite, increased fat storage, sleep apnea, hypocholesterolemia, insulin insensitivity and hypoglycemia

*lipids, weight, HbA1c, and BP should all be monitored in all patients on antipsychotic therapy

**susceptibility varies and we don't know why

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Antipsychotics with large weight gain

Clozapine, Olanzapine, Chlorpromazine, Thioridazine

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Antipsychotics with moderate weight gain

Risperidone, Quetiapine, Paliperidone, Iloperidone

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Antipsychotics with no weight gain (weight neutral)

Ziprasidone, Aripiprazole, Molindone, Haloperidol, Asenapine

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Potentially fatal cardiotoxicities with antipsychotics

Increased risk of sudden cardiac death (prolonged QT interval may cause Torsades de pointe arrythmias; highest risk with ziprasionde, pimozide and thioridazine)

Muscarinic and a1 adrenergic antagonist activities

Weight gain and CV disease increase

Smoking

37

Black Box Warning for Antipsychotics

Increased mortality in elderly patients with dementia related psychosis (1.6-1.7 times placebo)

Most deaths appeared to be either CV or infectious in nature (these drugs are not approved for the treatment of patients with dementia-related psychosis)

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Neuroleptic malignant syndrome

Rare, recurrent with 10% mortality, patients with severe EPS are more vulnerable (could be related to D2 antagonism)

Manifestations include: Hyperthermia and diaphoresis; altered mental status, including catatonia and stupor; flucutating blood pressure and pulse; tremor and muscle rigidity; acute renal failure

Treatment: Immediate discontinuation of all antipsychotic medication; dantrolene may be helpful; bromocriptine may be helpful

39

Hypersensitivity reactions to antipsychotics

Primarily with phenothiazines (5%): Dermal reactions including rash and photosensitivity, ocular opacities of the cornea and lens, jaundice

Alert for Asenapine: Serious hypersensitivity and anaphylaxis alert

40

Clozapine unique efficacy and toxicities

Significant advantage (uniquely effective in 25-30% of treatment-resistant patients; no reported EPS)

Serious toxicities make it a third line agent (Leukopenia can lead to agranulocytosis in 1.3% which can be fatal in 4-16% of patients; myocarditis; CV collapse including hypotension, respiratory or cardiac arrest)

Decreased seizure threshold

Sedation, antimuscarinic effects (severe constipation), etc.

41

Olanzapine

Very similar in structure and profile to clozapine but lacking the unique toxicities

2nd most effective antipsychotic of all

Weight gain is very problematic at effective doses making it a third line agent

42

Quetiapine (Seroquel)

Sedating - making it useful to reduce anxiety and agitation

Low EPS (active metabolite is an anti-muscarinic)

Low adrenergic blockade

Moderate weight gain/risk of metabolic syndrome

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Risperidone

Lack of sedation is attractive for some patients

Restlessness/agitation is a problem

Dose needs to be controlled to avoid EPS

Approved for irritability in autism spectrum disorders at age 5 and up

Used more often as a maintenance therapy for those looking to function in normal society

44

Paliperidone

Hydroxy metabolite of risperidone (similar pharmcologic profile, including restlessness and EPS)

Sustained release form leads to once monthly dosing

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Ziprasidone and Lurasidone

Low weight gain, low EPS

Problems including QT prolongation (less with Lurasidone)

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Iloperidone

Low EPS, low-anticholinergic effects, low weight gain, low tendency for metabolic syndrome

Hypotension is a problem and requires dose titration

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Asenapine

Minimal weight gain and metabolic disturbance

Extreme sedation from histamine receptor antagonism

Off-label use to treat PTSD

Serious hypersensitivity reactions including anaphylaxis alert issued by FDA in 2011

Concern with EPS due to relatively low affinity for muscarinic receptors

No better efficacy than other antipsychotics and noto as good in some trials

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Aripiprazole

D2 partial agonist (~30%)

Transient nausea

No endocrine disturbances (slight decrease in prolactin)

No receptor sensitization (low risk for EPS or TD)

Good efficacy (but may increase psychoses in a subset of patients)

Agitating (may be a problem in some patients)

Alpha 1 antagonist (increasing reports of weight gain with time)

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Brexipiprazole

Newer to market

Similar to aripiprazole but weaker D2 partial agonism (partial agonist at 5HT1, antagonist at 5HT2 receptors; low risk for EPS or TD)

Alpha 1 antagonism

Low affinity for histamine receptors

Common side effects include akathisia and moderate weight gain

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Cariprazine

Newer to market

Pharmcology similar to Aripiprazole (D2 partial antagonist, 5HT1A partial agonist, 5HT2 antagonist)

D3 partial agonist with higher affinity for D3 than D2

Extrapyramidal side effects in 1/4 to 1/3 patients

Low weight gain

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American Psychiatric Association top 5 recommendations from the "Choosing Wisely" initiative

Don't prescribe antipsychotic medications to patients for any indication without appropriate initial evaluation and appropriate ongoing monitoring

Don't routinely prescribe 2 or more antipsychotic medications concurrently

Don't use antipsychotics as first choice to treat behavioral and psychological symptoms of dementia

Don't routinely prescribe antipsychotic medications as a first-line intervention for insomnia in adults

Don't routinely prescribe antipsychotic medications as a first-line intervention for children and adolescents for any diagnosis other than psychotic disorders

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Additional Antipsychotic Indications

Tourette's (uncontrolled vocal outbursts, tics and repetitive movements | too much dopaminergic activity in the nigrostriatial pathway | treat with high affinity D2 antagonist like pimozide)

Neuroleptanesthesia (Innovar = Droperidol plus fentanyl)

Adjunct treatment to anti-depressants (not alone | approved for aripiprazole, quetiapine and olanzapine)

Behavioral problems, including irritability, in autism spectrum disorders (approved for risperidone and aripiprazole)

Bipolar disorder

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Additional indications-more on these in the GI unit

Severe nausea and vomiting (Promethazine and Prochlorperazine, D2 antagonists block the chemoreceptor trigger zone and increase GI motility, antihistamine and anticholinergic effects block motion sickness)

Intractable hiccups (Thorazine)

Insufficient lactation (Metoclopramide, inhibit D2 inhibition of prolactin release)