Antipsychotics Flashcards
Psychosis
a general term to describe loss of touch with reality, associated with a variety of disorders but most usually schizophrenia
Schizophrenia - positive symptoms
additional to normal behaviour, e.g. hallucinations
associated with acute episoded
Schizophrenia - negative symptoms
lacking compared to normal
harder to treat
associated with chronic schizophrenia
Schizophrenia disease background
typical age of onset is 23-28 for men and 28-32 for women - affects young people
often chronic
highly disabling - leads to suicide attempts
Genetics
schizophrenia has a significant yet unidentified genetic component
he more closely-related the family member to the person with schizophrenia, the greater their chance of developing the disorder
seems to involve several genes rather than just one
Positive symptoms
Hallucinations (auditory and visual). Perceptions in the absence of real stimuli.
Delusions of persecution and loss of control of own thoughts and actions. Nature of delusions determined by social and historical factors.
Thought disorders, making speech hard to follow. Also often have problems with “selective attention”.
Negative symptoms
Loss of empathy with others
Inappropriate or blunted mood; repetitive activity
Anhedonia, apathy, attention impairment.
Early treatment
Treatment for “lunatics” initially consisted of confinement in asylums. This remained the case into the 20th century.
Dopamine receptor subtype nomenclature
Molecular cloning has identified five dopamine receptor subunits (D1-D5).
These are grouped into two subtypes, D1 (D1 & D5) and D2 (D2, D3 & D4), based on their pharmacology.
Dopamine receptor subunits
expressed in the brain within distinct but overlapping areas
Key parameter for treating the positive symptoms of schizophrenia
Anti-psychotics affinity for the D2 receptor subtype
Dopamine theory of schizophrenia
proposed by Carlson
stated brain of schizophrenic patients produce more dopamine
now thought that schizophrenics have an abnormally high number of D2 receptors
Dopamine antagonists
effective in controlling the positive symptoms of schizophrenia, and in preventing amphetamine-induced behavioural changes
patients have either high levels of dopamine in postsynaptic neurone or high level of dopamine receptors on postsynaptic membrane, leading to positive symptoms of schizophrenia
D2 receptors
may be implicated in the positive symptoms
Over activity in mesolimbic pathway (activating D2 receptors)
D2 antagonists reduce positive symptoms in individuals who have overactivation of this pathway
D1 receptors
in the negative symptoms of schizophrenia
Decrease activity in mesocortical pathway (D1 receptors)
Delusions and hallucinations
mesolimbic dopamine pathway hyperactive, excess dopamine in synapse leading to positive symptoms
D2 antagonist
conventional antipsychotic, blocks dopamine from binding to the D2receptor, which reduces hyperactivity in mesolimbic pathway and thereby reduces positive symptoms
Typical/first generation antipsychotics
This loosely defined term describes the older antipsychotics. They tend to:
- cause extra-pyramidal side effects
- act against positive but not negative symptoms
- have unselective binding to dopamine receptors
e.g. Phenothiazines
chlorpromazine (1947)
(antagonist at D2, a1; Also blocks H1, 5HT2, D1, D3, D4, 5HT1, a2, mACh)
Butyrophenones
haloperidol
(antagonist at D2>D4>D3»D1/5 (also at a1)
Extra-pyramidal side-effects of typical antipsychotics
two main kinds of motor disturbance
Acute Dystonia
Involuntary movements, often similar to Parkinson’s. Includes:
rigidity
tremor
inability to sit still
slowing of voluntary movements
Tardive dyskinesia
Causes large involuntary movements. - side effect of antipsychotics that target D2 receptor
Symptoms may worsen with reduced antipsychotic doses.
- Results directly or indirectly from D2 receptor blockade in the nigrostriatal pathway.
- Extrapyramidal side effects constitute one of the main disadvantages of first-generation antipsychotic drugs (typical).
- Incidence of acute dystonias and tardive dyskinesia is less with newer, second-generation antipsychotics (atypical), and particularly low with clozapine, aripiprazole and zotepine.
Atypical antipsychotics
These are more recently developed compounds, exemplified by clozapine. They tend to have:
- fewer extra-pyramidal side effects
- stronger efficacy against both positive and negative symptoms
- a different receptor selectivity profile
Dibenzodiazepines
clozapine
(antagonist D4>D3>D1>D2, 5HT2A/2C)
risperidone
(antagonist D2, 5HT2A).
fewer side effects
Newer atypical antipsychotic drugs
benzamides, e.g. amisulpride
(selective antagonist at D2 receptors).
quetiapine
(similar binding profile to clozapine, but with lower affinities).
Subtype selectivity
Most antipsychotics are antagonists at the D2 subtype (D2, D3 &/or D4 subunits).
Extra-pyramidal side effects tend to result from block of the D2 subunit in the nigrostriatal pathway - atypical drugs may have less side effects due to other actions at other receptors
Lessening of side effects in newer drugs may be the result of other actions (e.g. at mACh & 5-HT2) counteracting this.
Clinical potency correlates with D2 receptor affinity
Correlation exists between the therapeutic dose of a antipsychotic and the drug’s affinity for the D2 receptor
larger dose is required if the drug’s affinity for the D2 receptor is relatively weak
Neural imaging
MRI scans reveal structural neuronal deficits.
In particular, schizophrenic patients have smaller cortices and larger ventricles (particularly in medial temporal lobe and left hemisphere).
Many of these changes are not progressive, indicating there are developmental changes, in addition to possible degeneration.
The ‘dopamine theory’
Compounds that increase dopaminergic signalling activity (e.g. amphetamines) can induce psychoses.
There is a correlation between D2 receptor antagonist affinity and clinical antipsychotic efficacy
(i.e. schizophrenia can be treated by blocking D2 receptor activation).
Structural deficits in the brain suggest a loss of control of dopaminergic function.
The ‘glutamate theory’
-drugs targeting this theory have failed
Dysfunction in glutamatergic neurotransmission has also been suggested as a cause of schizophrenia, based on:
- The psychotomimetic actions of NMDA receptor channel blockers (e.g. phencyclidine (PCP), ketamine).
- Reduced glutamate binding in post-mortem studies of schizophrenic patients.
Serotoninergic system
5HT (serotonin receptor) has been proposed to play a role, with some atypical antipsychotics selectively blocking 5HT2A receptors. LSD also has psychotomimetic properties.
Serotonin modulates DA actions, so this is not necessarily incompatible with the dopamine theory.
Clozapine
held back as a last resort to treat resistant schizophrenia
