Pharmacological interventions Flashcards
What characterises the psychopathology of psychosis?
Pathology of
- perception
- thinking
- beliefs
- selfhood
Patient experiences a fundamental transformation
What is the most common symptom of acute psychosis?
Loss/lack of insight
- patient doesn’t realise the falseness of their new reality
Which organic dysfunctions can be the direct cause of psychosis?
- Endocrine disorders
- Metabolic disorders
- Autoimmune conditions
- Psychoactive drugs
What characterises the negative symptoms of psychosis and schizophrenia?
- Loss of function
- Loss of drive, motivation, ambition, emotion, interests, romantic relationships, intellectual life
- Negative symptoms carry more prognostic and diagnostic weight than positive symptoms
- Poorer long-term outcomes
Which psychoactive substances can cause an acute psychotic episode after single use?
- Strong synthetic cannabinoids
- K2
- LSD
- Ketamine
Which psychoactive substances can cause an acute psychotic episode after repeated use?
- Methamphetamine
- Crack cocaine
What is the Indian snakeroot plant Rauwolfia serpentina?
- First effective treatment of psychosis
- Contains reserpine
- Used in Indian and Chinese medicine
- Trials conducted in 1950s showed reserpine was effective in treating schizophrenia
(depletes nerve varicosities of monoamine NTs, including dopamine) - By the end of 1950s, consensus decided that reserpine was less effective in schizophrenia
- > its use diminished
When did genuine effective pharmacological treatments for psychosis emerge?
Early 1950s-1970s
What were the consequences of the emerging pharmacological treatments for psychosis in the mid-20th century?
- Symptomatic improvement (not just sedation) for mania, thought disorder, delusions and hallucinations
- Maintenance treatment could prevent a relapse back into psychosis
When were the benefits of lithium and chlorpromazine confirmed in randomised controlled trials?
1954
- Lithium for mania
- Chlorpromazine for schizophrenia
What was the consequence of the introduction of antipsychotic drugs?
- Massive reduction in the number of hospital beds occupied by mental ill patients
- Social change
What is the priority in the acute stage of psychosis?
Symptom relief
- antipsychotics are highly effective
- symptoms of agitation, hallucinations, delusions can be addressed safely and efficiently
What is the priority in the maintenance stage of psychosis?
Avoid relapse
- high proportion of patients go on to experience further episodes of psychosis
What is the main predictor of relapse?
Non-adherence to medication
- patients who discontinue medication have fivefold higher chance of relapse
What are common predictors of relapse?
- Presence of substance abuse
- Critical comments
- Poor premorbid adjustment
What is associated to each relapse?
Progressive social and functional decline
- psychopathology becomes less responsive to treatment
What are the rates of relapse in the first year of recovery in those on medication and those off medication?
- 77% relapse in those off medication
- 3% relapse in those on medication
What does the meta-analysis of Leucht and colleagues (2012) on antipsychotic drugs vs placebo for relapse prevention show?
- Drug superior to placebo
- Being off and on treatment made no difference to wether patient found employment, probably because other factors determine employment type
What is CBT for psychosis recommended for?
- Recommended as treatment for psychosis by the National institute of clinical guidelines (UK)
- Benefits for symptoms
To which drugs does mania respond to?
- Lithium (first anti-manic agent)
- Valproate
- Carbamazepine
- Antipsychotics
Why did psychiatrists at Maudsley Hospital (London) consider that the first lithium trial by Baastrup and Mogens (1967) was not a “proper trial”?
- Open-label study
- No blinding or randomisation
What did RCTs in 1970 demonstrate about lithium?
Lithium was effective in protecting against relapse
What is the recommendation of the British Association for Psychopharmacology regarding lithium?
Lithium recommended as first-line treatment for maintenance therapy on bipolar I
What does maintenance pharmacotherapy consist of?
Reducing relapse
- with antipsychotics and mood stabilisers
- follow up of patients one or more years
What did the study of Whistler and colleagues (2011) on the continuation of quetiapine vs switching to placebo or lithium for maintenance treatment of bipolar I disorder show?
- In placebo group: 20% avoided relapse
- In quetiapine group and lithium group: 60% avoided relapse
What does the study of Suppes and colleagues (2009) on the combination of quetiapine with lithium or divalproex as maintenance treatment for Bipolar I disorder show?
Combination treatments outperform mono-therapy in avoiding relapse
- Monotherapy (lithium or divalproex): 60% chance of avoiding relapse (manic or depressive)
- Combination (quetiapine + lithium or divalproex):
90% chance of avoiding manic relapse
80% chance of avoiding depressive relapse
What was the first antipsychotic introduced in the 1950s?
Chlorpromazine (discovered in France)
What characterises chlorpromazine?
- Proven efficacy
- Wide safe
- Produce dramatic reduction in hallucinations, delusions, agitation
How were antipsychotics discovered?
Discovered by design:
- Paul Janssen observed that many cyclists developed acute psychosis after use of amphetamines to combat fatigue
- > he developed haloperidol (blocks amphetamine)
What characterises haloperidol?
- Blocks amphetamine
- Highly effective for schizophrenic psychoses
- In small doses: powerful treatment against hallucinations, delusions and agitation
How is conditioned avoidance?
Process of inhibition learning in animals, notably with chlorpromazine and haloperidol
How was conditioned avoidance used for antipsychotics?
Test to establish whether a new candidate molecule showed antipsychotic signature
- e.g. with chlorpromazine, animal is indifferent to environmental cue which predicts danger
- > ability to disrupt conditioned avoidance was a marker of a drug with antipsychotic activity in man
Where are dopamine neurons found?
In substantia nigra (specific brainstem nuclei)
How were Scandinavian researchers able to map out the dopamine pathways in the brain?
Using fluorescence methods
-> massive arborisation within the ‘higher centres’
What makes dopamine a slow neuromodulator?
- Evokes a diffuse, slow biochemical change in millions of target neurons
- Optimised for modulating higher networks
What is the function of dopamine?
- Modulates the fast synapse
- Can adjust the strength of connections
- > a teaching signal
- Critical role in learning and memory (e.g. conditioned avoidance)
What are varicosities?
Highly branching pattern of dopamine neurons
What are the three modes of firing of dopamine neurons that Wolfram Schulz identified?
- Spiking every second
- Burst firing mode
- Switching off
In which cases does dopamine fire in spiking every second?
- Awake brain
- Tonic concentration in target areas
- Tonic concentration for weed-rehearsed thoughts and motor patterns
When does dopamine enter a burst firing mode?
- Happens when animal encounters new stimulus which carries a reward
- For learning: adjusts the strength of point-to-point connections in the striatum
When does the dopamine firing mode switches off?
- When anticipated and predictable reward fails to materialise
What happens when dopamine does not fire (firing mode switched off)?
- New patterns of thought and behaviour, abandoning primitive and earlier ones
- Refining of existing network: main form of learning in the striatum
What are the functions of the striatum?
- Critical for learning new habits of thought and movement
- Striatal network when there’s integration of new habits of thought and movement
- > new connections
What is common to all antipsychotic drugs?
They all block dopamine D2 receptors
What differentiates antipsychotic drugs?
Their propensity to act at additional receptors (other than D2)
How to select antipsychotic drugs?
- For psychotic episode: emphasis on prompt relief of symptoms
- For maintenance: emphasis on avoiding side-effects
- > patients stick with treatment and lower risk of relapse
Are their drug “rankings”?
- For treatment resistant patients: clozapine is superior to other drugs
- Otherwise, there’s little difference between drugs in terms of efficacy
What is the effect of clozapine on treatment resistant patients?
- After 6 weeks: 30% get better
- After 6 months: 60-70% get better
How does clozapine work?
- Weak binding to D2 receptors
- Evidence that its unique effects come from activity at acetylcholine receptor in striatum
What are the strengths of the antipsychotic drug clozapine?
- Anti-suicidal effect
- Reduces aggression and violence
- No motor side effects (e.g. parkinsonism)
What are the weaknesses of the antipsychotic drug clozapine?
- Weekly and monthly blood tests are needed
- In 1% of patients it can cause potentially dangerous decrease in white blood cells (necessary to fight infections)
What is required when using clozapine for severely disable schizophrenic patients?
Combination treatment:
- provide alongside clozapine a package of rehabilitative support
- psychosocial rehabilitation to recover quality of life
- especially for patients disabled by negative symptoms and poverty
What is the benefice of long-acting depot antipsychotic injection?
Relapse rates are considerably lower
- Chances of relapse over the year following first psychotic episode is 7% with long-acting injectable risperidone
vs 50% risk of relapse with oral risperidone - Remains in the system for many weeks: sufficient time to carefully monitor and plan for patients who discontinue or mise a dose
- > gold standard treatment for avoiding relapse in psychotic disorders
What is the current issue with the treatment option of long-acting intramuscular risperidone?
Only 50% of patients taking oral risperidone are informed about the long-acting depot injection alternative
