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How to Taper Antidepressants to Avoid a Withdrawal (Discontinuation) Syndrome?

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Dr Sanil Rege discusses strategies to taper antidepressants to prevent or minimise a withdrawal (discontinuation) syndrome.

Hi everyone welcome to another edition of hub bytes i’m sanil reggae consultant psychiatrist and today i’ll be taking you through withdrawal symptoms related to antidepressants with a specific focus on withdrawal symptoms related to ssris which are selective serotonin reuptake inhibitors so let’s get going here is the presynaptic neuron and the postsynaptic

Neuron with the receptor sites now we know that ssris block the serotonin transporter which is essentially the protein that takes serotonin into the presynaptic neuron for breakdown now what ssris as i said does is it will block cert and when it blocks cert there will be lots of serotonin available in the synaptic cleft now what happens when we take away the

Ssris and particularly if we do it suddenly now we know that when receptors are bound by serotonin here over an extended period of time they down regulate if you take the ssri away suddenly the cert inhibition disappears and these particular receptors will suddenly almost start craving so they end up with that withdrawal type symptomatology and it’s because

Of a sudden deficiency of serotonin within the synaptic cleft so when we look at the diagram this is what we see on the left hand side you can see that you have the cert which is the reuptake pump in a way and the ssri on the right hand side blocks the reuptake pump and therefore there is lots of serotonin available in the synaptic cleft when the ssr is taken

Away there will be a deficiency in the synaptic cleft the receptors that have been down regulated suddenly get upregulated become super sensitive and start craving in a way so now let’s look at what are the symptoms of ssri withdrawal also known as discontinuation syndrome first the affective symptoms you can see individuals can have irritability anxiety or

Agitation low mood or depression tearfulness or a feeling of dread so in some cases it may appear as if they are having a relapse of the illness but often there are other associated symptoms as well that help in differentiating between a primary depressive illness versus a withdrawal or discontinuation syndrome sensory symptoms are quite common paresthesias

Numbness shock like sensations describe it as electric shock-like sensations rushing noises and palinopsia which is a visual trail general somatic symptoms flu-like symptoms lethargy or fatigue headache tremor sweating loss of appetite weakness and tachycardia then symptoms of disequilibrium dizziness lightheadedness vertigo ataxia and gait instability sleep

Disruption insomnia nightmares and excessive dreaming gastrointestinal symptoms nausea vomiting diarrhea anorexia sexual symptoms we one can have premature ejaculation or genital hypersensitivity and cognitive symptoms such as decreased concentration amnesia or confusion so this can be a really really distressing aspect of ssri treatment because once and it

Also happens with snris where the serotonin components there so if it’s suddenly stopped or in some cases even over a period of two to four weeks because some individuals are a lot more sensitive patients can experience all of these symptoms so what are the principles of antidepressant tapering the effect of a linear tapering regime so if we simply go from let’s

Say escitalopram 40 milligrams down to 30 down to 20 down to 10 and stop which is linear then individuals may be susceptible to having withdrawal symptoms and why does that happen because let’s look at take the example of cetalopram you can see certain inhibition decreases by three percent when citalopram is reduced from 20 milligrams to 15 milligrams when

You reduce it further from 15 milligrams to 10 milligrams and from 10 milligrams to 5 milligrams certain inhibition decreases by six percent and thirteen percent so really the drop when you think about it from twenty milligrams down to five milligrams is not that significant in terms of cert inhibition but where the biggest drop for certain inhibition comes

Is when citaloprams reduced from five to zero where the drop is by almost 58 and that’s where individuals can have significant withdrawal symptoms and this is reflective of the hyperbolic dose response curve where one reaches a plateau so if you think about a hyperbolic dose response curve it looks like this at lower doses you will have increases but then it

Will reach a sort of hyperbola a plateau and that’s what this is reflective of and you can see it between five to zero 58 reduction in cert inhibition therefore according to the the paper by horowitz and taylor in 2019 they suggested when tapering antidepressants clinicians are suggested to instead follow a regime that folk focuses on biological effect which

Is search occupancy rather than arbitrarily withdrawing medication using a linear stepwise approach from a practical viewpoint it may be necessary to switch to liquid formulations given the requirement for micro modifications of dose during the later stages of tapering so let me show you what the cert occupancy looks like if you look at the citalopram dose on

The left hand side at 60 milligrams you’ve got a cert occupancy of 87.8 percent but note as you come down let’s say at 9.1 which is approximately 10 milligrams you’ve got a search occupancy of 70 percent so from 87.8 to 70 percent about 17.8 percent decrease right then at 5.4 percent you’ve got 60 but once you’ve gone down to zero the minimal dose you’ve got

Ten percent so it’s gone down from sixty percent to ten percent almost a fifty percent reduction and this is what we call that sort of hyperbolic dose response curve that needs to be taken into account when considering reduction of antidepressants so now let’s look at how to practically consider a reduction and this is from the very helpful guidance by the

Royal college of psychiatrists in the uk where they outlined uh the article this stopping antidepressants so they’ve given the example of paroxetine so as you can see if we consider a reduction of dose by fifty percent every two to four weeks now we know that some people may need to reduce a lot more slowly so this is one approach you can see starting off at

40 milligrams a day of peroxidine then dropping it down to 20 milligrams a day then to 10 then to 5 but then going really really slow because we know that because of the hyperbolic dose response curve from 5 as i go down to 0 that’s when cert the reduction in certain inhibition will be the highest and therefore this is where you might want to consider liquid

Formulations now in some countries tapering strips are also available so this is where one can discuss it with the pharmacy or compounding form formulations can be utilized so from five milligrams a day you’re going to 2.5 milligrams liquid form then to 1.25 then to 0.6 and then finally stopping it the other approach is considering a reduction by ten percent

Of the last dose every two to four weeks using tablets and liquids so this is when individuals you’ve considered the first reduction in individuals are very sensitive to that reduction so they experience significant withdrawal symptom that tells you okay i need to go slower so here you can see you’re going down from 40 milligrams to 36 and in order to achieve

36 you’re using 30 milligram tablet plus a liquid formulation to achieve the six milligrams and then you go further down to 32 29 26 so on and so forth until you finally stop medication okay so let’s now look at ranking antidepressants based on their propensity for a withdrawal or discontinuation syndrome as you can see agamalatine has negligible withdrawal

Syndrome risk lower risk antidepressants would be bupropion and fluoxetine and fluoxetine mainly because it has a long half-life fluoxetines metabolite nor fluoxetine has a half-life of five to seven days therefore complete washout would be approximately in 35 days you multiply the half-life by five and that’s the washout period and therefore fluoxetine tends to

Have a lower severity and considered to have a lower incidence of withdrawal syndrome however it is important to recognize that the withdrawal syndrome with fluoxetine can occur much later compared to other antidepressants when we think about moderate risk antidepressants we have citalopram we have escetalapram murtazapine also features here and murtazapine has

Anti-istaminergic effect which gives sedation but also can contribute to weight gain now when we stop murtazapine at one can have a anti-histaminergic rebound so something to think about amongst the other novel antidepressants we have vortioxetine which also has a moderate risk because it is a serotonin modulator from a high risk perspective we’ve got amitriptyline

Chlamypramine paroxetine venlafaxine and duloxetine and peroxidine has a short half-life and therefore will have a more severe withdrawal syndrome similarly venlafaxine and desmethyl vandalar vaccine have higher rates of withdrawal syndrome and quite distressing withdrawals as well now when we think about the pharmacokinetics and the reason why we think about

Pharmacokinetics is mainly we’re thinking about the half-life we know that when we looked at the dose response curve we have a hyperbolic dose response curve for antidepressants similarly when we’re reducing antidepressants we’ve got to follow a hyperbolic dose reduction so as i mentioned with fluoxetine which has a long half-life withdrawal syndrome severity and

Withdrawal syndrome incidence may be lower but when we look at sertraline citalopram and escitalopram whose half-lives vary between 26 to 33 hours to 36 hours here you might have withdrawal syndromes and in paroxetine for example which has 20 hour half-life here withdrawal syndrome can start pretty early in about two to three days even so this is something to

Take into account when considering reduction of antidepressants so the article tapering of ssri treatment to mitigate withdrawal syndrome symptoms by horowitz and taylor stated we suggest that a personalized rate for withdrawal could be established by a initial trial reduction of ssri dose equivalent to a reduction of 10 serotonin transporter occupancy or 5 if

Being cautious with subsequent monitoring of the severity and duration of withdrawal symptoms an initial 10 reduction of in serotonin transporter occupancy is suggested because this would result in approximately halving the dose from the therapeutic minimum dose from 20 milligrams to 10 milligrams of citalopram which is tolerated well by most patients if the

Patient discontinuation emergence signs and symptoms score which is a scale were to have returned to baseline one month after the initial reduction then a rate equivalent to 10 reduction of serotonin transporter occupancy per month could be prescribed this process should be subject to ongoing monitoring with the rate titrated to patient tolerance so with that

I hope that this is something you can apply to clinical practice because a linear reduction of dose so from 40 milligrams of escitalopram down to 30 to 20 to 10 and then stopping can result in quite significant withdrawal symptoms so the aim here is to follow a hyperbolic dose reduction to reduce to the therapeutic minimums and then even further reductions

Below the therapeutic minimums may be required to prevent a distressing or with any signs and symptoms of withdrawal symptoms so with that do have a read of the the article that i’ve suggested and of course do visit cycling hub for other educational material as well so take care stay safe i hope to see you in another video of hot bites see you soon

Transcribed from video
How to Taper Antidepressants to Avoid a Withdrawal (Discontinuation) Syndrome? By Dr Sanil Rege’s Hub – Psychiatry Simplified