Clinical Case Studies Week 5 (Depression, Psychosis + Schiz, Dementia) Flashcards
What does the psychological treatment of depression consist of?
Structured problem-solving strategies
Stress management strategies
CBT
Interpersonal psychotherapy (IPT)
Short-term dynamic therapy
Which SSRI/SNRI will have withdrawal effects? Why? What are these withdrawal effects?
Fluvoxamine, paroxetine, and venlafaxine as these have short half lives.
Withdrawal effects for SSRIs and SNRIs: Dizziness, nausea, paraesthesia, anxiety, agitation, tremor, sweating, confusion, electric shock-like sensations
When do SSRI doses need adjustment?
Doses usually need adjustment in hepatic impairment
What differentiates escitalopram from other SSRIs?
Escitalopram - causes less sedation, sexual dysfunction and no agitation or weight gain due to high receptor selectivity
Explain the following drug interactions and precuations for SSRI
A) Platelet aggregation
B) Hyponatraemia risk
C) QT interval prolongation/arrhythmia risk
A)
- Caution with other drugs that effect clotting → bleeding risk (esp GI)
- E.g. Warfarin + SSRIs may increase anticoagulant effect and risk of bleeding; monitor INR and ↓ warfarin dose as needed.
B)
- Increase risk with other drugs causing this effect.
C)
- ↑ risk with other drugs causing this effect.
What type of impairment affects SNRI (metabolism)?
Dosage adjustments required in renal impairment (CrCl < 30ml/min)
Hepatic impairment - variable recommendations depending on the agent (duloxetine contraindicated)
What are the adverse effects of SNRIs? how do they differ from SSRIs?
Similar adverse effects and precautions to SSRIs due to serotonergic actions
Suicide risk, serotonin syndrome, hyponatraemia, risk of bleeding, narrow angle glaucoma
> narrow angle glaucoma is a NA side effect
Cardiac effects
Use cautiously in patients with cardiac disease
Increases in BP reported with desvenlafaxine, duloxetine (infrequent) & venlafaxine
Control hypertension before starting desvenlafaxine or venlafaxine
Lipid effects
Elevations have occured with desvenlafaxine, use with caution
When is agomelatine contraindicated?
Contraindicated in hepatic impairment or if aminotransferase concentration is > 3 X ULN.
> Caution if aminotransferases are already elevated or other risk factors for hepatic damage
> Additive hepatotoxic effects with other drugs
When are TCAs used? What do they have a role in? When are they potentially lethal?
Used generally after unsuccessful trials of at least 2 first-line treatments
- Have a role in severe melancholic depression
- Potentially lethal in overdose!!! (cardiotoxicity)
Precatuons of TCA?
suicide risk, CV disease, elderly, epilepsy (lowers seizure threshold like all antidepressants), hyperthyroidism
What makes vortioxetine desirable?
Can be stopped without tapering
For serotonin toxicity:
A) What are mild symptoms
B) What are the moderate symptoms
C) What are the severe symptoms
A)
- Mydriasis, shivering, sweating, mild tachycardia
B)
- disorientation, excitement, rigidity, tachycardia, hyperthermia (> 40) tremor, clonus, hyperreflexia
C)
- Delirium, hypertension, hyperthermia, muscle rigidity, tachycardia
What are te TWO treatment options for serotonin toxicity?
Cyproheptadine: 12mg single dose or 4 to 8mg tds
Chlorpromazine: 12.5 to 50mg slow IV infusion over 30 to 50min
How to commence antidepressants?
Generally commence antidepressants with a low dose and gradually increase over 2 to 4 weeks
When is the full effect of antidepressants seen?
Full effects may take 4 to 8 weeks but improvement seen within 1 to 3 weeks
How long to continue drug treatment for after a single episode of major depression?
Continue drug treatment for 4 to 12 months after a single episode of major depression
> high risk of relapse
How to adjust treatment for depression medication?
Increase dose if full response not achieved (check adherence before adjusting therapy)
- Up to maximum possible dose
- Depending on side effects
Assess respone after 2 to 4 weeks
If a change is necessary can switch to an antidepressant from the same or a different class
What to do for patients who fail to respond to antidepresasnt therapy? What are the key questions in assessing failure to respond to psychotropic drugs?
Is diagnosis correct
Has the patient been taking their medication regularly
Have possible underlying medical causes been identified and treated
Is the patient reacting adversely to a current medication
Have the drug dose and duration of administration been adequate
Have relevant psychosocial or personality factors been addressed
Have alcohol or other substance use problems been addressed n
Could an interacting drug be compromising the response
What are the FOUR options in treatment of resistant patients (refractory depression)?
Switching antidepressants
Augmentation strategies
Antidepressant polypharmacy
Electroconvulsive therapy (ECT)
For switching antidepressants;
A) What requires long washout periods?
B) TCAs and most SSRI (except fluoxetine) clear the drugs from the body within how long?
C) For other switches, what needs to be considered?
A)
- Specified long washout periods are mandatory for irreversible MAOIs
- Non selective irreversible MAOI and serotonin toxicity drug stays in body 2-3 weeks after it has been ceased –> severe HTN and serotonin toxicity
B)
around 5 days, the half life is around 20-30 hours
C)
Potential for withdrawal effects and need for tapering dose of agent being ceased
Half life of drug & continued effects → potential for interaction/toxicity during switch if the drug has a long half life
Clinical urgency for change/potential for relapse and exacerbation
What two antidepressants are most common for withdrawal effects? What is the general rule for discontinuing a drug?
Paroxetine and venlafaxine
Halve the dose every week until the daily dose is half of the lowest unit available, then stop after 1 week
What can rapid withdrawal of the more potently anticholinergic tricyclic antidepressants (TCAs) (eg amitriptyline) result in?
Cholinergic rebound (agitation, headache, sweating, gastrointestinal symptoms), parkinsonism and problems with balance.
> sailvation, lacrimation, urination, diarrhoea, GI distress, emesis SLUDGE = cholinergic effects
What is Electro-convulsive therapy (ECT)?
Delivery of an electric current to induce a seizure for a therapeutic response (uni or bilateral)
- Indicated for severe and unresponsive forms of depression
- Response rate of 50 to 80%
How often is ECT given? What is done to prevent high relapse rate? What are the side effects?
- Treatments given 3 times weekly or ↓ if cognitive impairment emerges
- 6 to 14 treatments (up to 24 treatments)
Relapse rate high
- Maintain recovery with pharmacotherapy (that has not been previously ineffective), lithium or mood stabiliser or combination
Side effects
- Memory loss, muscle aches and pains, headaches, transient confusion
How does exercise alleviate symptoms of depression?
↑ energy
Improve sleep
Positive distraction
Social support
↑ sense of control and self-esteem
May change levels of neurotransmitter
Trials have demonstrated regular exercise to be equally effective as antidepressants in mild to moderate depression
> decrease risk of developing depression
Key Messages about depression
- Depression may result in significant disability
- Depression may be associated with a number of medications and medical conditions, in particular co-morbid psychiatric illnesses
- Pharmacotherapy is indicated in moderate to severe MDD only
- SSRIs are first line (in general) – need to consider what is best for the individual
- Drug choice should be based on patient preference, past history of response, adverse effect profile, potential for toxicity in overdose, potential for drug interactions
- Consider interactions due to CYP450 enzymes
- Monitor for serotonin syndrome
- Avoid withdrawal syndrome
- Observe washout periods when switching antidepressants to reduce adverse effects
- There is little evidence to support combinations of antidepressants, although the risk of adverse events is well documented
Pyschosis from this card onwards …
What to do if EPSE occurs?
ideally reduce antipsychotic dose or switch to alternative antipsychotic
What treatment for the following EPSE?
A) Dystonias - stiffness, uncontrolled muscular spasms
B) Akathisia - inner restlessness, strong desire or compulsion to move
C) Parkinsonism - tremor and/or rigidity, mask- like face, shuffling gait, slow movements
D) Tardive Dyskinesia - involuntary abnormal movements of face, tongue, lips, hands or feet
A)
benzatropine (oral, inj), trihexyphenidyl (benzhexol)
B)
propranolol, clonazepam
C)
benzatropine, trihexyphenidyl
D)
Can be irreversible. Stop antipsychotic (preferred)
Treatment poor efficacy – tetrabenazine, Ginkgo biloba
What is first line treatment in schizophrenia?
2nd Generation Antipsychotics (SGAs)
More metabolic adverse effects
More expensive
Pharmacalogy of aripiprazole? What is it used to agument?
Is a dopamine system stabiliser (increased dopamine output when conc are low and decreased dopamine output when conc. are high)
- Less sedation, weight gain and prolactin elevation
- Good 1st choice antipsychotic
- Doesn’t provide sedation if patient acutely unwell
- May cause insomnia, akathisia and/or activation
> often used to augment other antipsychotics
> to reduce weight gain e.g. clozapine, olanzapine
> to reduce prolactin e.g. risperidone
Pharmacology of brexpiprazole
Indicated only in schizophrenia
May have positive effects on mood
Well tolerated – little weight gain, prolactin elevation, akathisia
Pharmaclogy of lurasidone
Take with food to increase absorption
Low incidence weight gain, small rise in prolactin
Theorised to improve mood & be useful in bipolar
Reports of increased irritability/rage
Pharmacology of olanzapine
Sedating – may be beneficial in acute psychosis
WEIGHT GAIN +++
Metabolic syndrome major concern. For this reason falling out of favour as long term treatment
Pharmacology of paliperidone
Active metabolite of risperidone, similar adverse effects to risperidone
- Swallow tablets whole –> Cannot be halved, crushed –> Empty tablet may appear in stools
- always with food or always on an empty stomach
- oral not commonly used but depot common
Pharmacology of Quietiapine
Prone to abuse – watch for doctor shopping and picking up supply earlyn
More sedating at lower doses
To get antipsychotic effect, some patients require higher dose
Pharmacology of Amisulpride? How does its MOA change from low to higher doses?
Indicated for treatment of schizophrenia
- At low doses (50-300mg) it is more effective for negative symptoms
- At higher doses (400-800mg) it is more effective for positive symptoms
- Not metabolised in the liver; reduce dose in renal impairment
- Dose-related EPSE & hyperprolactinemia
Clozapine pharmacology? Why is it not 1st line?
The most effective antipsychotic
50% of non-responders will improve with clozapine
Particularly effective for negative symptoms
Not 1st line due to serious adverse effects
- Agranulocytosis
- Neutropenia
- Cardiomyopathy
- Myocarditis
- Gastrointestinal Hypomotility – i.e. constipation = highest risk of mortality
What is the condition of clozapine being used?
Must have trialled ≥2 antipsychotics prior to clozapine initiation
- Not effective or not tolerated
- At least 1 must be atypical antipsychotic
What is done before treatment of clozapine can be done (monitoring)?
Monitoring systems record WCC and neutrophil count
- Clopine Connect
- Clozaril Patient Monitoring Service
Pre-treatment
- FBP, CRP, troponin, ECG, echocardiogram ( pregnancy test)
- Desired: LFTs, U&Es, lipids, weight, BSL/HbA1c, weight, waist circumferance,
What ongoing monitoring for clozapine?
Ongoing monitoring. Medication only supplied until next blood test
- FBP weekly for first 18 weeks
- CRP, troponin weekly for 4 weeks
red range (stop immediately)
> WBC less than 3.0 x 109
> Neutrophils less than 1.5 x 109
amber range (continue therapy with twice weekly blood tests)
> WBC 3.0-3.5 x 109
> Neutrophils 1.5-2.0 x 109
green range
> WBC greater than 3.5 x 109
> Neutrophils greater than 2.0 x109
Clozapine dosing/drug concentration
Slow dose titration to avoid/reduce dose dependent adverse effects
> Target drug concentration: 350-1000mcg/L
For clozapine;
A) What to use to treat hypersalivation
B) What to use to treat GI hypomotility (constiaption)
A)
- Atropine 1% eye drops sublingually
- Hyoscine wafers
- Ipratropium MDI sublingually
- Moclobemide, metoclopramide
B)
- Macrogol first line and BE AGGRESSIVE!
- Docusate/senna first line for prophylaxis
Why is medication used in acute agitation and arousal in patients with schizophrenia? What drugs to use?
Medication is used to calm/lightly sedate the patient and reduce the risk to self and/or others
- Oral benzodiazepine (lorazepam, clonazepam, diazepam)
- Oral antipsychotic (olanzapine, risperidone, quetiapine, haloperidol)
- IM medication (lorazepam, olanazapine, ziprasidone, haloperidol, droperidol, midazolam, clonazepam)
- IV med –> used in EDs, not used in psychiatric inpatient wards
Which IM medication is preferred for acute agitiation?
IM lorazepam available under SAS – more predictable absorption & effect –> refrigerate, 3 months shelf life once out of fridge
What is needed when benzodiazepines used IM/IV? When to use?
Have flumazenil available when benzodiazepines used IM/IV
Use if respiratory rate falls below 10/minute
Pharmacology of Zuclopenthixol acetate. When are they used?
Used if other short-acting treatment options for acute agitation and arousal have been ineffective
> Not for long-term use. Duration of Tx cannot exceed 2 weeks, 400mg or 4 injections
When is long acting (depot) antipsychotics used? How is it used?
Antipsychotic long-acting injections (LAIs) used where non-adherence to oral treatment is problematic, or patient prefers this formulation type
- Deep intramuscular injection (gluteal or deltoid)
- Medication slowly released into bloodstream, providing steady supply of medication.
- LAIs do not ensure adherence: they assure awareness of adherence
- Allow regular assessment of patient (due to regular injections)
Advantages and disadvantages of LAI antipsychotics?
Advantages
Proven reduction in relapse
Improved adherence
Fewer hospitalisations
Less fluctuation in drug concentration
Regular contact with clinicians
Less risk of overdose
Avoids first pass metabolism
Disadvantages
Pain at injection site
Cannot be withdrawn quickly (E.g. side effects)
Patient loses control of treatment
Less dosing flexibility
Monitoring required (olanzapine)
Pharmacology of aripiprazole LAI?
Gluteal or deltoid muscle
Oral test doses of aripiprazole
Oral antipsychotic required for 14 days after LAI is commenced
Indicated for treatment of:
Schizophrenia
BPAD – maintenance treatment (not PBS)
- Favourable metabolic and prolactin-sparing effects
All antipsychotics can reduce the seizure threshold/ What antipsychotics to avoid?
Clozapine, chlorpromazine – most epileptogenic
What are the effects of smoking and smoking cessation with antipsychotics?
Cigarette smoking induces CYP1A2
- Reduces plasma levels of drugs eg BZD, clozapine, olanzapine
Smoking cessation –> increased drug plasma levels –> consider dose reduction
What to use for smoking cessation?
NRT has been used effectively for smoking cessation
- Varenicline – Champix® - pschiatric adverse effects reported, but can be used with careful monitoring
- Bupropion – Zyban® - not routinely used in psychiatric setting. Lowers seizure threshold
What are effects of caffeine on antipsychotic drugs?
Caffeine can increase drug levels (clozapine and olanazapine)–> possibly due to competitive CYP1A2 inhibition
- Patients with mental illness have been reported to drink large amounts of caffeinated drinks
Why does NMS occur (Neuroleptic Malignant Syndrome)?
Thought to be due to a sudden over-blockade of dopaminergic function
> a very rare life-threatening syndrome that can occur with any antipsychotic medication
> antipsychotics that act on stronger dopamine receptors
Symptoms of NMS (Neuroleptic Malignant Syndrome)? How to treat?
Characterised by fever, muscle stiffness, altered consciousness and problems with the autonomic nervous system
- can be fatal if left untreated
- treatment is symptomatic and antipsychotic should be ceased
Concerns with elderly patients?
- More susceptible to adverse effects including EPSE and TD
- Lower starting doses of medications are used
- There is some concern that olanzapine and risperidone may increase the chance of a stroke
- Elderly patients more likely to have other illness or be on other medications
How to deal with side effects
A) Akathisia
B) Sedation
C) nausea
D) constipation
weight gain: combination of good diet and exercise, prevention better than treatment
> metformin and augmentation with aripiprazole can reduce weight gain
A)
stretching & exercise
B)
take medication at night (if once daily dose) e.g. clozapine small dose in morning and large dose at night
C)
take with or after food
D)
balanced diet, increase fibre and fluid intake
Coloxyl & Senna, Movicol
Dementia after this card…
What is dementia defined as?
Distinguished from lifelong intellectual disability and single learning disorders as dementia develops during life, and involves alteration in two or more cognitive functions
What is used to treat primary symptoms such as memory loss in alzheimers?
Anticholinesterases
NMDA antagonists
What is used to treat seconday symptoms such as depression and hallucinations in alzheimers?
Antipsychotics and Sedatives
How do anticholinesterases work?
> donepezil, galantamine, rivastigmine
Accumulation of AB (beta amyoloid) peptide results in destruction of cholinergic neurones and a fall in ACh concentration
> neurotransmitter essential for learning and memory
- Cholinesterase inhibitors (CIs) inhibit breakdown of ACh to increase concentrations in synaptic cleft
> enhances cholinergic function and reduces loss of cholinergic neurotransmitter activity
All three CIs seem to have similar efficacy, they dont alter pathology of AD, so how do they work?
> donepezil may be slightly more effective
temporarily delay progression and improve symptoms according to subjective measurements or cognitive assessment tools (e.g. MMSE)
> not everyone responds to treatment
What are the adverse effects (CIR) associated with CI? Which one has most GI adverse effects?
Adverse effects occur frequently with all three agents
Better tolerated if slowly titrated to target dose –> increase every four to six weeks
- full dose oral rivastigmine may have more GI adverse effects than donepezil or galantamine
Common
nausea, vomiting, diarrhoea, anorexia, abdominal pain, dyspepsia, headache, insomnia, vivid dreams, depression, fatigue, drowsiness, dizziness, tremor, weight loss, muscle cramps, urinary incontinence, increased sweating, hypertension, syncope
Infrequent or rare
bradycardia, heart block, seizure, agitation, hallucination, confusion, GI haemorrhage
Which non-alzheimer dementia should CI be used in?
There is good evidence to support treatment with rivastigmine and donepezil in in dementia with Lewy bodies and Parkinson’s disease dementia
Properties of memantine? MOA, is it effective? Who is it used for?
Thought to protect against elevated levels of glutamate
- NMDA antagonist
- but memantine does not stop AD progression
Generally reserved for severe dementia or those intolerant to CIs
Factors to consider in relation to continuing CI/ memantine use are the level of? How is this demonstrated?
Clinically meaningful response to treatment may be demonstrated by the person’s:
- quality of life
- cognitive function
- behavioural symptoms
> The presence of adverse effects that impact on quality of life and clinical symptoms should prompt a review of the ongoing need for the agent
> People who demonstrate ongoing, meaningful clinical benefit (functionally and/ or cognitively stable) should continue on the medication with ongoing monitoring for continued benefit or the development of any adverse effects
What are behavioural symptoms associated with dementia?
physical aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviours, sexual disinhibition, hoarding, cursing and shadowing.
What are psychological symptoms associated with dementia?
anxiety, depressive mood, hallucinations and delusions
1st line treatment for psychological and behavioural symptoms?
Non-pharmacological approaches first line for responsive behaviours because of a favourable balance of benefits and harms
> Drug therapy should not be first-line for patients with responsive behaviours
Who are antipsychotics reserved for? What symptoms are they ineffective for? Why risk of AE so high?
Reserve for residents with distressing agitation, aggression, delusions or psychoses
- Ineffective in treating wandering or disinhibition
AE: increased risk of mortality, stroke and extrapyramidal symptoms
what antipsychotics to use for hallucinations, delusions or seriously disturbed behaviour?
Risperidone or olanazapine
AE of antipsychotics?
AEs frequent as antipsychotics affect multiple neurotransmitter receptor types and subtype
Common: sedation, anxiety, agitation, EPSE, orthostatic hypotension, tachycardia, sexual adverse effects, weight gain, hyperprolactinaemia (may result in galactorrhoea and/ or gynaecomastia)
> EPSE and orthostatic HTN with risperidone
> Olanzapine and some older agents: blurred vision, mydriasis, constipation, nausea, dry mouth, urinary retention
> Avoid typical antipsychotics in residents with Lewy bodies dementia or Parkinson’s disease –> worsen movement disorders
When is extrapyramidal side effects highest? What drugs to avoid?
Incidence dose-related
> highest with haloperidol, lowest with some of the newer agents
- Reduce antipsychotic dose to avoid recurrent EPSE when possible
- Avoid anticholinergic drugs (e.g. benztropine)
> may add to anticholinergic effects and worsen tardive dyskinesia and cognition
What are some extrapyramidal side effects that may be mistaken for responsive behaviours when using antipsychotics?
Dystonias
- Torticollis, carpopedal spasm, trismus, perioral spasm, oculogyric crisis, laryngeal spasm and opisthotonos
Akathisia
- Feeling of motor restlessness; usually occurs 2–3 days (up to several weeks) after starting treatment and may subside spontaneously
- May present as agitation secondary to psychosis
Parkinsonism
- Tremor, rigidity or bradykinesia; usually develops after weeks or months
Tardive dyskinesia
- Involuntary movements of the face, mouth or tongue, and sometimes head and neck, trunk or limbs
Clozapine, olanzapine and quetiapine, associated with?
increased blood glucose, weight gain and dyslipidaemia
- clozapine and olanzapine associated with increased risk of type 2 diabetes
Increased death rate in which antipsychotics?
Increased risk of fatal and non-fatal strokes and TIAs in which antispychotics?
Increased death rate noted in placebo-controlled trials of aripiprazole, olanzapine, quetiapine and risperidone in dementia patients (due to CVD events or infections)
Olanzapine and risperidone associated with increased risk of fatal and non-fatal strokes and TIAs
> use for lowest possible dose and shortest amount of time
Risk of CVA increased for patients being treated with _________ for vascular or mixed dementia, compared with those taking it for Alzheimer’s dementia
risperidone
- TGA approval for use in responsive behaviour is limited to treatment (up to 12 weeks) of moderate to severe dementia only of the Alzheimer type
Points for withdrawal of antipsychotics?
- Most responsive behaviours tend to be transient exacerbations
- Many will resolve naturally as dementia progresses
- Regular monitoring and dose reduction/ withdrawal attempts should be undertaken to minimise exposure to antipsychotic use
- E.g. halve the dose every two weeks until the lowest possible dose is achieved, treat for a further two weeks then cease
- Antipsychotic treatment can always be reintroduced if required
How do BZDs work? what ar they used for? Which one to use?
Potentiate inhibitory effects of GABA throughout CNS –> results in Potentiate inhibitory effects of GABA in the CNS –> anxiolytic, sedative, hypnotic, muscle relaxant and antiepileptic effects
- Short term use may assist some behavioural and psychological symptoms of dementia (BPSD), especially insomnia, anxiety, irritability and tension
> also use as premedication for anxiety-inducing events
> To relieve symptoms of severe anxiety and agitation, use: oxazepam 7.5 mg orally, 1 to 3 times daily
AE of BZD? What happens if used for more than 2 weeks?
Worsen cognitive impairment, impair gait and increase the risk of falls
> Particularly long-acting agents, such as nitrazepam and diazepam
> Associated with increased risk of hip fracture among older people by >50%
- Use >2 weeks associated with tolerance to sedative effect
- Longer term use results in dependence
- Cognition and gait effects maintained
_____ ______ are often amongst the most difficult symptoms of dementia to adequately support. What medications have been used to try to alleviate these symptoms?
Responsive behaviours
- anticonvusaltant mood stabilisers, antidepressants, clonidine, cannabis, dextropropoxyphene
> citalopram for agitation has been shown to be effective
What is the most effective strategy for this: responsive behaviours are often amongst the most difficult symptoms of dementia to adequately support
Identifying and addressing the unmet need/ sources of responsive behaviour is typically the most effective strategy
> Specialist services are available for these situations –> DBMAS, SBRT, OAMHS
Summary
- Development of disease- modifying treatments has been unsuccessful
- Current pharmacological treatments for dementia are generally of limited effectiveness
> This includes medications for both the cognitive and behavioural/ psychological aspects of the condition
- Any medication used in managing dementia symptoms requires regular review for ongoing effectiveness and adverse effects
> Particularly antipsychotics and other sedatives
