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What is available and how does it work ? more than 30 agents for unipolar depression
Most antidepressants work by enhancing the activity of monoamine neurotransmitters : serotonin , noradrenaline /norepinephrine or dopamine this is based on theories that implicate a deficiency of monoamines in the biology of depression popularly called the ” Amine hypothesis ” it is either reuptake inhibition , enzyme inhibition or activity at pre- postsynaptic receptors
SSRIs –Selectively block the reuptake of 5-HT autoreceptors leading to ↑ed serotonin in the neuronal synaptic clefts- leading to down regulation of the receptors Examples – citalopram /escitalopram ,fluoxetine , paroxetine, sertraline , fluvoxamine Relatively safe in OD
Tricyclic antidepressants –TCAs block the reuptake of both norepinephrine ( NE ) and serotonin ( 5HT ) In addition TCAs also antagonize postsynaptic alpha 1 adrenoceptors , histamine ( H1 ) receptors , muscarinic cholinergic receptors and serotonin 5HT 2 receptors – reason for the excess SEs and toxicity Examples- Amitriptyline , nortriptyline , imipramine , clomipramine , dothiepin , doxepin , lofepramine Similar in structure to antipsychotics such as chlorpromazine and share the wide range of pharmacological action Greatest risk with OD ( except for lofepramine )
Monoamine-oxidase inhibitors Block the mitocohondrial enzyme monoamine oxidase which reduces the breakdown of serotonin , noradrenaline and dopamine Used less frequently than TCAs or SSRIs Poses risk – dietary and drug interactions , overdose toxicity Particular risk is hypertensive crisis following foods containing tyramine ( cheese reaction ) or drugs with sympathomimetic properties Examples -Isocarboxazid , phenelzine , tranylcypromine
Others –Serotonin-norepinephrine reuptake inihibitors – Venlafaxine , duloxetine NDRI – bupropion ( also used in smoking cessation ) NARI- reboxetine SARI- Trazodone ( tricyclics and related ) RIMA – moclobemide ( reversible inhibition of MOA type A ) NaSSA – Mirtazepine , Mianserin ( noradrenergic and specific serotonergic antidepressant ) Vortioxetine -precise mechanism not known . Though to inhibit serotonin ( 5HT ) and is antagonist at 5-HT 1A receptors Agomelatine – melatonin receptor agonist and selective serotonin receptor antagonist ( does not affect the uptake of serotonin, NE or dopamine )
Follow the NICE guidance and take into account Side effects Potential discontinuation symptoms Interactions Previous experience , tolerance , preference Comorbidities Currently no evidence to support using specific ADs for particular physical health problem Take into account toxicity in overdose for people at increased risk of suicide Explore concerns , give information and inform the fact that addiction does not occur Do not prescribe subtherapeutic dose of ADs
First line is an SSRI Citalopram , fluoxetine or Sertraline-Review in 2 weeks if not considered to be at inc’d risk of suicide Subsequently- for first 3 months review every 2-4 weeks and then at longer intervals if response is good Review after 1 week – if inc’d risk of suicide or people younger than 30 yrs Then frequently until the risk is no longer clinically important -Early side effects provide info monitor symptoms closely or change to a different AD Upto 2 week treatment with a benzodiazepine can be considered for problematic anxiety , agitation and / or insomnia (not for chronic anxiety and assess falls risk)
Monitoring –If no improvement after 2-4 weeks ○ check compliance If absent or minimal response after 3-4 weeks ( Rx at therapeutic dose ) ○ increase support ○ increase dose ( assuming no sig SEs ) ○ change to a different AD ( if SEs or the person prefers ) If some improvement by 4 weeks ○ cont another 2-4 weeks ○ consider switching ADs if response still not adequate side effects or person prefers to change drug
Second line –Alternative SSRI or Venlafaxine or Mirtazepine NICE suggests an AD of a different class that may be less well tolerated such as Venlafaxine , a TCA or MAOI
Options for treatment resistant depression ( refer , seek adv from specialist team first ) Augmentation with lithium , an antipsychotic ( eg aripiprazole , olanzepine , quetiapine or risperidone ) Combining antidepressants eg Mirtazepine with an SSRI or venlafaxine Keep in mind that using a single antidpressant is usually associated with lower SE and not all would tolerate combining ADs + risk of serotonin syndrome
SSRIs- which one –Newer SSRIs ( citalopram and escitalopram ) are considered more selective whereas older SSRIs ( paroxetine , sertraline , fluoxetine ) are less selective Fluoxetine has the longest 1/2 life ( upto 1 week ) and is associated with a lower risk of discontinuation symptoms can be a good choice for the patient who frequently misses medication Paroxetine has the shortest 1/2 life ( 15-20 hrs ) and is associated with a greater risk of discontinuation symptoms ( leads to more anticholinergic blockade and generally more sedating than citalopram ) Fluoxetine , fluvoxamine and paroxetine have the highest propensity of drug interactions Fluoxetine has the most risk of interactions For people with chronic physical health problems consider using citalopram or sertraline ( lower propensity for interactions ) Although widely recommended to ↑ dose after 3-4 weeks if no response to therapy – there is no evidence supporting a dose-related response in depression with any SSRI except escitalopram Side effects include anxiety , sleep disturbances , sexual dysfunction and GI disturbances ( nausea , diarrhoea , abdominal cramping , anorexia, constipation ) GI side effects can be minimised by taking medication with food , starting at 1/2 of the lowest target dose , slow ↑ in dose Most SEs are transient but sexual side effects can be persistent and distressing ( decreased libido and / or inorgasmia ) SSRIs are relatively safe in overdose Discontinuation symptoms may happen on stopping , missing dose or occasionally on reducing the dose Advice to reduce gradually over 4 weeks ( not necessary for fluoxetine unless high dose ie 40-60 mg ) as a general rule advice to cut the medication in 1/2 each 1-2 weeks until discontinued
safety issues –Increased risk bleeding – consider and offer gastroprotection Serotonin syndrome ○ clinical manifestation of excess serotonin in the CNS ○ can happen due to therapeutic use ( one or more ) or OD of serotonergic drugs ○ can be life threatening ○ combination of mental status changes ( eg agitation confusion ) , neuromuscular hyperactivity ( clonus , hyperreflexia , myoclonus rigidity ) and autonomic hyperactivity ( hyperthermia , tachycardia ) ○ interventions can range from stopping offending drug (s) to ITU cooling Discontinuation symptoms – happens with most antidepressants but usually mild and self limiting. Always advice to taper slowly over 4 weeks ( all ADs) With SSRIs – flu like symptoms , dizziness and electric shock sensations Peak within 1st week of withdrawal and taper off after 2-3 weeks Fluoxetine – unless high dose ( 40 or 60 mg ) treatment can be stopped abruptly Hyponatraemia – most ADs have been shown to cause hyponatraemia
References
- MRPharmS, Stephen Bleakley and Mcmhp. “Review of the choice and use of antidepressant drugs.” (2013). Progress in Neurology and Psychiatry November/December 2013 https://onlinelibrary.wiley.com/doi/pdf/10.1002/pnp.311
- Antidepressant Choices in Primary Care : Which to Use First Sherri Hansen MD Wisconcin Medical Journal 2004 Volume 103 No 6
- Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437-448. DOI: 10.15406/jabb.2017.03.00082:3(5) : 437-448
- Antidepressants Jon Nash David Nutt Psychiatry 6:7 2007 http://www.med.monash.edu.au/assets/docs/scs/psychiatry/psychopharmacology/nash-antidepressants-2007.pdf
- Maguire MJ, Weston J, Singh J, Marson AG. Antidepressants for people with epilepsy and depression. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD010682. DOI: 10.1002/14651858.CD010682.pub2. https://doi.org//10.1002/14651858.CD010682.pub2
- Serotonin syndrome Practice Pointer BMJ 2014 ; 348 :g1626 https://www.bmj.com/content/348/bmj.g1626
- What is the first choice antidepressant for patients with renal impairment? Michele Skipp UKMi Nov 2017 https://www.sps.nhs.uk/articles/what-is-the-first-choice-antidepressant-for-patients-with-renal-impairment/
- A practical approach to prescribing antidepressants Cleveland Clinic Journal of Medicine
- Guidelines on Choice and Selection of Antidepressants for the Management of Depression Hertfordshire Partnership University Foundation NHS Trust https://www.hpft.nhs.uk/media/3541/guidelines-on-choice-and-selection-of-antidepressants-for-the-management-of-depression-final-oct-2016-minor-amendment-dec-18.pdf
- Antidepressant treatment in adults NICE Pathways Sept 2018
- Treatment of Depression in Patients with Diabetes Mellitus : A Review Med Sci Tech 2016 ; 57 :110-115 ( Abstract )