Schizophrenia Unit 2

Schizophrenia Diagnostic Criteria… 

→→ at least two symptoms must be present for a significant percentage of time during 1 month

1. At least one must be: delusions, hallucinations, or disorganized speech

2. One or more areas of function: work, interpersonal relations, self-care must be markedly below previous levels

3. Duration of at least six months, including at least of month of symptoms at least two symptoms must be present for a significant percent of time during 1 month

Schizophrenia symptoms…

1. Lack of emotion 

2. Disorganized thinking

3. Delusions

4. hallucinations 

POSITIVE SYMPTOMS

1. Delusions 

2. Hallucinations 

3. Disorganized speech 

4. Grossly disorganized/catatonic behavior 

NEGATIVE SYMPTOMS 

1. Absence or reduction in function 

2. Emotional blunting 

3. Alogia - inability to speak

4. Avolition - lack of desire/motivation 

5. Anhedonia - inability to experience pleasurable emotions 

6. Asociality 

7. depression

8. demoralization

DSM-5 Criteria…

1. 2+ of the following for one or more months…positive symptoms 

   1. Hallucinations 

   2. Delusions 

   3. Disorganized thoughts 

   4. Disorganized behavior 

   5. Negative symptoms 

AT LEAST ONE MUST BE: hallucinations, delusions, disorganized thoughts 

1. Functional impairment/distress 

2. Continuous for 6 or more months 

3. No history of autism, substance use, or other medical conditions 

LAW OF THIRDS…

⅓ significant treatment effects 

⅓ signficiant improvement but not to the same degree 

• Relapses, hospitalizations, difficult with employment and social 

⅓ significant symptoms - mild response to treatment, needs assistance 

• 10% treatment resistant = institutionalized state hospitals 

Pathophysiology of Schizophrenia…

→ dopamine pathways:

1. HYPERdopaminergic limbic system  

   1. Excess D2 receptor activation

2. HYPOdopaminergic in pre-frontal cortex 

   1. Decreases activity 

→ glutamate 

1. Hypoglutamatergic state leading to increases symptoms 

2. Hyperglutamergic state leading to excitotoxicity 

→ serotonin

1. 5HT2A receptor inhibition causes release of dopamine

   1. Mesocortical pathway = improved cognition 

   2. Nigrostriatal pathway = decreases EPS

Pharmacological Arsenal…

1. Typical antipsychotics 

   1. 1st generation

   2. MOA: blockade of D2 receptors in mesolimbic pathway reduces POSITIVE SYMPTOMS 

2. Atypical antipyshcotics 

   1. MOA: dual blockade of D2 and 5HT2 receptors 

      1. Reduction in positive symptoms (D2)

      2. Improvement of negative symptoms (5HT2)

HIGH POTENCY TYPICAL (1ST GEN) ANTIPSYCHOTICS…

• Fluphenazine

• Haloperidol 

Increased risk of EPS with use

MID POTENCY TYPICAL (1ST GEN) ANTIPSYCHOTICS

• Thiothiexene 

• Trufluoperazine 

• Perphenazine 

• Loxapine

• Molindone

LOW POTENCY TYPICAL (1ST GEN) ANTIPSYCHOTICS 

• Mesoridazine

• Thioridazine

• Chlorpromazine

Decreased risk of EPS

Typical Antipsychotic ADEs…

1. Extrapyramidal symptoms 

2. Cardiovascular 

3. Endocrine

4. Central/Autonomic Nervous System 

5. Hematological 

6. Dermatological 

EXTRAPYRAMIDAL SYMPTOMS (EPS)

→ ACUTE

• Dystonia 

• Akathisia 

• Pseudoparkinsonism 

→ CHRONIC

• Tardive Dyskinesia 

→ EPS Emergency = neuroleptic malignant syndrome 

DYSTONIA?

Sustained uncontrollabl muscular contraction 

• Younger males at risk 

• High potency agents at high doses 

TX: 

1. Anticholinergics IM/IV → diphenhydramine, benzotropine 

2. Benzodiazepines → lorazepam IM, diazepam IV

Pseudoparkinsonism?

1. Hypertonia 

2. Abnormal gait

3. bradykinesia/akinesia 

4. Tremor 

Appears in first 1-3 months of TX

TX: decrease dose, add anticholingergic drug

Akathisia?

Internal and motor restlessness

• Pacing, shuffling, tapping feet

• Increased risk: use of SSRIs, high potency APs

TX: decrease dose, benzodiazepine, beta-blocker 

1. Lorazpeam, Clonazepam 

2. Propranolol, Metoprolol 

Tardive Dyskinesia?

Late-onset of abnormal involuntary movements associated with PROLONGED antipsychotic use

→ tongue/mouth movements 

• Upregulation of D2 receptors from SUSTAINED AP use leads to tardive dyskinesia 

• AIMS scale

TX: switch to atypical antipsychotic (clozapine)

• Vitamin E

• Valbenazine (VMAT inhibitor)  

  • Depletes monoamines through inhibiitn of monoamine transporters 

• Deutetrabenazine (VMAT inhibitor) 

  • ADE: parkinsonism, depression

Neuroleptic Malignant Syndrome

→ PSYCHIATRIC EMERGENCY 

• Severe muscle rigidity and increased temperature associated with antipsychotic usage 

  • Requires => 2 of the following…

    • Dipahoresis

    • Dysphagia

    • Tremor 

    • incontinence 

    • Change in consciousness

    • Increased blood pressure

    • Leukoctosis

    • Increased myoglobin 

a severe reduction in central nervous system dopaminergic activity

MANAGEMENT of Neuroleptic Malignant Syndrome

1. Moderate NMS: 

   1. Lorazepam

   2. Bromocriptine

   3. Amantadine 

2. Severe NMS:

   1. Dantrolene

   2. Bromocriptine

   3. Amantadine 

Endocrinological Effects of Typical APs

1. Hyperprolactinemia

   1. D2 blockade in tuberoinfundibular pathway 

      1. Galactorrhea

      2. Gynecomastia 

      3. Sexual dysfunction 

      4. Change in menstruation 

      5. Weight gain 

CNS/Cardiovascular Effects of Typical APs

1. CNS

   1. Antihistamine

   2. Anticholingergic blockade 

2. Orthostatic hypotension 

   1. A-1 blockade 

3. QTc prolongation 

   1. CLASS EFFECT OF ALL ANTIPSYCHOTICS 

   2. Black Box Warning:

      1. Thioridazine 

      2. Mesoridazine

Typical Antipsychotic Dosing

Chlorpromazine Dosing:

1. Initial 10 - 25 mg TID

2. 100 - 800 mg range 

Perphenazine Dosing: 

1. Initiation 4 - 8 mg 

2. 12 - 64 mg range 

Fluphenazine Dosing: 

1. Initiation 0.5 - 10 mg/day

2. 2 - 20 mg range 

Haloperidol Dosing

1. 1 - 15 mg/day

2. 2 - 20 mg range

Long-Acting Injectable APs

ADVANTAGES

1. Avoidance of non-adherence 

2. Simplified medication regimen 

3. Predictable bioavailability

   1. Avoids first pass metabolism 

4. Eliminates risk of suicide via overdose  

DISADVANTAGES

1. Inability to withdraw medication once injected → difficult to manage ADE

TYPICAL DECANOATES: fluphenazine, haloperidol

Atypical Antipsychotic Pharmacology:

Cortical dopamine release enhanced by 5HT2a receptor antagonism

• Increased dopamine in cortical area

Nigrostriatal pathway

• Blockade of 5HT2A receptor disinhibits DA release and reduces D2 blockade-reduced EPS

• blocking 5-HT₂A receptors can help preserve dopamine activity in certain areas rather than suppressing dopamine signaling everywhere

Less negative symptoms associated 

Second Gen ATYPICAL ANTIPSYCHOTICS LIST

1. Cloazpine

2. Olanzapine

3. Respideridone 

4. Queitapine

5. Ziprasidone 

6. Ariprazole 

7. Paliperidone 

8. Asenapine 

9. Lloperidone 

10. Lurasidone 

11. Brexipiprazole

12. Cariprazine

13. Lumateperone  

pines, peridones, prazoles, perones

→ serotonin hypothesis of schizophrenia 

ALL ATYPICAL ANTIPSYCHOTICS HAVE 5HT2A RECEPTOR ANTAGONISM PROPERTIES

Serotonin modulates dopaminergic, glutamergic, and GABAergic neutrotransmission

• Antipsychotic effects of 5HT2A antagonism 

Pharmacology of D2 partial agonists and revised Dopamine Hypothesis…

1. In the PREFRONTAL CORTEX, partial agonists function as agonists

   1. Because dopamine levels are LOW (deficient) in prefrontal cortex

2. In the STRIATIUM, partial agonists function as antagonists 

   1. Because dopamine levels are EXCESS in striatum (psychosis) 

Atypical D2 Partial Agonists: ABC

1. Aripiprazole

2. Brexiprazole

3. Cariprazine

Most likely to cause AKATHISIA

The Glutamate Hypothesis and Dopamine…

→ NMDA receptor hypofunction in schizophrenia 

• Activation of D1 receptors potenitates NMDA receptor glutamtergic neurotranmission 

• Modulate glutamate transmission in the prefrontal cortex via D1 agonism

Clozapine, Asenapine, Lumaterperone 

D1 Receptor Activation ATYPICALS C.A.L

→ atypical AP indirect glutamate transmission modulation 

1. Clozapine

2. Asenapine 

3. Lumateperone 

Risperidone (Risperdal)

Atypical, first line treatment 

→ HIGHEST RISK OF INCREASING PROLACTIN (ADR young men avoid)

• 5HT2A blockade

• D2 blockade

ADR:

• Orthostasis

• Prolactin increase 

• Weight gain

Dose: 2-8 mg/day

Olanzapine (Zyprexa)

• 5HT2A

• 5HT2C → weight gain 

• Muscarinic 1 and 3/Histamine 1 blockade 

  •  anticholingeric side effect + weight gain 

High sedation = acute treatment of psychosis 

Olanzapine Metabolic Side Effects

• Weight gain (with ALL atypicals)

• Elevated lipids 

• Blood glucos

Mechanism of Weight Gain for Atypicals…

1. Anticholinergic effects

   1. Increased appetite 

   2. Increased thirst 

2. 5HT2C antagonism 

3. Decreased energy expenditure 

4. Decreased insulin sensitivity

Metabolic Syndrome: requires 3 of the following criteria…

1. Waist circumference 

   1. Men > 40 inches

   2. Women > 35 inches 

2. Fasting triglycerides > 150 mg/dL

3. Fasting HDL

   1. Men < 40

   2. Women < 50 

4. Blood pressure > 130/85 mmHg

5. Fasting glucose > 110 mg/dL

Quietiapine (Seroquel)

→ 5HT2A, 5HT2C (weight gain), 5HT1A (angiolytic effects)

• First line treatment

• Decreased EPS rates

ADR:

• sedation/anticholinergic

• Metabolic effects

• Change in vision 

DOSE: 300-800 mg/day normal maintenance

Ziprasidone (Geodon)/Lurasidone (Latuda)

→ 5HT2C, 5HT1D, 5HT1A

• LOW RATE OF WEIGHT GAIN

Absorption issues → must be taken with 

• 500 cals per dose 

• Lurasidone = 350 cals per dose

QTc prolongation with Ziprasidone risk = MOST LIKELY DRUG TO PROLONG QTc interval 

Ziprasidone dose: 80-200 mg/day

Lurasidone: 40-160 mg/day

Aripiprazole (Abilify) 

D2 partial agonist

1st line therapy

• Low rate of weight gain 

• EPIs and GI upset ADR

Clozapine

→ EFFICACY IN REFRACTORY PATIENTS

• 3rd line treatment for those:

  • Symptom resistant patients

  • Patients with increased risk of suicide  

  • Patients with tardive dyskinesia

Clozapine BBW:

• Agranulocytosis

• Mycocarditis 

• hypotension/CV collapse 

• Seizures 

• Mortality in dementia patients

Clozapine Monitoring

Absolute neutrophil count = total WBC count x (total percentage of neutrophils)

1. Obtain baseline absolute neutrophil count BEFORE initiation 

2. During first 6 months of treatment = monitor ANC WEEKLY

3. For months 7-12, monitor ANC every 2 weeks

4. After 12 months → monitor ANC monthly 

5. After 2 years of stable therapy → no ANC monitoring needed

DC clozapine if:

• ANC falls below 1 x 10^9 or 0.5x10^9 for those with DUFFY NULL

Clozapine Dosing

• 12.5 mg BID, increase by 25-50 mg/day 

  • Maintenance: 300-450 mg/day, max = 900 mg/day

EMERGENCY TREATMENT OF PSYCHOSIS…

Treatment of agitation

• Haloperidol 5 mg IM + lorazepam 2 mg IM

• Olanzapine 10 mg IM

  • DO NOT COMBINE WITH LORAZEPAM due to hypotension ADR

• Ziprasidone 20 mg IM

• Aripiprazole 9.75 mg IM

• Risperidone 2 m g

• Loxapine 10 mg inhalation

CATIE TRIAL: 

Primary outcome: time to discontinuation of antipsychotic  

• 74% of patients discontinue treatment before 18 months 

• Olanzapine patients remained on treatment for longest period of time

  • Those that do dc → metabolic problems greatest issue

Weight-Neutral Antipsychotics

• Aripiprazole (Abilify)

• Ziprasidone (Geodon)

• Lurasidone (Latuda)