Psychopharmacology Flashcards
What are the general pharmacological strategies?
Indication
- establish a diagnosis and identify the target symptoms that will be used to monitor therapy response
Choice of agent and dose
- select an agent with an acceptable side-effect profile and use the lowest effective dose
- remember the delayed response for many psychiatry medications and drug-drug interactions
Management
- adjust dosage for optimum benefit, safety and compliance
- use adjunctive and combination therapies if needed, however, always strive for simplest regime
Indications for antidepressants
Unipolar and bipolar depression
Organic mood disorders
Schizoaffective disorder
Anxiety disorder including OCD, panic, social phobia, PTSD, premenstrual dysmorphic disorder and impulsivity associated with personality disorders
What is selection of an antidepressant based on?
Past history of a response, side effect profile and co-existing medical conditions
What is the typical delay after a therapeutic dose is achieved before symptoms improve with antidepressant therapy?
2-4 weeks
If no improvement in symptoms is seen after a trial of adequate length (at least 2 months) and adequate dose, what should be done?
Switch to another antidepressant or augment with another agent
Antibiotic prophylaxis features
First episode - continue for 6 months to a year
Second episode - continue for 2 years
Third episode - discuss lifelong
Antidepressant classifications
Tricyclics Monoamine oxidase inhibitors Selective serotonin reuptake inhibitors Serotonin/noradrenaline reuptake inhibitors Novel agents
General features of TCAs
Very effective but potentially unacceptable side effect profile
Lethal in overdose
Can cause QT lengthening even at a therapeutic serum level
What is the side effect profile of TCAs?
Anticholinergic
Antihistaminic
Antiadrenergic
Features of tertiary TCAs
Tertiary amine side chains
Side chains prone to cross-react with other types of receptors which leads to more side effects
Have active metabolites including despiramine and nortriptyline
Examples of tertiary TCAs
Amitriptyline
Imipramine
Doxepine
Clomipramine
Features of secondary TCAs
Often metabolites of tertiary amines
Primarily block noradrenaline
Side effects same as tertiary TCAs but generally less severe
Examples of secondary TCAs
Desipramine
Nortriptyline
Features of MAOIs
Bind irreversible to monoamine oxidase preventing inactivation of amines e.g. norepinephrine, dopamine and serotonin, leading to increased synaptic levels
Very effective for resistant depression
Side effects of MAOIs
Orthostatic hypotension Weight gain Dry mouth Sedation Sexual dysfunction Sleep disturbance
Examples of MAOIs
Phenelzine
Selegiline
What is the ‘cheese reaction’?
Hypertensive crisis that can develop when MAOIs are taken with tyramine-rich foods e.g. cheese, wine or sympathomimetics
What is serotonin syndrome?
Can develop if MAOIs taken with medications that increase serotonin or have sympathomimetic actions
Symptoms include abdominal pain, diarrhoea, sweats, tachycardia, hypertension, myoclonus, irritability and delirium
Can lead to hyperpyrexia, cardiovascular shock and death
How do you avoid serotonin syndrome?
Wait 2 weeks before switching from SSRI to MAOI
Exception is fluoxetine where you need to wait 5 weeks due to long half-life
Features of SSRIs
Block presynaptic serotonin reuptake
Treat both anxiety and depressive symptoms
Very little risk of cardio toxicity in overdose
Can develop discontinuation syndrome is stopped quickly
Side effects of SSRIs
GI upset Sexual dysfunction, 30+% Anxiety Restlessness Nervousness Insomnia Fatigue/sedation Dizziness
SE usually last 2 days but can last up to a month
Symptoms of discontinuation syndrome
Agitation
Nausea
Disequilibrium
Dysphoria
Examples of SSRIs
Sertraline Paroxetine Fluoxetine Citalopram Escitalopram Fluvoxamine Venflaxine Duloxetine
Features of activation and discontinuation syndromes
SSRIs
Activation syndrome causes increased serotonin, can be distressing for patient
Nausea, increased anxiety, panic and agitation
Typically lasts 2-10 days
Discontinuation syndrome - agitation, nausea, disequilibrium and dysphoria
More common with shorter half-life drugs so consider switching to fluoxetine
Pros and cons of sertraline
Pros
- very weak P450 interactions
- short half-life with lower build up of metabolites
- less sedating when compared to paroxetine
Cons
- max absorption requires full stomach
- increased number of GI ADRs
Pros and cons of paroxetine
Pros
- short half-life with no active metabolite so no build up, good if hypomania develops
- sedating properties offer good initial relief from anxiety and insomnia
Cons
- sedating, weight gain, more anticholinergic effects
- likely to cause discontinuation syndrome
Pros and cons of fluoxetine
Pros
- long half-life so decreased incidence of discontinuation syndrome
- good for patients with medication non-compliance issues
- initially activating so may provide increased energy
- secondary to long half-life, can give one 20mg tab to taper someone off SSRI when trying to prevent discontinuation syndrome
Cons
- long half-life and active metabolite may build up, not a good choice in patients with hepatic illness
- significant P450 interactions so may not be a good choice in patients already on a number of medications
- initial activation may increase anxiety and insomnia
- more likely to induce mania than some other SSRIs
Pros and cons of citalopram
Pros
- low inhibition of P450 enzymes so fewer drug-drug interactions
- intermediate half life
Cons
- dose-dependent QT interval prolongation with doses of 10-30mg daily, risk doses > 40mg/day not recommended
- can be sedating
- GI side effects but fewer than sertraline
Pros and cons of escitalopram
Pros
- low overall inhibition of P450 enzymes so fewer drug-drug interactions
- intermediate half life
- more effective than citalopram in acute response and remission
Cons
- dose-dependent QT interval prolongation with doses of 10-30mg daily
- nausea, headache
Pros and cons of fluvoxamine
Pros
- shortest half life
- found to possess some analgesic properties
Cons
- shortest half life
- GI distress, headaches, sedation, weakness
- strong inhibitor of CYP1S2 and CYP2C19
Features of SNRIs
Inhibit both serotonin and noradrenergic reuptake like the TCAs but without the antihistaminic, anticholinergic or antiadrenergic effects
Used for depression, anxiety and possibly neuropathic pain
Examples of SNRIs
Venlafaxine
Duloxetine
Pros and cons of venlafaxine
Pros
- minimal drug interactions and almost no P450 activity
- short half-life and fast renal clearance avoids build up, good for geriatric population
Cons
- can cause 10-15mmHg dose-dependent increase in diastolic BP
- may cause significant nausea primarily with immediate release tabs
- can cause bad discontinuation syndrome and taper recommended after 2 weeks of administration
- noted to cause QT prolongation
- side effects in > 30%
Pros and cons of duloxetine
Pros
- some data to suggest efficacy for physical symptoms of depression
- far less BP increase compared to venlafaxine
Cons
- CYP2D6 and CYP1A2 inhibitor
- cannot break capsule as active ingredient is not stable within stomach
- higher dropout rate in pooled analysis
Examples of novel antidepressants
Mirtazapine
Bupropion
Pros and cons of mirtazapine
Pros
- different mechanism of action might provide good augmentation strategy to SSRIs
- 5HT2 and 5HT3 receptor antagonist
- can be utilised as hypnotic at lower doses, secondary to antihistaminic effects
Cons
- increases serum cholesterol by 20% in 15% of patients and triglycerides in 6% of patients
- very sedating at lower doses
- doses 30mg + can become activating and require change of administration time to the morning
- associated with weight gain, particularly at doses < 45mg
Pros and cons of bupropion
Pros
- good for use as augmenting agent
- mechanism of action likely reuptake of dopamine and norepinephrine
- no weight gain, sexual side effects, sedation or cardiac interactions
- low induction of mania
- second line ADHD agent so consider if co-occurring diagnosis
Cons
- may increase seizure risk at high doses (450mg+), should be avoided in patients with traumatic brain injury, bulimia and anorexia
- does not treat anxiety, can cause anxiety, insomnia and agitation
- has abuse potential as it can induce psychotic symptoms at high doses
Approach to treatment resistance
Combination of antidepressants
Adjunctive treatment with lithium
adjunctive treatment with atypical antipsychotic e.g. quetiapine, olanzapine, aripiprazole
ECT
Indications for mood stabilisers
Bipolar
Cyclothymia
Schizoaffective
Classes of mood stabilisers
Lithium
Anticonvulsants
Antipsyhoctics
Features of lithium
Only medication to reduce suicide rate
Effective in long-term prophylaxis of both mania and depressive episodes in 70+% of patients with BAD
Factors predicting positive response to lithium
Prior long-term response to lithium
Classic pure mania
Mania followed by depression
How to use lithium
Before starting get baseline U&Es, TSH and pregnancy test
Monitor - steady state achieved after 5 days, check 12 hours after last dose, once stable check level at 3 months and TSH and creatinine at 6 months
Goal - blood level between 0.6 and 1
Side effects of lithium
GI distress, including reduced appetite, nausea/vomiting, diarrhoea
Thyroid abnormalities
Non-significant leucocytosis
Polyuria/polydipsia secondary to ADH antagonism
Interstitial renal fibrosis
Hair loss
Acne
Reduces seizure threshold, cognitive slowing, intention tremor
Features of mild lithium toxicity
Level 1.5-2.0 Vomiting Diarrhoea Ataxia Dizziness Slurred speech Nystagmus
Features of moderate lithium toxicity
Level 2.0-2.5 Nausea Vomiting Anorexia Blurred vision Clonic limb movements Convulsions Delirium Syncope
Features of severe lithium toxicity
Level > 2.5
Generalised convulsions
Oliguria
Renal failure
Features of valproic acid
As effective as lithium in mania prophylaxis but not as effective in depression prophylaxis
Better tolerated than lithium
Factors predicting positive response to valproic acid
Rapid cycling patients (females > males)
Co-morbid substance issues
Mixed patients
Patients with co-morbid anxiety disorders
How to use valproic acid
Before started, get baseline LFTs, pregnancy test and FBC
Avoid in women of child-bearing age due to neural tube defects
Monitoring - steady state achieved after 4-5 days, check 12 hours after last dose and repeat CBC and LFTs
Goal - target level between 50-125
Side effects of valproic acid
Thrombocytopenia and platelet dysfunction Nausea Vomiting Weight gain Sedation Tremor Increased risk of neural tube defect Hair loss
Examples of anticonvulsants
Valproid acid
Carbamazepine
Lamotrigine
Features of carbamazepine
First line agent for acute mania and mania prophylaxis
Indicated for rapid cyclers and mixed patients
How to use carbamazepine
Before starting get baseline LFTs, FBC and ECG
Monitoring - steady state achieved after 5 days, check 12 hours after last dose and repeat CBC and LFTs
Goal - target level 4-12mcg/ml
Need to check level and adjust dosing after around 1 month because it induces the patient’s own metabolism
Side effects of carbamazepine
Rash - most common Nausea Vomiting Diarrhoea Sedation Dizziness Ataxia Confusion AV conduction delay Aplastic anaemia and agranulocytosis Water retention resulting in hyponatraemia Drug-drug interactions
Features of lamotrigine
Indication similar to other anticonvulsants
Also used for neuropathic/chronic pain
Before starting get baseline LFTs
Initiation/titration - start with 25mg daily for 2 weeks then increase to 50mg for 2 weeks, then increase to 100mg, faster titration but higher incidence of serious rash
If patient stops medication for 5 or more days then need to re-start at 25mg
Side effects of lamotrigine
Nausea Vomiting Sedation Dizziness Ataxia Confusion Most severe are toxic epidermal necrolysis and Stevens Johnson's Syndrome Character/severity of rash if not a good predictor of severity of reaction so if any rash develops discontinue use immediately Blood dyscrasias - rare
What drugs increase lamotrigine level?
VPA
Sertraline
Indications for use of antipsychotics
Schizophrenia
Schizoaffective disorder
Bipolar disorder - for mood stabilisation and/or when psychotic features are present
Psychotic depression
Augmenting agent in treatment resistant anxiety disorders
What are the key pathways affected by dopamine in the brain?
Mesocortical
Mesolimbic
Nigrostriatal
Tuberoinfundibular
Features of mesocortical pathway
Projects from ventral tegmenjtum to the cerebral cortex
Felt to be where the negative symptoms and cognitive disorders arise
Problem here for a psychotic patient is too little dopamine
Features of mesolimbic pathway
Projects from dopaminergic cell bodies int he ventral tegmenjtum to the limbic system
Where the positive symptoms come from e.g. hallucinations, delusions and thought disorders
Problem here for a psychotic patient is too much dopamine
Features of nigrostriatal pathway
Projects from dopaminergic cell bodies in the substantial migrant to the basal ganglia
Involved in movement regulation
Dopamine hyperactivity can cause Parkinsonia movements - rigidity, bradykinesia, tremors, akathisia and dystonia
Features of tuberoinfundibular pathway
Projects from hypothalamus to the anterior pituitary
Blocking dopamine in this pathway will predispose patient to hyperprolactinaemia
Features of typical antipsychotics
D2 dopamine receptor antagonists
High potency typical antipsychotics bind to D2 receptor with high affinity
Higher risk of extra-pyramidal side-effets
Low potency typical antipsychotics have less affinity for D2 receptors but tend to interact with non-dopaminergic receptors resulting in more cardiotoxic and anticholinergic adverse effects
Examples of high potency typical antipsychotics
Fluphenazine
Haloperidol
Pimozide
Examples of low potency typical antipsychotics
Chlorpromazine
Thioridazine
Features of atypical antipsychotics
Atypical agents are serotonin-dopamine D antagonists
Considered atypical in the way they affect dopamine and serotonin neurotransmission int he four key dopamine pathways in the brain
Examples of atypical antipsychotics
Risperidone Olanzapine Quetiapine Aripiprazole Clozapine
Features of risperidone
Available in regular tabs, IM depots and rapidly dissolving tablet
Functions more like a typical antipsychotic at doses > 6mg
Increased extrapyramidal side effects (dose dependent)
Most likely atypical to induce hyperprolactinaemia
Weight gain and sedation - dose dependent
Features of olanzapine
Available in regular tabs, immediate release IM, rapidly dissolving tablet and depot form
Weight gain - can be as much as 30-50lbs even with short-term use
May cause hypertriglyceridaemia, hypercholesterolaemia, hyperglycaemia
May cause hyperprolactinaemia
May cause abnormal LFTs
Features of quetiapine
Available in regular tablet form only
May cause abnormal LFTs
May be associated with weight gain, though less than seen with olanzapine
May cause hypertriglyceridaemia, hypercholesterolaemia, hyperglycaemia but less than with olanzapine
Most likely to cause orthostatic hypotension
Features of aripiprazole
Available in regular tabs, immediate release IM formation and depot form
Unique mechanism of action as D2 partial agonist
Low EPS, no QT prolongation, low sedation
CYP2D6, 3A4 interactions
Not associated with weight gain
Features of clozapine
Available only in regular tablet form
Reserved for treatment of resistant patients due to side-effect profile, but highly effective
Associated with agranulocytosis and therefore requires weekly blood draws for 6 months then 2 weekly for 6 months
Increased risk of seizures, especially if lithium also being used
Associated with the most sedation, weight gain and abnormal LFTs
Increased risk of hypertriglyceridaemia, hypercholesterolaemia, hyperglycaemia, including non-ketotic hyperosmolar coma and death with/without weight gain
What is the commonest psychotic symptom?
Lack of insight
Why do people with psychotic illnesses most commonly relapse?
Non-compliance
What percentage of patients take medications as prescribed?
30%
Adverse effects of antipsychotics
Tardive dyskinesia
Neuroleptic malignant syndrome
Extrapyramidal side effects
Agents for treatment of extrapyramidal side effects
Anticholinergics e.g. benzotropine, trihexyphenidyl, diphenhydramine
Dopamine facilitators e.g. amantadine
Beta blockers e.g. propranolol
Need to watch for anticholinergic side effects
Features of anxiolytics
Used to treat many diagnoses including pain disorder, generalised anxiety disorder, substance-related disorders and their withdrawal, insomnias and parasomnias
In anxiety disorders, often used in combination with SSRIs or SNRIs for treatment
Pros and cons of buspirone
Pros
- good augmentation strategy, mechanism of action is 5HT1A agonist, works independently of endogenous release of serotonin
- no sedation
Cons
- takes around 2 weeks before patients notice results
- will not reduce anxiety in patients that are used to taking benzodiazepines because there is no sedation effect
Features of benzodiazepines
Used to treat insomnia, parasomnias and anxiety disorders
Often used for CNS depressant withdrawal protocols
Side effects/cons of benzodiazepines
Somnolence Cognitive deficits Amnesia Disinhibition Tolerance Dependence
