Schizophrenia Flashcards
General Definition
Schizophrenia is a highly debilitating but common disorder with a lifetime risk of ~1 %. A further 2- 3% of the population suffers from the related schizotypal personality disorder. Onset occurs typically in the mid-twenties and many sufferers never recover. It is a neurodevelopmental disorder that is probably the result of both genetic and environmental causes i.e. multifactorial. Two types of symptoms characterize the disorder
Type 1 symptoms
Type I. Positive Symptoms (reflecting the presence of symptoms). These characterize the psychotic episodes of the disorder. They include; i. Auditory hallucinations: - the most common sign occurring in 65% of cases. ii. Delusions: - usually of persecution or control by an outside force. iii. Disordered thoughts, e.g. incoherence, loss of normal association between ideas
Type 2 symptoms
Type II. Negative or Residual symptoms (reflecting the absence of symptoms). These characterize the non-psychotic periods. They are the most unmanageable aspects of the disorder in that drug therapy is commonly ineffective. The development of these symptoms – the prodromal signs - also signals disease onset. i. Social isolation / withdrawal ii. Decreased emotions iii. Loss of drive iv. Apathy v. Poverty of speech vi. Affective flattening (no emotion)
Dopamine theory
THE DOPAMINE THEORY OF SCHIZOPHRENIA The prevailing idea is that hyperactivity of the dopaminergic system underlies the psychotic symptoms of schizophrenia. The lines of evidence are, however, largely indirect. 1. Amphetamine, a dopamine releaser, promotes positive symptoms. 2. Dopamine D2 receptor agonists (apomorphine, bromocriptine) also promote positive symptoms. 3. D2 antagonists and reserpine, a dopamine depleter, are effective at controlling the positive symptoms. 4. A strong correlation exists between the affinity of neuroleptic drugs for D2 receptors and the effective therapeutic dose.
Glutamate theory
THE GLUTAMATE THEORY OF SCHIZOPHRENIA Schizophrenia is a disorder of disrupted glutamate neurotransmission resulting in reduced function of NMDA glutamate receptors. 1. This is supported by evidence of deficits in identified presynaptic proteins and post-synaptic receptors that characterise glutamate synapses 2. Increased mesolimbic DA release in schizophrenia results from reduced NMDA glutamate receptor function on GABAergic interneurones that would normally regulate DA release (disinhibition). 3. Reduced NMDA receptor function directly reduces mesocortical DA release leading to negative symptoms
Antipsychotics
ANTIPSYCHOTICS (anti-schizophrenics, neuroleptics). Drugs used in the treatment of schizophrenia are known as antipsychotics. (a) First Generation “typical” antipsychotic drugs (e.g. chlorpromazine, haloperidol) are effective in controlling the positive symptoms though large doses may be needed and they are not useful for controlling the negative symptoms. (b) Recurrence of schizophrenic attacks may be effectively controlled by chronic treatment, however, ~40% of patients are poorly controlled by classical antipsychotics though “atypical” second generation drugs may be useful in some of these refractory cases and, arguably, have some efficacy against negative symptoms.
First Generation Antipsychotics
First Generation “Typical” Antipsychotics. These show a preference for antagonism at D2 receptors but also block 5-HT2 , -adrenergic and muscarinic acetylcholine receptors. PHENOTHIAZINES, subdivided according to the nature of the side chain. i. Aliphatic e.g. chlorpromazine – first developed neuroleptics. ii. Piperazine e.g. fluphenazine iii. Piperidine e.g. thioridizine THIOXANTHINES e.g. flupenthixol BUTYROPHENONES e.g. haloperidol
Second Generation Antipsychotics
Second Generation “Atypical” Antipsychotics These show some effectiveness against negative as well as positive symptoms and generally have fewer “extrapyramidal” side effects. As well as being effective blockers of D2 receptors (though D4 and presynaptic D1 receptors may also be blocked) their higher potency block of 5-HT2A receptors is regarded as an important factor in their different therapeutic and side effect profile. DIBENZAZEPINES e.g. clozapine. Weak antagonism of D2 but also blocks D1, D4, , 5-HT2,5,6,7 and mAChR. BENZAMIDES e.g. sulpiride
Apripriazole
Aripiprazole New atypical which acts as a partial agonist at D2 receptors thereby stabilizing neurotransmission in the meso-limbic and meso-cortical pathways. It is also an antagonist at 5-HT2A receptors and this is thought to confer efficacy against negative symptoms and reduce extra-pyramidal side-effects. Finally, it is a partial agonist at 5-HT1A receptors. This may confer efficacy against affective (mood) symptoms associated with schizophrenia.
Main effects of antipsychotics
Main Effects of Antipsychotics i. Induce state of apathy and reduced initiative, ii. Patients display few emotions, iii. Are slow to respond to external stimuli, iv. Drowsiness. However, i. The patients can be easily aroused, ii. Responds to questions accurately with no obvious confusion or loss of intellectual function, iii. Aggressive tendencies are inhibited.
Extrapyramidal Side effects
Extrapyramidal (EP) side effects (movement disorders). 1. Acute reversible effects associated with Parkinsonism type symptoms of muscle rigidity, tremor and loss of mobility. Onset is dose dependent and the severity declines with progressive treatment. Due to D2 receptor blockade in the striatum. 2. Chronic, irreversible effects. Tardive dyskinesia: - involuntary movement of particularly the face and tongue but also the trunk and limbs. These have a delayed appearance in 20-40% of cases after prolonged treatment for months to years. They are resistant to drug therapy and worsen if the treatment is stopped. THIS IS A SERIOUS SIDE EFFECT.
Endocrine distrubances
Endocrine disturbances. Notably lactation associated with increased prolactin production.
Neurotransmitter related side effects
Side effects related to actions at other neurotransmitter receptor subtypes. 1. -adrenoceptor block can lead to cardiovascular effects such as postural hypotension. 2. autonomic effects related to block at mAChR e.g. blurred vision, dry mouth / eyes, constipation, urinary retention. N.B. though anti-muscarinic action may be good for low extrapyramidal side effects e.g. phenothiazine piperidine derivatives. CHEMICAL PHARMACOLOGY 2 – 2 nd February 2017 3 3. Sedation 4. Weight gain common and troublesome but of unknown mechanism. 5. Idiosyncratic and hypersensitivity reactions. e.g. jaundice, leucopenia and agranulocytosis. 6. Neuroleptic Malignant syndrome. ~1% incidence. Due to collapse of autonomic N.S.
Atypical antipsychotic side effects
Side Effects – Atypical Antipsychotics. Lower incidence of EP side effects but, 1. Leucopenia and agranulocytosis 2. Weight gain 3. Impaired glucose tolerance – metabolic effects such as increased risk of diabetes.
Pharmacokinetics
Pharmacokinetics - A wide variation in plasma concentration between patients is common. This is due to a large and variable amount of tissue binding giving a volume of distribution greatly exceeding the total body volume. In the blood ~90% is bound to plasma protein and the half-life is 15 - 30 hours. Major metabolic pathways are hepatic oxidation and conjugative reactions. Fortunately drugs like chlorpromazine have a wide therapeutic range with only slight risk of acute toxicity, therefore, dosage can be established on an individual trial and error basis.
