Drugs used in the treatment of psychoses

Department of Pharmacology, CSU

Zhang xiaojie

What are psychoses?

•They are severe, chronic, disabling brain diseases

•Major disturbances in reasoning, affection and behavior

Types of psychoses

1. Schizophrenia (split mind)

2. Affective disorders (Depression / Mania)

3. Anxiety

Schizophrenia A clinical syndrome characterized by profound

disruption in cognition and emotion, affecting the most fundamental attributes: language, thought, perception, affect and sense of self

Positive Symptoms Delusions Hallucinations Erratic/extreme emotions Thought disorder

Negative Symptoms Withdrawal from social contacts Lack of interest/enjoyment in

activities Blank facial expression, less

facial variability

Causes - Dopamine Hypothesis Schizophrenia: with excessive dopaminergic activity

Evidences:1.Drugs (L-dopa and amphetamine) that increase DOPA ca

n aggravate the symptom of schizophrenia

2.Dopamine receptor density ↑ in schizos

3.Anti-psychotic drugs block postsynaptic D2 receptor in CNS

There is some evidence for involvement of 5-HT, and possibly other mediators, such as glutamate

Classification of Antipsychotic drugs

Typical antipsychotics

Phenothiazines (chlorpromazine, perphenazine,

fluphenazine, thioridazine et al)

Thioxanthenes (flupenthixol, clopenthixol)

Butyrophenones (haloperidol, droperidol)

Atypical antipsychotics

(e.g. clozapine, risperidone, sulpiride, olanzapine)

Distinction between ‘typical’ and ‘atypical’ groups is not clearly defined, but rests on: Incidence of extrapyramidal side-effects (less i

n ‘atypical’ group) Efficacy in treatment-resistant group of patien

ts Efficacy against negative symptoms.

Classification of Antipsychotic drugs

Chlorpromazine: winterminePharmacologic effects :

(1) CNS: a. neuroleptic effect1. In animals: suppress spontaneous movements and complex behaviors, but spinal reflexes remain intact

2. In normal humans: reduce initiative and interest, produce drowsiness and slowness in response to external stimuli

3.In psychotic patients: soon become less agitated, aggressive and impulsive behavior diminishes. Gradually, psychotic symptoms of hallucinations, delusions, and disorganized thinking ameliorate.

b. antiemetic effect--- inhibit chemoreceptor trigger zone or directly depress the medullary vomiting center, but with no effect against nausea caused by vestibular stimulation (motion sickness)

c. temperature-regulating effect--- produce hypothermia with physical cooling

Pharmacologic effects :

(1)CNS:

Chlorpromazine

Chlorpromazine

Pharmacologic effects:

(2) autonomic nervous system: block α-adrenergic and M-Cholinergic receptors and result in hypotension, dry mouth, constipation and blurred vision.

(3) Endocrine system: increase the release of prolactin and decrease corticotropin release and secretion of pituitary growth hormone.

Mechanism: antidopaminergic action

1. Nigrostriatal pathway: extrapyramidal system， adjust motor function

2. Mesolimbic pathway： related to affection

3. Mesocortical pathway : related to cognition, reasoning and thinking

4. Tuberoinfundibular pathway :control the secretion of pituitary hormones

Dopaminergic neuron pathway

Dopamine receptors

Five subtypes of Dopamine receptors: D1, D2, D3, D4, D5

D1 and D5 are named as DD11 like like receptorreceptor

Increase cAMPIncrease cAMP

D2, D3 and D4 are named as DD22 like like receptorreceptor

Decrease cAMPDecrease cAMP

DD22 like like receptor is highly related to schizophreniareceptor is highly related to schizophrenia

Mechanism of chlorpromazine

a nonspecific dopamine receptor blocker

Mesolimbic

MesocorticalBlock D2 Antipsychotic effects

Nigrostriatal

TuberoinfundibularBlock D2

Adverse effects

Therapeutic uses

(1) treatment of psychotic disorders: schizophrenia, mania, alcoholic hallucinosis.

(2) treatment of nausea and vomiting of certain causes (digitalis, uremia, cancer)

(3) anesthesia in hypothermia and artificial hibernation (used with pethidine and promethazine)

Adverse Effects

1. Ordinary side effects

(1)Anticholinergic (antimuscarinic) side effects:

Dry mouth, blurred vision, urinary retention

(2)Antiadrenergic (Alpha-1) side effects:

Orthostatic hypotension w/ reflex tachycardia

(3)Antihistamine effect: sedation, weight gain

Adverse Effects2. Extrapyramidal side effects (EPS)(1) Acute dystonisa : spasm of muscles of tongue, face, neck, back, may mimic seizures, during the first 1 -5 days of Rx

(2) Akathisia: motor restlessness

(3) Parkinson-like symptoms:bradykinesia, rigidity, tremor, mask facies

Mechanism: nigrostriatal dopaminergic function weakened, while cholinergic function strengthened

Treatment: anticholinergic :benzhexol

(4) Tardive dyskinesia : involuntary movements of face and tongue, appearing after months or years of antipsychotic treatment.

Mechanism:① Dopamine neurons reduce activity.② Postsynaptic D-2 receptor numbers increase (compe

nsatory response).③ When D2 blockade is reduced, DA neurons resume f

iring and stimulate increased of receptors >> hyper-dopamine state >> tardive dyskinesia

Treatment:increase neuroleptic dose; switch to clozapine

Atypical neuroleptics

Clozapine:(1) be effective in treating some patients with psychosis u

nresponsive to standard neuroleptic drug,effective against negative symptoms

(2) blocks D4 receptor and have low affinity for D1 and D2 dopamine receptors.

(3) lacks extrapyramidal side effects.

(4) must monitor the granulocyte counts weekly.

Risperidone:

(1)Highly effective against positive and negative symptoms

(2)Dopamine-2 and Serotonin-2 receptor blockade

(3)EPS incidence is dose-related

be used for first episode and chronic schizophrenia

Weight gain, prolactin elevation

Clinical Efficacy of Antipsychotic Drugs

Antipsychotic drugs are effective in controlling symptoms of acute schizophrenia, when large doses may be needed.

Long-term antipsychotic treatment is often effective in preventing recurrence of schizophrenic attacks, and is a major factor in allowing schizophrenic patients to lead normal lives.

Clinical Efficacy of Antipsychotic Drugs

Long-acting preparations are often used for maintenance therapy.

Antipsychotic drugs are not generally effective in improving negative schizophrenic symptoms.

Approximately 40% of chronic schizophrenic patients are poorly controlled by antipsychotic drugs; clozapine may be effective in some of these ‘antipsychotic-resistant’ cases.

Anti-Manic Agents

Mania-- State of elevated mood and psychomotor acceleration, with excess catecholamines activity and decrease 5-HT activity

Treatment: lithium carbonate

LITHIUM PHARMACOKINETICS

ABSORPTION : virtually complete within 6 -8 hrs; peak plasma levels in 30 min to 2 hrs

DISTRIBUTION: in total body water; slow entry into intracellular compartment. No protein binding

METABOLISM: None

EXCRETION: virtually entirely in urine; plasma half life is about 20 hours

Mechanism

Substitute for sodium in generating action potentials

Decrease norepinephrine & dopamine turnover

Block dopamine receptor supersensitivity

Enhance effects of serotonin

lithium carbonate

lithium carbonate

Adverse effects:

① Nausea, vomiting and diarrhea.

② Tremor.

③ Renal effect: polyuria (with resulting thirst)

④ Various neurological effects, progressing from confusion and motor impairment , to coma, convulsion and death.

♫ narrow therapeutic limit for the plasma means the monitoring is essential

Antidepressant

Depression Syndrome: depression, anxiety, tension, bodily complaints, guilt (> 60%)

Types of antidepressant drug

Tricyclic antidepressant (TCA):

Selective 5-HT uptake inhibitors:

NE uptake inhibitors:

Atypical antidepressant: phenelzine

imipramine amitriptyline

Fluoxetine,paroxetine, sertraline

desipramine

【mechanism of action】• to block NA and 5-HT reuptakes into the pre

synaptic neurons to increase NA and 5-HT level in the synaptic cleft in CNS.

• Monoamine receptor densities in the brain may change over 2 to 4 week with drug use and may be important in the onset of activity.

Imipramine

Imipramine

Pharmacologic effects:

(1) CNS: a normal person experiences sleeping. In the depressed patient, an elevation of mood occurs 2-3 weeks after administration begins.

(2) autonomic nervous system: anticholinergic effects.

(3) cardiovascular effects: orthostatic hypotension and arrhythmias.

Therapeutic uses

(1) Treatment of severe endogenous depression (characterized by regression and inactivity).

(2) Treatment of enuresis.

(3) Treatment of obsessive-compulsive neurosis accompanied by depression, and phobic-anxiety syndromes, chronic pain and neuralgia.

Adverse effects: anticholinergic effects

Fluoxetine

Mechanism of action:(1) is a selective inhibitor of serotonin uptake in the

CNS.

(2) has little effect on central norepinephrine and dopamine function.

(3) has less adverse effects because of minimal binding to cholinergic, histaminic, and α-adrenergic receptors.

Therapeutic uses:(1) is used for treatment of mild to

moderate endogenous depression.

(2) be useful in treating obsessive-compulsive disorder, obesity.

Adverse effects:

(1) cause anorexia.

(2) precipitate mania or hypomania.

(3) result in nausea, nervousness, headache, and insomnia.

(4) cause 5-HT syndromes (hyperpyrexia, convulsions, and coma) when combinated with and MAO inhibitor.