L12 Schizophrenia Flashcards
Define ‘psychosis’.
Refers to an acute & severe mental condition:
- Being out of touch with reality; disordered thought process, beliefs, perceptions
- Lack of insight from affected individual
Define ‘schizophrenia’.
1) One of the more common forms of psychosis
2) Heterogenous syndrome of disorganised & bizarre thoughts, delusions, hallucinations, inappropriate affect & impaired psychological functioning:
- Delusions: fixated forced belief that doesn’t change despite repeated correction & NOT based in reality.
- Hallucinations: auditory (most common), visual, tactile, olfactory & gustatory
3) Onset commonly in late adolescence to early adulthood
- Males: Usually early 20s
- Females: Usually late 20s to early 30s
What are some pharmacological agents that may be associated with psychotic symptoms as adverse side effects?
1) Dopamine agonists (e.g. levodopa & bromocriptine)
2) Excessive corticosteroids
3) Thyroid hormones
4) Alcohol
5) Psychoactive substance abuse (e.g. BZDs, barbiturates, CNS stimulants & hallucinogens)
6) Antidepressants
7) Beta-blockers (e.g. propranolol)
Lead to mania & potentially precipitate psychosis.
What is the primary pathophysiological abnormality influencing the etiology of schizophrenia?
Dysregulation of one of the three main neurotransmitters function:
1) Dopaminergic (DA)
2) Serotonergic (5-HT)
3) Glutamatergic
What is the mechanism of action of typical / first-generation antipsychotics (FGA)?
Dopaminergic D2 receptor antagonism
What is the most common mechanism of action of atypical / second-generation antipsychotics (SGA)?
Serotonergic (5-HT2A) & dopaminergic (D4»D2) receptor antagonisms as core MOA
- Not all SGA work via this mechanism though.
What are some predisposing factors that may increase the vulnerability of an individual to precipitate schizophrenia?
GENPP:
1) Genetics
2) Environment in utero
3) Neurodevelopment effects
4) Personality
5) Physical, psychological & social factors in infancy & early childhood
What are some precipitating factors that may increase the risk of an individual manifesting symptoms of schizophrenia?
C-PED:
1) Cerebral tumours or injury
2) Personal misfortune
3) Environment of highly expressed emotion
4) Drugs
- Alcohol, BZDs, barbiturates, antidepressants, corticosteroids, CNS stimulants, hallucinogens, BBs (e.g. propranolol) & dopamine agonists (e.g. levodopa & bromocriptine)
What are some perpetuating factors that may prolong the course of schizophrenia?
PLSS:
1) Poor adherence w/ antipsychotic medications
2) Lack of support / Poor socioeconomic status or environment
3) Social withdrawal
4) Secondary demoralisation
Based on the DSM-5 criteria for diagnosis of schizophrenia, describe the clinical presentation of an individual symptomatic of schizophrenia.
1) At least 2 of the following smx (i.e. 4 positive e.g. + negative smx), each persisting for a significant portion of at least 1-month period:
- Delusions that are persecutory in nature
- Hallucinations
- Disorganised speech manifested from tangential thought process OR slurred, unrecognisable speech patterns (e.g. mm, ah, uh)
- Grossly disorganised OR catatonic behaviour (medical emergency!!)
- Negative symptoms (e.g. affecting flattening of emotions, avolition/loss of motivation)
2) Social/occupation dysfunction
3) Duration: Continuous signs of disorders for at least 6 months
- Inclusive of at least 1 month of criteria 1 symptoms
- May include prodromal or residual symptoms
4) Schizoaffective or mood disorder has been EXCLUDED
5) NOT due to underlying medical disorder or substance abuse
6) If Hx of pervasive development disorder present, symptoms of hallucinations or delusion MUST be present for at least 1 month
What are two important screening questions to ask psychiatric patients in evaluating the efficacy and tolerability of their antipsychotic Tx?
1) Adherence to medication?
- To be reassessed on every visit.
2) Any suicidal/homicidal ideations & risks?
- Conduct mental state exam (MSE) for accurate diagnosis, including suicidality risk!
- Reassess MSE on every interview to evaluate efficacy & tolerability to antipsychotic medications.
What lab parameters should be investigated to exclude other differential diagnoses from schizophrenia?
- Vitals, weight & BMI
- FBC (WBC in particular for infections e.g. meningitis/encephalitis/neurosyphillis)
- Renal panel: Urea, electrolyte, creatinine
- LFTs
- TFTs (thyroid) for hypothyroidism
- ECG for CV risk
- Folate & Vit B12 for anemia
- Fasting blood glucose for hypoglycemia & diabetes
- Lipid panel for CV risk
- Urine toxicology for substance misuse & pregnancy
To exclude general medical conditions or substance-induced symptoms e.g. psychosis / depression / mania / anxiety / insomnia
What are some non-pharmacological recommendations to manage patients diagnosed with schizophrenia?
1) Individual Cognitive Behavioural Therapy (CBT)
- Primarily used in anxiety disorders
- Used in conjunction w/ antipsychotic medications & family intervention
- Applicable for (a) preventing psychosis in “at risk” group (b) first-episode psychosis to assess for PTSD (c) schizophrenia
- However, it is difficult to counsel highly irrational & aggressive pt. w/ schizophrenia!!
2) Neurostimulation
- Electroconvulsive Treatment (ECT): Reserved for treatment-resistant schizophrenia
- Repetitive Transcranial Magnetic Stimulation (rTMS): Effective for reducing auditory hallucinations in schizophrenia
3) Psychosocial rehabilitation programs: to improve patient’s adaptive functioning
- Individual: Supportive/counselling, personal therapy, social skills therapies, vocational sheltered (esp. for males)
- Group: Interactive/social
- Cognitive Behavioural: CBT, adherence/compliance therapy
What are the therapeutic goals in the treatment of schizophrenia?
1) Acute Stabilisation:
- Minimise threat to self and others; may require physical / forceful interventions during acute aggressive psychosis
- Minimise acute symptoms i.e. agitation, aggression, hostility, sleep improvement
- Improve role functioning (NOT to pre-morbid levels, BUT to function sufficiently)
- Identify appropriate psychosocial interventions (e.g. increased awareness of +ve & -ve symptoms & how to manage)
- Collaborate w/ family & caregivers for support
2) Stabilisation
- Minimise / prevent relapse
- Promote medication adherence
- Optimise dose vs adverse effects
3) Stable / Maintenance Phase
- Improve functioning & quality of life
- Maintain baseline functioning
- Optimise dose vs adverse effects
- Monitor for prodromal smx of relapse
- Monitor for adverse effects of antipsychotic medications (e.g. tardive dyskinesia)
Why are antipsychotic drugs used in the treatment of schizophrenia?
1) Relieve symptoms of psychosis e.g. thought disorders, hallucinations & delusions, thus preventing relapse
- Usually less effective in apathetic withdrawn patients
- Pt. w/ acute symptoms of schizophrenia generally respond better than those w/ chronic symptoms
2) Long-term Tx often necessary after 1st episode of psychosis & prevent illness from becoming chronic
- Relapse may occur if maintenance Tx of stable pt is withdrawn inappropriately
3) Relapse often delayed for several weeks after cesssation of Tx
- Adipose tissue act as depot reservoir after chronic regular usage of antipsychotics until depletion.
What are some methods to overcome poor treatment adherence to antipsychotic medications?
1) IM long-acting injections of antipsychotic medications
2) Community psychiatric nurse
3) Patient & family (caregiver) education
Explain the mechanism of action of antipsychotics in general, with respect to the central dopamine system.
Intended MOA:
1) Blockade of the mesolimbic tract
- Common MOA of ALL antipsychotics
- Overactivity in mesolimbic tract is responsible for +ve symptoms of schizophrenia
Unintentded MOA resulting in adverse effects:
1) Blockade of mesocortical tract:
- Responsible for higher-order thinking & executive functions
- Hypofunction / DA blockade results in -ve symptoms
2) Blockade of nigrostriatal tract:
- Responsible for modulation of voluntary movement
- DA blockade results in extrapyramidal side effects (EPSE), such as tardive dyskinesia, akathisia & acute dystonia
3) Blockade of tuberinfundibular pathway
- Regulates prolactin secretion into blood circulation
- DA blockade causes hyperprolactinemia & thus results in gynecomastia in males OR breast swelling, pain & increased lactation in females
What are some receptor affinities of antipsychotics?
What are the clinical implications associated to these receptor affinities?
1) D2 Antagonism:
(+) Improve +ve smx
(-) EPSE, hyperprolactinemia
2) 5-HT1A agonism:
(+) Anxiolytic
3) 5-HT2A antagonism:
(+) Improve -ve smx (?), antidepressant effect (?)
4) 5-HT2C antagonism:
(-) Weight gain, increased appetite
5) H1 antagonism:
(-) Sedation, weight gain
6) alpha-1 adrenergic antagonism:
(-) Orthostatic hypotension
7) M1 antagonism:
(-) Anticholinergic SE: Blurry vision, dry mouth, constipation, urinary retention, confusion, memory dysfunction
8) hERG / Ikr antagonism:
(-) QTc interval prolongation (pro-arrhythmic)
Explain the algorithm guiding the pharmacological treatment of schizophrenia.
1) Use a SINGLE FGA or SGA (EXCEPT clozapine)
- Individualise medication selection based on physician’s assessment, past responses/failures on antipsychotics, pt needs, efficacy & side effect profiles.
2) Use another SINGLE FGA or SGA (EXCEPT clozapine) that was NOT previously tried, if there is adequate or no response.
3) If NOT responsive to at least two adequate trials (i.e. at least 2-6 weeks of optimal therapeutic doses) of antipsychotics, of which one is an SGA, use CLOZAPINE for Tx-resistant schizophrenia.
4) If still resistant to Tx w/ clozapine, add augmenting agent such as another FGA/SGA/ECT (electroconvulsive therapy) to clozapine.
- Adequate trial for clozapine requires more time (up to 3 months) to confirm therapeutic response.
- Adequate augmentation trail of up to 8-10 weeks is required if another antipsychotic is added to clozapine.
5) If pt. refused clozapine or experience intolerable side effects from clozapine, adopt last-line combination therapy of antipsychotic combination (either FGA+FGA, or FGA+SGA), or antipsychotic + either ECT or another agent (e.g. mood stabiliser)
* If adequate response AND no tolerable side effects AND adherent, continue antipsychotic Tx.
Under what condition is clozapine clinically indicated in the treatment of schizophrenia?
Treatment-resistant schizophrenia
- At least TWO adequate trials of antipsychotics, of which one is an SGA must be administered prior to starting clozapine.
- Best in reducing suicidality.
- However, routine haematological monitoring of baseline & periodic absolute neutrophil count REQUIRED when using clozapine due to risks of neutropenia, cytopenia or clozapine-induced agranulocytosis!!
If a patient is inadequately adherent to his/her PO antipsychotic medications or prefers less frequent administrations, what other alternatives can you recommend to this patient?
Consider a long-acting antipsychotic injectable.
- IM risperidone microspheres
- IM paliperidone prolonged-release suspension
- IM aripiprazole long-acting injection
- IM haloperidol decanoate
- IM flupenthixol decanoate
- IM zuclopenthixol decanoate
What are some precautions to look out for before prescribing antipsychotics for the Tx of schizophrenia?
1) Cardiovascular disease
- C/I in pt w/ QTc interval prolongation
- ECG required for pt. w/ CV risk factors, Hx of CV disease or admitted as inpatient
2) Parkinson’s disease
- EPSE worsened by antipsychotics
- Quetiapine is recommended in pt w/ schizophrenia & PD
3) Epilepsy & conditions predisposing to seizures
- Lowered threshold w/ concomitant administration of FGA esp. chlorpromazine & clozapine
4) Blood dyscrasia (esp. w/ clozapine)
5) Elderly w/ dementia
- Increased risk for mortality & stroke
- May need to give PRN antipsychotics during delusion episodes
6) Prostatic hypertrophy
7) Closed-angle glaucoma
8) Severe respiratory disease
9) Depression
10) Myasthenia gravis
11) Hx of jaundice
In the event of a psychiatric emergency, recommend an adjunctive treatment with appropriate dose to a schizophrenic patient who is cooperative when presented to the emergency department.
Consider either of these PO medications for cooperative patients: (lorazepam & risperidone recommended)
1) PO lorazepam 1-2mg (reduced risk of muscle stiffness & dystonia)
2) PO antipsychotics:
- *Risperidone 1-2mg (tab, orodispersible, solution)
- Haloperidol 2-5mg (tab, solution) w/ pre-Tx ECG (difficult)
- Quetiapine 50-100mg (tab, immediate-release)
- Olanzapine 5-10mg (tab, orodispersible)
3) Oral-inhaled loxapine 10mg
- MUST ensure salbutamol is available
- C/I in asthma/COPD
In the event of a psychiatric emergency, recommend an adjunctive treatment with appropriate dose to a schizophrenic patient who presents to the emergency department with aggressive behaviour.
Consider fast-acting IM injection if pt. remains agitated/aggressive & uncooperative:
*1) IM lorazepam 1-2mg
2) IM olanzapine (immediate-release) 5-10mg
- 2nd dose >= 2h after 1st dose
- 3rd dose >= 4h after 2nd dose
- IM olanzapine & IM lorazepam must NOT be given w/in 1h from each other (risk of cardiopulmonary fatality)
3) IM aripiprazole (immediate-release) 9.75mg
- Less hypotensive than IM olanzapine
4) IM haloperidol 2.5-10mg w/ pre-Tx ECG (very difficult)
- Consider use of anticholinergics where appropriate due to increased risk of tremors/EPSE
5) IM promethazine 25-50mg
6) IM lorazepam + IM haloperidol
7) IM haloperidol + IM promethazine
In the event of a schizophrenic patient being presented with catatonia in the emergency department, recommend an adjunctive treatment for this patient.
IM > PO lorazepam
Which SGAs should be recommended to take with food to increase bioavailability?
Lurasidone & ziprasidone
What is the purpose of the decanoate attachment in the formulation of long-acting IM haloperidol injection?
To prolong the half-life of haloperidol by mixing with an oily vehicle.
- Sustained release of haloperidol achieved upon gradual enzymatic hydrolysis of long aliphatic chain to release free haloperidol into the bloodstream.
Administration of IM risperidone long-acting injection should be supplemented with three weeks of PO risperidone, upon initiation with first injection of IM risperidone. True or false?
True.
IM risperidone long-acting injection should be supplemented with PO formulation for three weeks upon initiation of IM Tx
- Microspheres containing risperidone in the IM formulation requires at least 3 weeks to break down to release risperidone into the bloodstream.
Which SGAs are known to have minimal side effects & are often prescribed to schizophrenic patients with Hx of dyslipidemia or T2DM?
Aripiprazole, brexpiprazole, lurasidone & ziprasidone
Which antipsychotics are known to cause metabolic disorders as a potential side effect?
Olanzapine, Clozapine
Which class of antipsychotics are known to cause hyperprolactinemia as a potential side effect?
FGA
Which class of antipsychotics are known to result in extrapyramidal side effects?
FGA > SGA
Which antipsychotic is known to have a high risk of causing dystonia as a potential side-effect?
Haloperidol
How is antipsychotic-induced dystonia pharmacologically managed?
Administer IM anticholinergic (benztropine»_space; diphenhydramine).
Switch to lower-potency SGA (e.g. quetiapine)
How is antipsychotic-induced parkinsonism pharmacologically managed?
Reduce dose of antipsychotics or switch to SGA (e.g. quetiapine).
If persist, administer PRN anticholinergics
- Benztropine»_space; trihexyphenidyl (benzhexol)
How is antipsychotic-induced akathisia pharmacologically managed?
Reduce dose of antipsychotics or switch to lower-potency SGA (e.g. quetiapine).
If persist, administer low-dose clonazepam PRN
- Anticholinergics generally unhelpful
How is antipsychotic-induced tardive dyskinesia pharmacologically managed?
Reduce dose of antipsychotics or switch to low-potency SGA (e.g. quetiapine).
DISCONTINUE any anticholinergics!
Administer Valbenazine 40-80mg/day as potential antidote
- Valbenazine: reversible inhibitor of vesicular monoamine transporter 2 (VMAT2)
- Clonazepam PRN as alternative
Trihexyphenidyl can be used to manage patients experiencing haloperidol-induced tardive dyskinesia. True or false?
FALSE
Anticholinergics are CONTRAINDICATED as they worsen antipsychotic-induced tardive dyskinesia!
- Should discontinue all other anticholinergics.
- Antipsychotic-induced tardive dyskinesia has a 50% chance of irreversibility
How is antipsychotic-induced hyperprolactinemia pharmacologically managed?
Switch FGAs to aripiprazole
How is antipsychotic-induced weight gain pharmacologically managed?
1) Maintain on current antipsychotics to prevent relapse BUT treat emergent diabetes & dyslipidemia pharmacologically (i.e. metformin & statins respectively) w/ lifestyle modifications (e.g. diet & exercise)
OR
2) Switch to lower risk SGA
- i.e. aripiprazole, brexpiprazole, lurasidone & ziprasidone
What rare but serious medical emergency condition is associated with the use of high-potency antipsychotics?
Neuroleptic malignant syndrome (NMS)
Describe the clinical presentation of a patient experiencing the neuroleptic malignant syndrome.
MAFIA (LID): Muscle rigidity / "lead-pipe" rigidity Altered consciousness Fever Increased creatinine kinase (in levels of 1000s) Autonomic dysfunction - Labile/fluctuating BP - Increased pulse rate - Diaphoresis / excessive sweating
How is neuroleptic malignant syndrome pharmacologically managed?
Administer IV Dantrolene 50mg TDS (muscle relaxant), PO dopamine agonist (e.g. amantadine, bromocriptine) & provide supportive measures ASAP.
- Subsequently switch current antipsychotics to SGA
What are some monitoring parameters to watch out for in the pharmacological management of schizophrenic pt.?
Therapeutic/Efficacy:
1) Mental State Examination (not specific)
2) Early improvements:
- 1st week: decreased agitation, aggression & hostility
- 2-4 weeks: reduced paranoia, hallucinations & improved thought organisation
3) Late improvements:
- 6-12 weeks: reduced delusions, -ve smx may improve
- 3-6 months: cognitive smx may improve w/ SGAs
Toxic/Safety:
1) BMI -> Drug-induced weight gain
2) Fasting blood glucose or HbA1c -> T2DM onset
3) Lipid panel -> Hyperlipidemia onset
4) BP -> esp. elderly due to orthostatic hypotension
5) EPSE examination for drug-induced rigidity, tremors, akathisia & tardive dyskinesia
6) WBC & ANC esp. for clozapine
- Weekly monitoring for 18 weeks for agranulocytosis risk, then monthly in SG
Which antipsychotics may be recommended in a patient with schizophrenia who is currently pregnant?
Olanzapine > clozapine
- Monitor for gestational diabetes
Which antipsychotics may be recommended in a patient with schizophrenia who is currently breastfeeding?
Olanzapine or quetiapine
- Pt on clozapine should continue on the drug BUT should NOT breastfeed.
Haloperidol is the most appropriate antipsychotic for the treatment of schizophrenia on a patient who is currently 67 years old. True or false?
FALSE
AVOID drugs w/ high propensity for alpha-1 adrenergic blockade or anticholinergic SE for elderly patients diagnosed with schizophrenia!!
- Antiadrenergic SE: Orthostatic hypotension
- Anticholinergic SE: Constipation, urinary retention & delirium
What are some considerations when prescribing an appropriate antipsychotic drug to an elderly patient diagnosed with schizophrenia?
1) Avoid FGAs due to high propensity for elderly pt experiencing alpha-1 adrenergic blockade or anticholinergic SE!
- Antiadrenergic SE: Orthostatic hypotension
- Anticholinergic SE: Constipation, urinary retention & delirium
2) Start low, go slow & simplify regime
3) Avoid long T1/2 drugs
4) Avoid adverse interactions
Which disease will concomitant administration of antipsychotics worsen?
Parkinson’s disease
- Due to EPSE of antipsychotics
List potential clinically significant DDI that may occur with co-administration of antipsychotics.
1) CNS depressive drugs
- e.g. alcohol, opioids, BZDs
- Additive CNS effects
2) Drugs w/ anticholinergic, antihistaminic, anti-alpha-1-adrenergic and antidopaminergic activity
- Additive adverse effects
3) Dopaminergic agents
- e.g. levodopa, bromocriptine
- Mutual antagonism w/ antipsychotics
4) 5-HT augmenting agents
- e.g. SSRI, SNRI, NaSSA, SMS
- May antagonise 5-HT2A receptor blockade, thus reducing DA release & worsen EPSE
5) Antihypertensive & trazodone
- Worsen hypotensive effects
6) CYP1A2 inhibitors:
- e.g. fluvoxamine, quinolones, macrolides (except azithromycin), isoniazid, ketoconazole
- Increased haloperidol, clozapine, olanzapine & ziprasidone concentration
- Increased seizure risk
7) Carbamazepine
- Increased risk of clozapine-induced agranulocytosis, due to reduction in WBC/ANC
Differentiate the clinical efficacy & toxicities between FGAs & SGAs.
Efficacy:
- SGA: Both +ve smx & mood smx
- FGA: MAINLY +ve smx
Toxicity:
- FGA: generally more EPSE
- SGA (-pine): generally more metabolic SE, weight gain & more sedating
- SGA (-one & - piprazole): relatively less sedating, weight gain
- SGAs with minimal SE are aripiprazole, brexpiprazole, lurasidone & ziprasidone
What non-pharmacological advice would you give when a patient complains of experiencing frequent dizzy spells whenever he/she wakes up when he/she is on haloperidol for schizophrenia Tx?
Rise up slowly from a lying/sitting position.
- Likely due to orthostatic hypotension as SE of haloperidol
