schizophrenia is a genetically influenced developmental brain disorder, that tends to run in families, but environmental (nongenetic) factors also play a role.
The onset of the disorder usually occurs in late adolescence or early adulthood
Schizophrenia strikes 1% of population, with 100,000 new cases diagnosed each year and 1.2 million Americans presently having schizophrenia.
symptomssymptoms "positive" symptoms, expressed as
behaviors or mental states that schizophrenics exhibit but normal people lack
Delusions Hallucinations, especially auditory Bizarre behavior Loose associations and fragmented
thoughts
"negative" symptoms are expressed as behaviors or mental states that normal people may have but that schizophrenics lack, such as:
Impaired emotional responses or detachment
Apathy: Social withdrawal A decrease in reactivity to the
environment Lack of self-initiated goal-driven activity,
Loss of motivation and interest
According to the DSM, for a diagnosis of schizophrenia, an individual must be functioning below his or her highest level previously achieved, in these areas, for more than 6 months.
"dopamine hypothesis","dopamine hypothesis",
which associated schizophrenia with increased levels of the neurotransmitter dopamine within certain areas of the brain,
mostly in the Mesolimbic system
Traditional antipsychotic drugs are blockers (antagonists) of dopamine2 receptors D2 or D3 receptors.
Blockage of D2 receptors is correlated with clinical effectiveness of antipsychotic agents.
ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC DRUGS
PHENOTHIAZINES Chlorpromazine Prochlorperazine Fluphenazine Promethazine
BENZISOXAZOLES
Risperidone DIBENZODIAZEPINES
Clozapine, Olanzapine, Quetiapine BUTRYOPHENONES
Haloperidol (acute psychotic symptoms)
The Phenothiazines:The Phenothiazines:
The phenothiazines are the most widely used class of drugs for treating psychosis.
The prototypical phenothiazine is Chlorpromazine (Thorazine).
Both the therapeutic and the most serious of the side effects, associated with the phenothiazines, are based upon them being competitive antagonists for dopamine (D), specifically the dopamine2 receptors (D2).
Limbic system: Increased dopaminergic activity in the neurons that regulate the expression of emotion, which integrates thought and emotion, are associated with the positive symptoms of schizophrenia.
By reducing the dopaminergic activity in these
neurons, chlorpromazine: Decreases fear, and agitation. Reduces the intensity of schizophrenic delusions
and hallucinations. Relieves agitation, restlessness and
hyperactivity.
Brain Stem: By blocking dopamine receptors, phenothiazines suppress centers of behavioral arousal.
in the medulla, exerting anti-vomiting (antiemetic) effects via the chemoreceptor trigger zone.
Basal Ganglia: The most serious side effects of the phenothiazine are caused by their blockade of dopamine receptors within the extrapyramidal system, consisting of the caudate nucleus and the putamen of the basal ganglia. These effects are motor disturbances such as:
1. Dystonia: Involuntary muscle spasms and sustained, abnormal bizarre postures of the limbs, trunk, face and tongue.
2. Akathesia (inability to sit still): Subjective feelings of anxiety accompanied by restlessness, pacing, rocking back and forth, other repetitive and purposeless actions. Feeling of “Ants in the Pants”.
3. Neuroleptic induced Parkinson's Disease: which develops in 90% of individuals treated with phenothiazines.
Treated by giving anti cholinergics like trihexyphenidyl or benztropine.
4. Tardive dyskinesia: Persists after the drug is withdrawn
irreversible, severely disabling disorder symptoms involve involuntary and
hyperkinetic movements of the: Trunk: Tongue: twisting, darting or pushing Face: Sucking and smacking of lips Lateral jaw movements Choreiform movements of the extremities
Hypothalamus-pituitary Increased levels of Prolactin: A
hormone whose release causes enlarged breasts Gynaecomastia in males and lactation in females.
block ejaculation in men and reduce their libido
block ovulation and suppression of menstrual cycles in women, which can result in infertility.
Anti PsychoticsAnti PsychoticsBlock the following receptorsBlock the following receptors
Chlorpromazine –D2, H1, alpha adr, cholinergic… Rx of intractable hiccups
Prochlorperazine – D2 Promethazine – D2, H1, Rx of pruritus Fluphenazine – D2, Rx of Drug induced Nausea Thioridazine –D2, cholinergic – less EPS
Haloperidol – D2
Risperidone – D2, 5 HT2, Clozapine –D4, 5 HT2, cholinergic, alpha, H1
Aripiprazole – Partial agonist at D2, 5HT receptors
USESUSES
Treatment of schizophrenia. Treatment of nausea and vomiting –
Prochlorperazine. As tranquilizers – for agitation & disruptive
behavior. For hiccups – chlorpromazine. Pruritus – Promethazine Pimozide - Blocks dopamine receptors, used to
treat Tourette's syndrome
SESE
Tremors Postural hypotension Constipation Urinary retention Confusion Sexual dysfunction Tardive dyskinesia
haloperidolhaloperidol butyrophenone, named haloperidol was
developed, as the first therapeutic alternative to the phenothiazines
to treat individuals who's psychosis do not respond to the phenothiazines.
Its pharmacological effects are very similar to the phenothiazines,
Its mechanism of action, like the phenothiazines, is to competitively block D2 receptors so it also shares the side effect profile with the phenothiazines.
Can also be given parenteral IM route.
Neuroleptic Malignant SyndromeNeuroleptic Malignant Syndrome
Fatal side effect of neuroleptic drugs. Manifestations include – hyperthermia,
fluctuating levels of consciousness, muscular rigidity, tachycardia, sweating, urinary incontinence…
Stop the drug. If not serious then , symptoms may be
there for 5-10 days after withdrawing the drug.
There is no specific treatment and only supportive measures are needed.
It will subside normally within a week after discontinuing the drug.. If serious conditions are not there.
Some drugs such as Apomorphine or Bromocriptine and Dantrolene have shown improvement in some cases.
Apomorphine (a potent dopamine agonist) Bromocriptine – dopamine agonistSkeletal muscle relaxant Dantrolene -- Inhibits ionized calcium release
from sarcoplasmic reticulum and results in direct muscle relaxation.
Used to treat NMS-associated muscular rigidity and hyperthermia.
ATYPICAL ANTIPSYCHOTIC AGENTS Clozapine, Arpiprazole, Risperidone
(mainly for negative symptoms of schizophrenia).
Clozapine, mainly for treatment of resistance psychosis (resistant schizophrenia).
Risperidone (Risperdal): it is recommended in the treatment of individuals experiencing their first episode of schizophrenia, where negative symptoms predominate.
It is a potent blocker of D2 receptors and 5-HT2a receptors.
It is as effective as haloperidol in reducing positive symptoms but without extrapyramidal effects at low doses.
Clozapine has been beneficial in the treatment of so called
"treatment resistant" cases, 30-60% of cases where traditional neuroleptics have not been successful.
D4, 5HT2 receptors effective as the phenothiazines in controlling the
positive symptoms of schizophrenia, could also alleviate the negative symptoms
Less extrapyramidal side effects Can cause fatal bone barrow suppression -
agranulocytosis Wet pillow syndrome
Olanzapine (Zprexa): similar to clozapine but without agranulocytosis.
It exhibits a higher affinity for D2 receptors and lower for 5-HT2a receptors, also blocking acetylcholine, which possibly accounts for its lack of extrapyramidal side effects.
It improves both positive and negative symptoms