CNS e-book Flashcards
depression - Aetiology
Potential causes include genetic factors, environmental factors, biochemical factors, endocrine factors, physical illness (e.g. Diabetes and thyroid disease) or the side-effects of medication (e.g. antihypertensives, benzodiazepines and varenicline)
depression - Epidemiology:
It is estimated that 350 million people worldwide live with depression. It affects 4-10% of people at some stage in their lives and is twice as common in women as men. Depression can affect all ages but the average age of onset is estimated to be in the late 20s and peaks between ages 35 to 45 years old.
NICE base the severity of depression on number of symptoms and the amount of
functional and social impairment:
o Subthreshold depression — less than the five symptoms
o Mild depression — few, if any, symptoms in excess of the five required to make the diagnosis, and only minor functional impairment.
o Moderate depression — symptoms or functional impairment between mild and severe. Some symptoms would be expected to be marked.
o Severe depression — several symptoms in excess of those required to make the diagnosis. Some symptoms would be expected to be severe and markedly interfere with functioning
Drug therapy depression
SSRIs are the first-line choice. Monitor symptoms, side effects and suicide risk (especially if <30years old), particularly when initiating treatment.
- Duration: Continue for at least 6 months after remission if first treatment episode.
Doses should generally remain at the same therapeutic dose. Remember to advise patient that antidepressants are not addictive. If second episode continue for at least
two years after symptoms remit.
- Discontinuation: Reduce slowly generally over 4 weeks, quicker with fluoxetine as has longer half-life. If discontinuation abrupt – risk of discontinuation syndromes
The main pharmacological options for treatment of depression
Drug class Examples
-Tricyclic antidepressants (TCAs): amitriptyline, imipramine, lofepramine
-Selective serotonin reuptake inhibitors
(SSRIs): Examples include fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline (is structurally distinct)
- Monoamine-oxidase inhibitors (MAOIs): Non-selective and irreversible inhibitors of MAO-A and MAO-B. Reversible Inhibitor of MAO-A (RIMA)
Traditional MAOIs – phenelzine, isocarboxazid, tranylcypromine; RIMA – Moclobemide
- Other drugs e.g. Selective Noradrenaline Reuptake Inhibitors (SNRIs), Noradrenaline re-uptake inhibitor (NARI), and Noradrenaline and serotonin-specific antidepressant (NaSSa): Venlafaxine (SNRI), reboxetine (NARI), mirtazapine (NaSSa), Agomelatine (melatonin receptor agonist and selective serotonin-receptor antagonist)
Tricyclic antidepressants
Key points
- Blocks re-uptake of noradrenaline and / or serotonin.
- Also affects receptor sensitivity
- Use low initial doses especially in the elderly
- NICE recommends maintain on low dose if clear clinical response, with careful monitoring. Increase dose if response inadequate provided no major side effects
- Some TCAs are major metabolites of others e.g. nortriptyline is a major metabolite of amitriptyline
- Lofepramine is considerably less toxic – less severe antimuscarinic effects, less sedating, and safer in overdose
- The BNF states that 10-20% of patients fail to respond to a TCA
- TCAs can be useful in agitation, retardation and severe depression, less useful in elderly, psychotic, physically ill, history of bipolar disorder, suicidal
- Effective in relapse prevention – continue treatment dose
Main side-effects, interactions and contraindications - TCAs
- Discontinuation syndrome: somatic symptoms, insomnia, vivid dreams, gastrointestinal symptoms, mood change (e.g. anxiety, agitation, and rarely psychosis)
- TCAs commonly cause antimuscarinic effects — do not use in prostatism, narrow angle glaucoma, or urinary retention
- Do not use a TCA in people who have had a recent myocardial infarction, or who have an arrhythmia. Where possible, avoid in heart failure
- Trazodone and mianserin are tricyclic related - Lower incidence of antimuscarinic side effects than older TCAs.
May be lower risk of cardiotoxicity in overdose - Mianserin can cause leucopenia, agranulocytosis and aplastic anaemia – full blood count recommended every 4 weeks during first 3 months of treatment. If fever, sore
throat, stomatitis or other signs of infection develop, stop treatment and take a full blood count
Selective serotonin reuptake inhibitors
Key points
- As effective as TCAs (not more so), better side-effect profile and less toxic in overdose
- Inhibits platelet aggregation and increases the risk of bleeding
- Antidepressant-induced hyponatraemia (Syndrome of Inappropriate Antidiuretic
Hormone secretion or SIADH) – most likely with serotonergic drugs? - Each has other actions on different neurotransmitter systems
- Escitalopram is an isomer of citalopram but has not been proven to be any more effective and is more expensive
- Little evidence of dose-related response in usual dose range so less need for dose titration
- Fluoxetine – long half-life of parent drug and primary active metabolite desmethylfluoxetine
- SSRI’s useful in the elderly, depression with anxiety/ Obsessive Compulsive Disorder, suicidal patients (safer in overdose than TCAs)
- Effective in relapse prevention – continue treatment doses
- When initiating SSRIs, actively look for signs of agitation and anxiety - If occurs can switch antidepressant or briefly add benzodiazepine (2 weeks).
Main side effects, interactions and contraindications - SSRIs
- Akathisia – restlessness, ranging from anxiety to inability to lie, sit quietly or sleep
- Discontinuation syndrome: sensory abnormalities (including electric shock-like sensations)
- Mood change (depression, anxiety/agitation, rarely mania and psychosis)
- Drugs most likely to cause discontinuation syndrome: paroxetine (with extrapyramidal-type movements)
- Interactions with fluvoxamine (due to cytochrome P450-1A2 inhibition): caffeine, clozapine, theophylline
- Interactions with fluoxetine and paroxetine (due to cytochrome P450-2D6, 3A3/4 inhibition): antipsychotics, opiates and tricyclic antidepressants
- Interactions with sertraline and citalopram (and escitalopram?) reduced propensity for interactions with drugs metabolised by the cytochrome P450-2D6 isoenzyme
- Risk of bleeding exacerbated by concomitant use of aspirin and NSAIDs
- Contraindications: SSRIs should not be used if the patient enters a manic phase
Monoamine Oxidase Inhibitors
Key points
- MAOIs increase the storage and release of serotonin and noradrenaline
- Reserve for patients refractory to other treatments
- Hypertensive crisis with tyramine (see section 2.5)
- Tranylcypromine most hazardous because of its stimulant action; Phenelzine or isocarboxazid less stimulant, phenelzine probably safest
- Toxic levels can occur in slow acetylators
- Half-life not as important as the time taken to replace stores of MAO after irreversible blockade (two weeks)
- Discontinuation symptoms – agitation, irritability, ataxia, movement disorders, insomnia, somnolence, vivid dreams, cognitive impairment, slow/ pressured speech
- Abrupt withdrawal can lead to discontinuation symptoms
Main side-effects, interactions and contraindications - MAO
- Main side effects: postural hypotension and dizziness
- Main interactions: Hypertensive crisis
- Contraindications: Phaeochromocytoma
Other antidepressants
- Includes SNRIs, NARIs, NaSSas etc.
- Little evidence that they any more effective than other antidepressants
- Associated with high incidence of discontinuation symptoms
- More toxic than SSRIs in overdose
- SNRIs e.g. venlafaxine, duloxetine. Venlafaxine: may increase blood pressure at high doses. Avoid in heart disease, electrolyte imbalance or hypertension. ECG
monitoring required. Lacks sedative and antimuscarinic effects of TCAs - NARIs e.g. reboxetine. Not sedating, may help reduced motivation and energy.
- Side effects: dry mouth, insomnia, constipation, urinary hesitancy and tachycardia
- NaSSa e.g. mirtazapine. Can be sedating in low dose - give nocte to aid sleep.
Can cause weight gain. Withdrawal: nausea, vomiting, dizziness, agitation, anxiety and headache are the most common features of withdrawal if treatment is stopped abruptly or the dose is substantially reduced. The dose should be reduced gradually over several weeks.
Uncommon side effects: agranulocytosis.
Stop drug and perform full blood count if the patient develops fever, sore throat, stomatitis or other signs of infection during treatment
Agomelatine is a melatonin receptor agonist and a selective serotonin-receptor antagonist. It has been associated with serious dose-related hepatotoxicity. The BNF recommends LFTs before commencing treatment and at weeks 3, 6, 12 and 24 after starting, and then regularly thereafter when clinically indicated. Patients should also be given a booklet with more information on the risk of hepatic side-effects, told how to recognise signs of liver disorder, and advised to seek immediate medical attention if symptoms such as dark urine, light coloured stools, jaundice, bruising, fatigue, abdominal pain, or pruritus develop.
St John’s wort
NICE recommends do not prescribe or advise its use because:
- Uncertainty about appropriate dose
- Variation in nature of preparations
- Potential serious interactions e.g. oral contraceptives, anticoagulants, anticonvulsants
Serotonin syndrome
Can occur when two or more drugs affecting the serotonin are given at the same time or one is stopped and another is started. Symptoms usually develop within hours of starting the second drug, but can occur later. Drug-induced serotonin syndrome is often mild and resolves when offending drugs are stopped, but can be severe and deaths have occurred.
The drugs implicated include the following (although any drug with serotonergic activity has the potential to cause serotonin syndrome):
- MAOIs (both selective and non-selective)
- TCAs
- SSRIs
- Pethidine
- Lithium
- Dextromethorphan
Beware when switching from SSRI to MAOI and vice versa (SSRIs, especially fluoxetine, have long half-life need to allow sufficient wash-out period)
Symptoms of serotonin syndrome
Confusion Disorientation Abnormal movements Exaggerated reflexes Fever Sweating Diarrhoea hypotension or hypertension
Hypertensive crisis
MAOIs reduce the breakdown of noradrenaline in the adrenergic nerve ending. This leads to large stores, which can be released into the synaptic cleft in response to a
neuronal discharge or an indirectly acting amine. Interactions between MAOIs and indirectly acting sympathomimetic amines are thus likely to result in massive release of noradrenaline from nerve endings with a resulting syndrome of sympathetic overactivity
(hypertensive crisis) characterised by hypertension, headache, hyperpyrexia and cardiac arrhythmias. Fatal intracranial haemorrhage and cardiac arrest may result. Symptoms usually develop about two hours after ingestion of compound. Hypertensive crisis is usually managed by α- blockade with phentolamine. The risk of interaction continues for several weeks after the MAOI is stopped, as new MAO enzyme must be synthesised. Note: Moclobemide (a RIMA) has very limited potential for this interaction.
Patients must be advised to avoid concurrent use of MAOIs and indirectly acting sympathomimetic amines. They should also be given a warning card.
Drugs and foods that interact with MAOIs to cause hypertensive crisis
Drugs
Tyramine containing foods
Sympathomimetics (commonly found in cough and cold remedies) – e.g. ephedrine, pseudoephedrine, phenylpropanolamine. Many cheeses (e.g. mature cheeses)
Illegal drugs – e.g. amphetamines, MDMA. Some alcoholic drinks (e.g. chianti, home-made beers, real ales and wines) and dealcoholised drinks. Safest: gin, vodka and other clear spirits
Pickled herring
Broad bean pods
Liver pâté, Bovril®, Oxo®, Marmite® or similar meat or yeast extract or fermented soya bean extract
Meat and meat products that might be stale or ‘going off’ (game should be avoided)
General principles
Possibility of discontinuation/withdrawal symptoms on stopping or missing doses or reducing the dose – symptoms usually mild and self-limiting but can be severe
- Do not stop antidepressants abruptly
- Reduce doses gradually over a 4-week period (fluoxetine usually shorter)
- If symptoms mild, reassure patient and monitor
- If symptoms severe, reintroduce original antidepressant at the effective dose and reduce gradually while monitoring symptoms
- Symptoms can be mistaken for relapse of illness or emergence of new physical illness.
- Maudsley – do not stop abruptly when taken continuously for 6 weeks or longer – For example cross-taper.
General principles when switching from one antidepressant to another
- Gradual and modest incremental increase of dose
- Consider the potential for pharmacokinetic interactions between antidepressants
- Consider the potential for pharmacodynamic interactions e.g. serotonin syndrome
- No firm guidelines- cautious approach and close monitoring required
Switching antidepressants examples
- SSRI→SSRI Withdraw 1st before initiating 2nd. NB. Wait 4 -7/7 after stopping fluoxetine
- SSRI → TCA Mirtazapine, or reboxetine (or vice versa): cross-taper when switching
- SSRI → MAOI Withdraw SSRI and wait at least 2/52 (5/52 if fluoxetine)
- TCA → MAOI Withdraw TCA and wait at least 2/52
Patient counselling points
- Discuss patient’s concerns about medication (e.g. antidepressants are not addictive or habit forming, they do not alter personality, they do not lose their effect if you keep taking them, i.e. tolerance does not develop)
- When starting treatment tell patients about risk of discontinuation/withdrawal symptoms and potential side effects
- Inform patients about delay in onset, time course of treatment and need to take medication as prescribed – in particular do not stop taking them suddenly
- Provide written information appropriate to patients’ needs
Antenatal and Postnatal depression
- Antenatal depression can affect up to 20% of women
- Postnatal or postpartum depression is estimated to affect between 10-22% of mothers
- Treatment depends on the severity of the depression, history of mental health illness and drug and alcohol use, and whether the mother is breastfeeding
- If drug treatment is used postnatal TCAs, SSRIs and SNRIs are recommended by NICE
Main side effects - TCAs
- Anticholinergic: dry mouth, constipation, urinary retention,
glaucoma, accommodation - Antihistaminergic: sedation, weight gain
- Others: postural hypotension, cardiotoxicity e.g. QT prolongation, arrhythmias, convulsions, discontinuation
Main side effects - SSRIs
Nausea/vomiting
Agitation, Akathisia,
Sedation/dizziness (10-20%)
Convulsions (rare)
Sexual dysfunction (most with parox, least with fluvox)
?↑ risk of suicidality
Discontinuation syndrome: ‘flu-like symptoms, sensory abnormalities, disequilibrium,
Main side effects - MAOIs
Postural hypotension Restlessness, insomnia Peripheral oedema – beware ascites/pleural effusion Nausea, dizziness, sexual difficulties, sweating, tremor
Contra-indications - TCAs
heart block, hypomania or mania, recent MI
Contra-indications - SSRIs
if patient enters a manic phase
Contra-indications - MAOIs
CVD, cerebrovascular
disease, hepatic disease,
Phaeochromocytoma
Hyperthyroidism
