Choosing an antidepressant

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 Review of the choice and use of antidepressant drugs Stephen Bleakley MRPharmS , MSc,MCMHP Progess in Neurology and Psychiatry Nov / Dec 2013 Antidepressant Choices in Primary Care : Which to Use First Sherri Hansen MD Wisconcin Medical Journal 2004 Volume 103 No 6 Antidepressants :mechanism of action , toxicity and possible amelioration Khushboo Sharma B Journal of Applied Biotechnology and Bioengineering 2017 :3(5) : 437-448 Antidepressants Jon Nash David Nutt Psychiatry 6:7 2007 Antidepressants for people with epilepsy and depression Cochrane Database of Systemic Reviews 2014 , Issue 12 Serotonin syndrome Practice Pointer BMJ 2014 ; 348 :g1626 What is the first choice antidepressant for patients with renal impairment ? UKMi Nov 2017 A practical approach to prescribing antidepresssants Cleveland Clinic Journal of Medicine Vol 80 Number 10 October 2013 Guidelines on Choice and Selection of Antidepressants for the Management of Depression Hertfordshire Partnership University Foundation NHS Trust 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 )

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