Case 8 - Schizophrenia Flashcards
What are the 3 functional divisions of the striatum?
- Sensorimotor (dorsal) = putamen
- Associative (mid) = globus pallidus
- Limbic (ventral) = Ventral Tegmental Area
Which brain regions are the main source of input to the 3 functional divisions of the striatum?
Motor areas of cortex > to sensorimotor
Dorsolateral prefrontal cortex > associative
Hippocampus and amygdala > limbic
What are the 4 dopamine system pathways?
Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular
For the nigrostriatal pathway, where is dopamine released from/ to? What is the role of this pathway?
From substantia nigra pars compacta (SNc) to the striatum (caudate + putamen). Has 2 functional divisions:
- SNc -> sensorimotor (dorsal) striatum = involuntary motor control
- Snc -> associative (mid) striatum = cognition and emotion
For the mesolimbic pathway, where is dopamine released from/ to?
From ventral tegmental area to limbic regions in the midbrain, including the nucleus accumbens, amygdala, hippocampus and medial prefrontal cortex
What is the role of the mesolimbic pathway?
Associated with reward, motivation, affect and memory
For the mesocortical pathway, where is dopamine released from/ to? What is the role of this pathway?
From ventral tegmental area to the frontal cortex (particularly the dorsolateral prefrontal cortex)
Role: normal cognitive function, motivation and emotional response
For the tuberoinfundibular pathway, where is dopamine released from/ to? What is the role of this pathway?
From tuberal region of the hypothalamus to the median eminence (top of pituitary stalk)
Role: dopamine inhibits release of prolactin from the anterior pituitary
What dopamine abnormality is present in psychosis?
Increased dopamine presynaptic function in the nigrostriatal pathway, thought to be secondary to an abnormal glutamate or GABA system
Explain the 2 principal dopamine abnormalities present with schizophrenia
1: Excessive dopamine release in the striatum, via the nigrostriatal pathway (particularly associative branch) during acute psychotic episodes
2: Inadequate dopamine release in the frontal cortex (constant)
What symptoms is an increase in dopamine in the nigrostriatal pathway associated with? What is the relationship between DA and these symptoms?
Positive symptoms, and is positively correlated (i.e. higher excess dopamine = higher severity of symptoms)
What is associated with a better treatment response to antipsychotics?
Higher excess dopamine release in the nigrostriatal pathway (associative branch)
What symptoms is inadequate dopamine release in the frontal cortex associated with? What is the relationship between DA and these symptoms?
Deficits of cognitive function, i.e. working memory (less dopamine in the frontal cortex= worsened cognitive impairment)
Define schizophrenia
Severe mental disorder with distortions of thinking and perception, and affects that are inappropriate or blunted. Clear consciousness and intellectual capacity are usually maintained but cognitive deficits may evolve over time
What is a hypothesised explanation for negative symptoms?
Decreased dopamine release in the ventral striatum
What receptor is responsible for the altered release of dopamine in schizophrenia?
NMDA receptor - hypofunction
What is the glutamate-dopamine hypothesis for schizophrenia?
1: hypofunctional NMDA receptor = less glutamate release = less stimulation of GABA neurones
2: Low GABA doesnt adequately suppress cortico-brainstem glutamate outflow
3: Excessive glutamate stimulation of substantia nigra dopamine neurones = increased dopamine in associative and sensorimotor striatum
4: Excessive glutamate = stimulates GABA interneurone = increased GABA inhibits mesolimbic and mesocortical dopamine neurones in the VTA, so dopamine will be low in the VTA = negative symptoms
5: inhibition to dorsolateral prefrontal cortex = decreased cortical dopamine = cognitive deficit
What are positive symptoms (psychosis) of schizophrenia? Give examples
Positive = presence of experiences additional to what the person is usually like
- Delusions
- Hallucinations
- Thought disorders
Define delusion
A fixed, false belief, unshakeable by superior evidence to the contrary, and out of keeping with a person’s cultural norms.
Name the types of delusions that may be seen in schizophrenic patients
- Reference
- Persecution
- Control
- Bizarre and impossible
What is a reference delusion?
Believing everyday events have a strong personal coincidence/ refer to them, i.e. believing people are spying on them
What is a persecution delusion?
Believing others are out to harm or kill the patient
What is a control delusion?
Belief that their thoughts, beliefs, impulses and behaviour are under the control of other people or an external force
What type delusion may be present during mania of a patient with bipolar disorder?
Grandiose = belief that you have special powers, wealth or fame
What type delusion may present with depression?
Hypochondriacal or somatic: refer to one’s health or body, belief they have a disease or abnormality
What 2 types of delusion may be present in psychotic depression?
Nilhistic = belief they no longer exist, or part of their mind/ body is missing
Guilt = believing you’re worthy of punishment, usually from small acts in the past
What is a hallucination?
Abnormal sensory perception, internally generated, in the absence of an external stimuli
What are the potential types of hallucinations?
Any sensory modality:
- Visual
- Taste (gustation)
- Auditory
- Smell (olfactory)
- Somatosensory (tactile)
- Kinaesthetic (body position)
- Temperature
- Pressure
What type of hallucination is typically seen in schizophrenia?
Auditory
What is a thought disorder?
Breakdown of logical association between words, recognised when it is difficult/ impossible to follow a patient while talking. May be described as ‘derailment’ (i.e. train of thought coming off its track)
What term is used to describe thought disorder when it is completely unrecognisable?
World salad
What is the difference between a delusion and hallucination?
Delusion = abnormal belief (fixed, false)
Halucination = abnormal sensory perception
What is a negative symptom of schizophrenia?
Absence of capacities usually present, which disproportionately contribute to functional impairment and poor psychosocial outcomes in schizophrenia
Give some examples of negative symptoms of schizophrenia
- Anhedonia = inability to experience pleasure
- Poverty of speech (alogia) / reduced speech
- Flat or blunted affect (mood) and emotion
- Lack of motivation (avolition)
- Lack of desire to form relationships (asociallity) and/or social withdrawal
- Apathy
What can cognitive symptoms of schizophrenia affect?
Memory and executive functions, i.e. working memory, learning, planning, mental flexibility, impulse control
Other than positive, negative and cognitive symptoms of schizophrenia, what other symptoms may be apparent?
- Disorganised symptoms: incoherent speech, bizarre and unpredictable behaviour
- Excitement and agitation
What areas of the brain might be affected with visual hallucinations in schizophrenia?
Primary visual cortex (Brodmann’s area 17)
Cortical areas responsible for visual processing
Visual association areas (Brodmann’s areas 18 and 19) - more complex hallucinations
What areas of the brain might be affected with auditory hallucinations in schizophrenia? What neurotransmitters might be implicated with this?
Spontaneous activation of the auditory network in your brain, i.e. superior temporal gyrus, temporal lobe
= serotonin and dopamine imbalance
What symptoms are predominant with paranoid schizophrenia?
Positive symptoms are predominant (hallucinations and delusions), with unreasonable suspicion
What symptoms are predominant with disorganised (hebephrenic) schizophrenia? Give examples
Disorganised symptoms:
- Disorganised speech, e.g. word salad
- Disorganised behaviour, e.g. difficulty starting/ finishing a task, inappropriate social behaviour
- Flat or inappropriate affect, i.e. lack of eye contact, lack of facial expression
Why is catatonic schizophrenia now a rare subtype?
Occurs with untreated schizophrenia, so now we have early intervention and treatment it occurs less
What is catatonic schizophrenia characterised by?
Considerable increase or decrease in movement, i.e. largely immobile or excessive movements, echolalia (repeating what others say), echopraxia (mimicking other’s movement)
What is residual schizophrenia?
Happens after schizophrenia, i.e. left over symptoms, usually negative. Doesn’t experience delusions or hallucinations but symptoms to a lesser extent, i.e. odd beliefs
What is schizophreniform disorder?
Schizophrenia but only present for 1-6 months (for schizophrenia to be diagnosed has to be > 6 months)
What are some risk factors for schizophrenia?
- Family history (greatest risk)
- Genes, i.e. affecting COMT enzyme, dysbindin
- Substance abuse, i.e. cannibis (greater use and earlier usage= higher risk)
- Child sexual abuse
- Migration
- Peri-natal oxygen deprivation (i.e. birth asphyxia)
- Low birth weight
- Urban living, overcrowding
What symptoms of schizophrenia is cannibis use associated with?
Positive (psychotic) symptoms and risk of full psychosis
A young (<40) male with poor premorbid function is diagnosed with schizophrenia. What type symptoms is he likely to present with?
More likely to have negative symptoms and a poor outcome
What is thought to be the cause of schizophrenia?
Genes x environment interaction: additive effect, i.e. urban living AND family history = much higher risk
What is thought to precede schizophrenia?
‘At Risk Mental State’ (ARMS): clinical presentation considered to develop psychosis or schizophrenia, e.g. odd, mild symptoms. 20-30% will transition to schizophrenia in next few years
What is a thought echo?
Hearing your thoughts as an auditory hallucination (can occur before or during your thoughts)
What is a thought insertion?
Believing not all your thoughts in your head are your own, i.e. put in there by another agency
What is thought withdrawal?
Believing some of your thoughts have been taken out of your head by an external agency
What is thought broadcasting?
Experience that your thoughts are no longer private, they can be known, heard or read by others
What is neologism?
New word or expression, nonsensicle and unrecognisable (i.e. making up new words)
What is catatonic behaviour?
Striking motor behaviour, either reduced voluntary movement or hyperactivity and agitation
What is mutism?
Absence or reduction of speech
What is stupor?
State close to unconsciousness
What is the ICD-10 diagnostic criteria for schizophrenia?
At least 1 first-rank symptom for at least 1 month:
- Thought echo, insertion, withdrawal or broadcasting
- Delusions of control, influence or passivity (body or limb movements, thoughts)
- Auditory hallucinations
- Persistent delusions that are completely impossible
OR:
At least 2 second-rank symptoms for at least 1 month:
- Other persistent hallucinations in any modality
- Thought disorder: neologism, derailment, incoherent speech
- Catatonic behaviour: stupor, mutism etc.
- Negative symptoms, not due to depression or medications
What is the DSM-5 diagnostic criteria for schizophrenia?
2 of:
- Delusions
- Hallucinations
- Disorganised speech
- Disorganised or ‘catatonic’ behaviour
- Negative symptoms
Must include one of the first 3 symptoms, present most of the time for 1 month, within an episode of illness lasting > 6 months
How does cannibis lead to psychosis?
Cannibis binds to CB1 receptors, which inhibits the GPCR = reduced release of GABA and glutamate, this then has impact on dopamine.
What medical conditions can cause temporary psychosis?
Addison’s disease: electrolytes, cortisol and aldosterone are altered which can manifest as psychosis
Undiagnosed diabetes: hypoglycaemia and DKA can cause delirium
Enephalopathy (brain disease) seen in advanced liver disease
Wilson’s disease: accumulation of copper in organs
Major depression: usually nihilistic illusions (i.e. that their body is rotting), less hallucinations
Hypothyroidism
What are other organic causes of psychosis?
Renal infections/ UTI - can trigger pscyhotic episodes
Encephalitis - inflammation of brain caused by autoimmune or infection
Parkinson’s medication
Corticosteroids
What is the most common age of presentation of schizophrenia?
20 years old, but is a second peak at around age 40-45 years
Is schizophrenia more common in males or females?
Under the age of 40, males outnumber females 2:1
Over the age of 40, slightly higher in females
= Overall is male to female 1.4:1
What is the life expectancy of patients with schizophrenia?
60 years: a 15-25 year reduction, mostly due to physical ill health
What seems to be correlated with severity of negative symptoms?
Younger you are= more severe negative symptoms
More severe in males than females with younger age
What are the 2 principles for managing schizophrenia?
1: Mileu (social environment) - get people into right environment, i.e. ongoing warmth, empathy, positive regard. Support to engage in meaningful daily activity (i.e. cooking)
2: Antipsychotic drugs
What is the mode of action of all antipsychotic drugs? How is dose predicted?
Reversible D2 receptor antagonists
Dose is predicted by efficacy of D2 receptor
What does the percentage occupancy of D2 receptors need to be for anti-psychotic effects?
> 65% of D2 receptors in the associative striatum
What percentage occupancy of D2 receptors is associated with side effects?
> 75% of D2 receptors in motor striatum, hypothalamus and pituitary can cause motor side effects (i.e. Parkinsonism) and hyperprolactinaemia
How would motor side effects of antipsychotics be treated?
- Reduce dose of antipsychotic
- Anticholinergics
- Beta-blockers, i.e. propanolol
What receptor types are found in high concentrations in all 3 areas of the striatum?
True D1 and true D2
What receptor type is predominant in the frontal cortex?
D4 receptors (D2-like)
What’s the difference between typical (first-generation) and atypical (second-generation) antipsychotics?
Typical (first-gen): blocks D2 receptors
Atypical (second-gen): lower affinity and occupancy for D2 receptors, but high degree of occupancy of 5-HT2A receptors
What is the first line treatment for schizophrenia?
Risperidone, or another 2nd generation antipsychotic
What is Risperidone’s mode of action?
Blocks presynaptic D2 receptors in nigrostriatal associative pathway (decreases positive symptoms), and also blocks 5-HT2A (high affinity), a1, a2 and H1 receptors.
Blocking serotonin receptors in mesocortical pathway leads to increased dopamine and thus lower negative symptoms
(dual action)
What is the dosage for risperidone, haloperidol and olanzapine when treating schizophrenia?
Risperidone= 2mg daily
Olanzapine= 7.5mg daily
Haloperidol= 1.5mg daily
(to achieve >65% occupancy)
What are the side effects of risperidone?
Adverse effects seen with D2 antagonism
As well as:
- Weight gain (alpha adrenergic and serotonin receptors affect leptin)
- Hypotension
- Sedation
- Cardiotoxicity
What are the side effects of D2 antagonism?
Mesolimbic: worsening of negative symptoms
Nigrostriatal sensorimotor branch: Parkinsonism
Mesocortical: exacerbates low dopamine so decreased cognitive function
Tuberoinfundibular: hyperprolactinaemia
What can hyperprolactinaemia lead to if untreated?
- Sexual dysfunction: diminished libido and arousal
- Reproductive dysfunction: amenorrhea, subfertility
- Breast pathology: galactorrea
- Hypogonadism: decreased bone mineral density
- Miscellaneous (acne)
How can hyperprolactinaemia be treated?
- Decrease dose of antipsychotic
- Replace antipsychotic with another that has low risk (i.e. quetiapine, aripiprazole)
- Add a small dose of aripiprazole to existing antipsychotic (as it lowers prolactin)
How long does it take for the effects of antipsychotics to become evident?
Symptoms can improve by day 1, but mostly after 2 weeks improvement is clear
What drug is used for Treatment Resistant Schizophrenia? When else might this drug be prescribed?
Clozapine; best drug for 20-30% of patients who are resistant to treatment
May also be given if other antipsychotics cannot be tolerated
What is treatment resistant schizophrenia?
Schizophrenic patients that have failed to respond to 2+ antipsychotics (one of which being atypical), given at an adequate dose for >6-8 weeks
What are the side effects of clozapine?
Sedation, hunger, hypersalivation, diabetes, dry mouth, dry eyes, weight gain, agranulocytosis (can be dangerous!)
How can clozapine lead to sedation and dry eyes / mouth?
Sedation - due to its high histamine-1 affinity
Dry mouth and eyes - due to high muscarinic (M1) affinity
Which antipsychotics have the highest risk of weight gain? Why?
Clozapine and olanzapine
There’s evidence for lots of receptors causing weight gain, and these 2 antipsychotics block lots of different receptors so the effect is cumulative
What needs to be monitored continuously when prescribing clozapine to a patient? Why?
White blood cell count (and full blood cell count before prescribed)
Due to the risk of agranulocytosis (low WBC count) which can be fatal
What might be done if a patient is responding poorly to clozapine?
Add a 2nd antipsychotic: clozapine binds best to D4 so add a D2 or D3 antagonist like supiride or amisulpride to ‘fill the gap’
What is highly correlated to mortality with antipsychotics?
Constipation
What fatal condition can be caused by initiating antipsychotics, or by rapid increasing dosages? Name the antipsychotics that pose this risk
Neuroleptic syndrome - rare, but leads to rapid onset of coma, high temperature, rigidity and possibly death.
Can be caused by risperidone or haloperidol
What are some risk factors for non-adherence?
- Not seeing medication benefit
- Not thinking you’ll relapse
- Not liking the medication
- poor relationship with practitioner
- poor illness insight
What is insight?
Knowing you’re ill / suffering from the condition, it predicts adherence better longitudinally than other measures (wont keep up adherence without insight)
What factors are associated with adherence?
- Positive attitude towards medication
- Family involvement
- Illness insight
How could non-adherence be overcome with risperidone?
Inject it every 2 weeks
What is the danger of non-compliance with antipsychotics?
- Suicide risk
- Self-neglect
- Risk to others (especially before diagnosis)
What is cognitive remediation?
Video games that set tasks and acquire you to stretch your memory, judgement and concentration the more the game goes on.
How does CBT work to treat psychosis?
1:1 with a therapist who asks about symptoms and then gets the patient to try out various approaches to deal with them, e.g. logic of delusions and check whether they are true, reduce voice’s impact by listening to music, checking logic of the voice’s claims
What is a family intervention for treating schizophrenia?
Works with the family to find the behaviour they find problematic and try out ways to deal with them. Also educates about the illness and how their relative is driven to react and behave
What is the recommended ‘dose’ for family intervention? What is it best at preventing?
> 12 sessions over 6-12 months
Prevents relapses
What is the Mental Health Act?
put in place to treat individuals who suffer from a mental disorder, safeguard individuals who lack capacity, and to protect individuals and others.
What is the criteria for detention under the Mental Health Act?
1: Suffering from a mental disorder which warrants the detection of the patient for assessment (followed by treatment) for at least a limited period, AND
2: The person ought to be detained in the interest of their own health or safety, or with a view to protect others
Explain the use of section 2 for detention under the MHA
For assessment - it lasts for up to 28 days = this is for when you don’t know the diagnosis. Allows 2 doctors and a practitioner to detain under this
Explain the use of section 3 for detention under the MHA
For treatment - lasts for up to 6 months, then can be renewed for another 6 months, and then again for 12 months.
This is when you know the diagnosis and treatment requirements
Explain the use of section 4 for detention under the MHA
For emergencies - lasts for up to 72 hours; if another doctor isn’t available to undertake the assessment, admit tot he ward and then when the doctor is available can convert the section 4 to a section 2
Explain the use of section 5(2) and section 5(4) for detention under the MHA
Section 5(2) = doctors holding power, lasts for up to 72 hours. I.e. a doctor may detain a patient under this while waiting for a more senior doctor to assess them
Section 5(4) = nurses holding power, lasts for up to 6 hours
What is a community treatment order? When might it be used?
Allows someone discharged from section 3 to be readmitted if they don’t obey specific conditions, usually adherence to medication.
i.e. can be recalled back to the hospital randomly for prompt treatment - for those that stop taking their medications then become unwell and then violent (pose a risk to them or others)
What is the Mental Capacity Act?
legal framework for acting and making decisions on behalf of individuals who lack the mental capacity to make particular decisions for themselves.
What are the principles of the Mental Capacity Act?
- A person must be assumed to have capacity unless shown otherwise
- A person shouldnt be treated as unable to make a decision unless all practicable steps to help him do so have been done
- A person isnt treated as unable to make a decision if they make an unwise one
- A decision under this act must be in their best interests
- Always go for their least restrictive option for decisions
What are Early Intervention Services?
EIS aims to intervene in a non-stigmatising way, as soon as possible after first episode, to minimise delay in first treatment. It covers the first 3 years of treatment in 13-65 year olds
What are the main domains of the recovery model?
- Health = make choices to support physical and mental wellbeing
- Home = stable place to live
- Purpose = meaningful daily routines, work, family, participation
- Community = support social relationships, emotional availability
