Behavioral disturbances that can manifest itself as any of the following......

Paranoid - Persecution, conspiracy, talking about you, others control your actions

Disorganized/Excited - Conceptual Disorganization, disorientation, excitement

Depressive - retardation, apathy, self punishment, blame

- Hallucinatory voices

- Voices that accuse/blame/threaten

- Visions

- Hallucinations of touch, taste, odor, vision

- Peculiar rigid postures

- Overt tension

- Inappropriate grins/giggles

- Repetitive gestures

- Talking/muttering/mumbling to oneself

- Glancing around

- Most deterioration occurs from first episode to 5 years

- 10-15% are disorder free after first episode

- 5-10 years most patients level out

- 10-15% remain chronically psychotic, with 25-50% of these attempting suicide and 10% completing it.

Best Characteristics for good prognosis:  Female, no family history, higher IQ or social skills, later onset, married, acute onset with precipitating stress, mostly positive sx not disorganized or negative

Positive symptoms - Dopamine receptor hyperactivity in the caudate

Negative Symptoms - Dopamine hypofunction in prefrontal cortex

Cognitive Impairment - Dopamine hypofunction in prefrontal cortex

Positive Symptoms:  An excess or distortion of normal functions

Psychotic:  Distortions in thought content, Delusions, perceptions, hallucinations

Disorganizational Dimension:  Language and thought process, disorganized speech, self monitoring behavior, grossly disorganized or catatonic behavior

Negative symptoms - Decrease or loss of normal functions

- Restrictions in emotional expression

- Affective flattening-restriction in the range and intensity of emotion

- Decrease in thought and speech

- Alogia - restrictions in fluency and productivity of speech

- Avolition - reduced desire, motivation, or persistence

- Low energy

- Attention

- Working memory

- Executive function

Psychotherapeutic - CBT, rehabilitation centers, case management, psychoeducation, targeted cognitive therapy, basic living and social skills, employment and housing support

Pharmacotherapy - First gen. atypical antipsychotics, second generation atypical antipsychotics, augmentation agents. 

Drugs include Clozapine, Risperidone, Paliperidone, Olanzapine, Quetiapine, Ziprasidone

- Reduced output to help with (+) sx, but not enough to block pleasure/reward center.  Also normalizes mesocortical, nigrostriatal, and Tuberoinfundibular regions. 

- Increase DA release

- Improve cognitive, negative, and affective sx

- Reduces EPS and Prolactin elevation

- Decrease glutamate release (reduces (+) sx)

- Stimulates DA release

- Improves positive symptoms

- Reduces negative symptoms

- Reduces EPS

- Reduces Prolactin levels

- Serotonin - Dopamine antagonism

- Rapid dissociation of D2 antagonism

- Dopamine partial agonist

Huge drug chart showing First gen and Second gen antipsychotics.  Can you name initial dose, frequency, MDD, and Half-life?

• Class/Generic	Brand	Initial * Dose (mg)	Usual Dose Range(mg/day)	Chlorpromazine Equivalents (mg/day)	Half-Life  (hours)
  First Generation
  Phenothiazine			(manuf max)
  Chlorpromazine*	Thorazine	10 1-4	100-800      (2000)	100	6
  Fluphenazine*	Prolixin	1 3-4	5-20             (40)	2	33
  Perphenazine*	Trilafon	4-8 3	10-64           (64)	10	10
  Trifluoperazine	Stelazine	1-2 2	10-50           (80)	5	24
  Thioridazine*	Mellaril	50-100 3	100-800       (800)	100	24
  Others
  Loxapine	Loxitane	10 2	10-100         (250)	10	4
  Molindone	Moban	50-75 1	10-100         (225)	10	24
  Thiothixene*	Navane	2 3 -5 2	10-50           (60)	4-5	34
  Haloperidol*	Haldol	0.5-5 2-3	5-20             (100)	2	21
  Second Generation
  Aripiprazole*	Abilify	10-15 1	10-30           (30)		75
  Clozapine*	Clozaril	12.5 1-2	150-600       (900)		12
  Olanzapine*	Zyprexa	5-10 1	10-30           (20)		33
  Paliperidone	Invega	6 1	3-9               (12)		23
  Quetiapine*&	Seroquel	25 2	250-500       (800)		6
  Risperidone*&	Risperdal	0.5 2	2-8               (16)		24
  Risperidone	Risperdal  Consta	25 IM	25-50 Q 2 weeks		23
  Ziprasidone*	Geodon	20 2	40-160         (200)		7

- Sedation

- Ach effects

- alpha-blockade (?)

- Decrease EPS

M1 (Muscarinic receptor) - Dry mouth, blurred vision, constipation, cognitive blunting, beneficial effect is decreased EPS

H1 (histamine receptor) - Weight gain and drowsiness

A1 (alpha-1 adrenergic receptor) - CV effects like orthostatic hypotension, dizziness, drowsiness

D2 in tuberofundibular - Causes rise in prolactin, galactorrhea and menstrual irregularities, gynecomastia and galactorrhea in men, tolerance does NOT develop,

*Olanzapine, Quetiapine, Ziprasidone or aripiprazole do not rise prolactin

- Significant weight gain in 40% of patients

- More at risk for CVD or DM

- ADA suggests changing med if weight gain > 5%

- Highest with second gen., spec. Olanzapine and Clozapine

- Orthostatic hypotension is > 20mmhg drop in SBP due to alpha blockage

- Associated with low potency FGA and SGA, notably Clozapine

- EKG changes typical of Thioridazine, Clozaril, and Ziprasidone

Dystonia - Can be life-threatening, 1-3 days after dose change or increase, primarily with FGA, treat with benzo or anticholinergic

Akathisia - Inability to sit still, 20-40% with FGA's but some SGA, Quetiapine and Clozapine lowest risk, antichol. not useful, change up dose

Pseudoparkinsonism - Postural abnormalities, dec. motor activity, 15-36% FGA's after dose change, antichol. will help, benztropine 1-2mg 1-2 times a day

Tardive Dyskinesia - FGA 1-60%, SGA 1%, irreversible if not caught soon enough

Sedation and Cognition - Early in therapy, tolerance can develop, SGA's improve affective and cog. sx

Seizures - Clozapine and Chlorpromazine responsible, seen in rapidly inc. dose, decrease dose if starting anticonvulsant

Thermoregulation - Poikilothermia, body is unable to regulate temperature, low pot. FGA's and anticholinergic SGA's

Neuroepileptic Malignant Syndrome - Similar to SS, D/C antipsychotic immediately

Opthalmologic - In glaucoma, use meds with low Ach effects.  Chlorpromazine causes opaque deposits.  Quetiapine and cataracts?  Thioridazine and retinitis pigmentosa at high doses

Hepatic System - Jaundice in 2% of people on FGA's

Genitourinary - Urinary incontinence and retetion, seen in FGA's and high prolactin levels

Hematologic - Agranulocytosis in chlorpromazine, thioridazine, and sometimes in clozapine

Dermatologic - rashes within 8 weeks of initiation, d/c and use steroid.  Photosensitivity with both FGA and SGA.  Chlorpromazine can yield blue or purplish cornia, and other low potency FGA's.

Misc - Excessive drooling in clozapine patients

• Class/Generic	Brand	CYP 1A2	CYP 2C19	CYP 2D6	CYP 3A4
  First Generation
  Phenothiazine
  Chlorpromazine	Thorazine				X(S)
  Fluphenazine	Prolixin			X (S)
  Perphenazine	Trilafon			X (S)
  Thioridazine	Mellaril			X (S)*
  Others
  Haloperidol	Haldol	X (S)		X (S)*	X (S)*
  Second Generation
  Aripiprazole	Abilify			X (S)*	X (S)*
  Clozapine	Clozaril	X (S)*	X (S)		X (S)
  Olanzapine	Zyprexa	X (S)			X (S)
  Quetiapine	Seroquel				X (S)
  Risperidone	Risperdal & R. Consta			X (S)*
  Ziprasidone	Geodon				X (S)

Assuming that each prior stage was a partial/no-response.......

Stage 1:  First episode and trial of single SGA

Stage 2:  Trial of single different SGA or FGA

Stage 3:  Clozapine

Stage 4:  Clozapine + FGA or SGA or ECT

Stage 5:  Trial of single SGA or FGA not in 1 or 2

Stage 6:  Combination therapy SGA, FGA, ECT, or adjunctive

Stages 1-3 are supported by randomized trials

Stages 4-6 are supported with case reports and expert opinions

Goals:  Decreased agitation, hostility, aggression, combativeness, anxiety, tension, normalization of sleeping/eating behavior

First Episode patients:  Require lower dosing, more sensitive to EPS effects, no consensus on FGA of SGA first line

Titration:   To mid range over first several days assuming no SE's

Partial responders:  If already at max dose can be titrated higher with supervision and follow-up

No response:  No response at 3-4 weeks go to stage 2, switch to different SGA or FGA.

- Increased socialization

- Improvements in self-care habits and mood

- Improvements in thought disorder

Maintenance:  Maitenance therapy prevents relapse (20-30% with Rx, 60-80% with placebo)

Meds continued for at least 12 months after remission

Some recommend up to 5 years after remission, lowest possible effective dose

Tapering:  at least 1-2 weeks for every antipsychotic, Low potency FGA's and clozapine have withdrawal sx.  During switching, taper several weeks after starting 2nd agent

Stage 1 and 2 - No greater than 12 weeks at therapeutic doses

Stage 3 - Up to 6 months

Stage 4, 5, 6 - 12 week trial at therapeutic doses, if > 20% improvement at any stage continue for additional 12 weeks

- Every 2-4 weeks depending on the agent

- Haloperidol every 4 weeks

- Fluphenazine every 1-3 weeks

- Risperidone every 2 weeks

- You're on clozapine, refractory status after two failed antipsychotics

- History of 6 agents:  unreliable historian?  undetermined dose and duration?

- Would require close monitoring with weekly blood draws

- Missing 2 or more days of treatment requires re-starting titration at 12.5mg twice daily

• 	Baseline	4 weeks	8 weeks	12 weeks	Yearly
  Family History	X
  Height/Weight (BMI)	X	X	X	X	X
  Waist Circumference	X				X
  Blood Pressure	X	X	X	X	X
  Fasting Lipid Panel	X			X	X
  Fasting Plasma Glucose	X			X	X

• Duration of therapy	Hematologic Parameters	Monitoring Frequency
  Initiation	WBC > 3500/mm3 and ANC > 2000/ mm3	Weekly for 6 months
  6-12 months	WBC > 3500/mm3 and ANC > 2000/ mm3	Every 2 weeks for 6 months
  12 months	WBC > 3500/mm3 and ANC > 2000/ mm3	Every 4 weeks
  Discontinuation	WBC > 3500/mm3 and ANC > 2000/ mm3	Weekly for 4 weeks after