Agents For Schizophrenia

Front 1

“positive” symptoms of Schizophrenia

Back 1

Positive symptoms reflect the presence of abnormal thoughts and behaviors
• Delusions
• Hallucinations
• Disorganized speech
• Disorganized or catatonic behavior

Front 2

“negative” symptoms of Schizophrenia

Back 2

Negative symptoms reflect the absence of responses that are normally present.
• Reduced expression of emotion
• Poverty of speech (alogia)
• Difficulty in initiating goal-directed behavior
• Memory impairment

Front 3

DSM-IV diagnosis of Schizophrenia

Back 3

Two or more present for a significant portion of time during a 1-month period
– Delusions
– Hallucinations
– Disorganized speech
– Grossly disorganized or catatonic behavior
– Negative symptoms

Front 4

Dopamine (DA) Hypothesis of Schizophrenia

Back 4

Elevated levels of DA and D2 receptors in limbic regions of unmedicated schizophrenics
Drugs that increase DA levels can aggravate schizophrenia or produce psychosis
strong D2 antagonism are able to reduce positive symptoms
Negative symptoms may result from decreased DA levels and are reduced by DA receptor partial agonists or 5-HT2a antagonists

Front 5

5-HT Hypothesis of Schizophrenia:

Back 5

Agents that activate 5-HT2a receptors promote hallucinations
Serotonergic receptors are present on DAergic neurons
5-HT has an inhibitory effect on DA release, thus possibly contributing to negative symptoms.
Elevated 5-HT concentrations have been found in chronic schizophrenics
Atypical antipsychotics are 5-HT2 receptor antagonists

Front 6

Glutamate Hypothesis of Schizophrenia

Back 6

phencyclidine (PCP) intoxication parallel both + and - symptoms of schizophrenia. PCP has no direct effect on DA receptors, but acts as a NMDA (glutamate) receptor antagonist. PCP is used to produce mouse models of schizophrenia.
mice with reduced NMDA receptors display schizophrenic behavior

Front 7

Glutamate Hypothesis of Schizophrenia: continued

Back 7

NMDA receptors may reside on GABA interneurons which have an inhibitory effect on glutamate neurons, so reduction of NMDA receptors may result in “disinhibition” of excitatory glutamate neurons. AMPA receptors are another type of glutamate receptor implicated in schizophrenia. Drugs that potentiate effects of AMPA receptors (ie. Ampakines) correct schizophrenic behaviors in animal models. Ampakines can elevate BDNF levels in neurons.

Front 8

BDNF

Back 8

BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the areas vital to learning, memory, and higher thinking.

Front 9

Aripiprazole

Back 9

(Abilify), Schizophrenia, Bipolar Disorder, Treatment-resistant Depression
D2 and 5-HT1A partial agonism, 5-HT2A antagonism, 5-HT1D antagonist:
CYP 2D6, 3A4
headache, anxiety, insomnia, nausea, akathisia, dizziness

Front 10

Asenapine

Back 10

(Saphris -SL) Schizophrenia,Bipolar Disorder
5HT2A/D2 antagonist, Antagonist actions at 5HT2C and alpha 2 receptors suggest potential antidepressant properties.
CYP450 1A2
QTc prolongation,syncope, hyperprolactinemia,EPS and akathisia, tardive dyskinesia, agranulocytosis, hyperglycemia and diabetes mellitus

Front 11

Clozapine

Back 11

(Clozaril) Schizophrenia
5-HT2, D1,D2, D3, D4, M1, H1, α1 and α2 antagonism
CYP450 1A2, 3A4, and 2D6
Sedation, Weight gain, Orthostatic hypotension (all PROBLEMATIC)
Agranulocytosis must monitor
hypersalivation,severe constipation, tachycardia
Use with caution in patients with
renal impairments

Front 12

Iloperidone

Back 12

(Fanapt) Schizophrenia
5HT2A/D2 antagonistic, some Alpha 1
CYP450 2D6 and 3A4
Rare neuroleptic malignantsyndrome, QTc prolongation,
syncope, hyperprolactinemia and akathisia, tardive dyskinesia,
agranulocytosis, hyperglycemia and diabetes mellitus
Contraindicated to take with another drug that causes QTc
prolongation Not recommended for patients with hepatic impairments

Front 13

Olanzapine*

Back 13

(Zyprexa) Schizophrenia, Bipolar Disorder, Treatment-resistant Depression
5-HT2A, 5-HT2C, D1, D2, D3, D4, M1-5, H1, and α1- antagonism
CYP450 1A2
Weight gain, mid Sedation, Cases of hyperglycemia, diabetic ketoacidosis reported, weight gain severe in some patients

Front 14

Paliperidone

Back 14

(Invega) Schizophrenia
5HT2A/D2 antagonist, a2 adrenergic antagonism, is the active metabolite of risperidone
Not metabolized by liver
weight gain, insulin resistance, and diabetes as well as prolactin
elevation, similarly to risperidone
first atypical antipsychotic approved as a once-monthly

Front 15

Quetiapine

Back 15

(Seroquel) Schizophrenia, Bipolar Disorder: Treat resitst Depression
5HT2A/D2 antagonist, rapid D2 dissociation, hardly any EPS, no prolactin elevation. 5HT2C-blocking properties, eff ectiveness at treating mood and cognitive disorders
CYP450 3A4
Sedation! (chemically related to clozapine) Hyperglycemia, diabetic ketoacidosis, orthostatic hypotension
possible

Front 16

Risperidone

Back 16

(Risperdal) Schizophrenia, Bipolar Disorder:
5HT2A/D2 antagonist, H1, α1- and α2 antagonism
CYP450 2D6
if the doses are pushed, it can, lead to EPS, Hyperglycemia, ketoacidosis
and coma, renal impairments,
only use long-acting depot

Front 17

Ziprasidone

Back 17

(Geodon) Schizophrenia, Bipolar Disorder
D2, D3, 5-HT2A, 5-HT2C, 5-HT1D and α1 antagonism; moderate inhibition of 5-HT and NE reuptake; 5-HT1A FULL agonism
Not aff ected by CYP450
Liver/Kidney safe
Contraindicated in patients with QT prolongation

Front 18

Lurasidone

Back 18

(Latuda) NEW dopamine partial agonist, only agent with stronger affinity for D3 over D2 receptors, with both
actions being partial agonist (5-HT1A partial agonist)
in testing for schizophrenia, acute bipolar mania, bipolar depression, and treatment-resistant depression

Front 19

Haloperidol

Back 19

Haldol - FGA
Schizophrenia, Tourette’s Syndrome
D2 antagonists
EPS!, Prolactin!!

Front 20

Chlorpromazine**

Back 20

* Thorazine* FGA
Schizophrenia, N/V
D2 antagonists
MANY side effects! All for D2

Front 21

Adverse Effects Due to “Dirty” Receptor
• H1 Histamine Antagonism: Sedation, weight gain
• Anti-muscarinic effects: Anti-SLUD effects + Tachycardia; Memory impairment
• a1-adrenergic antagonism: Orthostatic Hypotension, reflex tachycardia
• 5-HT2C antagonism: Weight gain

Back 21

Other notable Adverse Effects (LO10):
• QT prolongation: Thioridazine >Ziprasidone>Haloperidol
• Decreased Seizure threshold: clozapine and chlorpromazine primarily
• Toxic-confusional states: high doses of drugs with anticholinergic properties
• Agranulocytosis: clozapine requires weekly monitoring
• Skin reactions: most common with phenothiazines (5% incidence), particularly chlorpromazine

Front 22

• Ocular Complications: thioridazine associated with condition similar to retinitis
pigmentosa: vision “browning” may occur.

Back 22

Neuroleptic Malignant Syndrome
o Muscle rigidity
o Fever, particularly if sweating is impaired (eg. by anticholinergics)
o Autonomic instability (BP, pulse fluctuations)
o Altered consciousness
o Potentially fatal
o Risk factors–“high potency” FGAs

Front 23

Alpha-2 adrenergic receptor

Back 23

Vasodilation of arteries
Vasoconstriction of veins
Inhibition of insulin release in pancreas
Induction of glucagon release from pancreas (inc BS)
platelet aggregation