What they don’t tell you about antidepressants

For generations, people have known that fish and walnuts are good for the brain. They didn’t need to know why, only that they worked. When queried, they might have pointed out the textural similarity between fish flesh and the grey matter of the brain, or the bi-lobed crenellations of walnut structure. Nowadays we know that it’s the omega-3 oils, and the protective effect on brain neurons, but those findings lagged behind folk knowledge. Which is just to say, people will use whatever seems to work and science has to play catch-up.

walnuts

So here’s the thing about antidepressants:

These drugs have been developed in the modern age, based on scientific knowledge and testing. They act to increase levels of neurotransmitters in the synapses of the brain – serotonin, noradrenaline, dopamine – which are known to induce feelings of ease and satisfaction, or alertness, or pleasure. That seems to make sense, and these drugs have been shown to be effective, so one tends to assume that the medical profession understand how they work, and that their recommendations on safe dosage, term of use and discontinuation can be trusted.

The reason for this post is because I’ve been taking a low dose of one of these drugs for 8 months and last week I decided I was feeling consistently OK and I wanted to come off it. This led me to go online to check safe ways to quit. What I discovered was conflicting and somewhat disturbing:

  1. Official advice from drug companies and the medical community included the following:
  • For drugs with a short half-life, discontinue by tapering off, reducing by 25-50% of the original dose every 2-4 weeks to avoid ‘discontinuation syndrome’ (that is, withdrawal symptoms). Normally takes 4-6 weeks.
  • Discontinuation syndrome (characterised by flu-like symptoms, insomnia, nausea, poor balance, sensory disturbances, hyperarousal or anxiety) is not dangerous and usually subsides over 1-2 weeks.
  • If you’re on the lowest therapeutic dose (like me), you don’t need to taper at all and can just stop taking the drug.
  1. A vast quantity of unofficial advice (‘folk knowledge’) from the blogosphere indicating:
  • Some people experience withdrawal symptoms for months or years after they stop taking the drugs. Since this is not ‘supposed to’ happen and because symptoms can be similar to mood disorders, doctors may take this to be a relapse of the original condition.
  • Some people, particularly those who’ve been taking the drugs for several years, have been unable to come off the drugs due to horrible withdrawal symptoms.
  • To be on the safe side, it’s best to taper very slowly, at a rate of 10% every 2-4 weeks – and that is 10% off the current dose, not the original dose. This requires careful pill-cutting, opening capsules to remove beads, or creation of solutions to administer increasingly tiny doses, and takes months.
  • The invention of ‘taper strips’, which pre-package pills in reducing doses to suit your needs.
  1. Recent scientific papers and articles which are essentially admitting (according to my inferences and in my own words):
  • The notion that anti-depressants act by correcting a problem with brain chemistry is not correct. If that were the case, peak benefit should be obtained as soon as the drug reaches steady-state concentration in the body (typically within about a week). In practice, peak mood improvement typically takes 6 weeks or more. In other words, they still don’t understand exactly how the drugs work.
  • Drug testing has typically been undertaken over short periods of 6-8 weeks. There is limited data on safety of drug use over the long term or on safe discontinuation.
  • Old advice on tapering was based on a linear reduction in drug concentration (same percentage off original dose at each step). New research indicates that a hyperbolic taper (reduction in smaller and smaller increments over a long period of time) results in a linear reduction in neurotransmitter concentrations in the brain. (So the folk knowledge may have got that right). https://www.nytimes.com/2019/03/05/health/depression-withdrawal-drugs.html
  • When antidepressants are used over the long term, the brain adapts to the constant high levels of neurotransmitters by down-regulating (reducing the number of receptors). When people stop taking the drug it may take a long time for these to switch back on or re-grow (or in some people they may never return to original levels). In other words, it is possible to become permanently dependant on these drugs.

While that all sounds rather scary, I should say that roughly half the people coming off antidepressants report no withdrawal symptoms at all, and of those that do, half do not rate them as serious. That still leaves a sizable minority who experience major issues, though. I think it’s all down to differences in dosage, length of time on the drug, and personal variations in metabolism and brain chemistry.

I should also say that I’m not against the use of anti-depressants. In fact what they do is really quite amazing. I found this fascinating paper online, entitled “How antidepressant drugs act: A primer on neuroplasticity as the eventual mediator of antidepressant efficacy”. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025168/

What it says, to paraphrase, is that prolonged or severe stress changes the wiring of our brains, increasing activity in the amygdala and impairing function of the hippocampus, prefrontal cortex and downstream structures. This re-wiring is what creates symptoms of anxiety or depression, not a chemical imbalance. (Makes sense to me! See my previous blog posts)

The paper hypothesises that what antidepressants do is produce chemical conditions that encourage synaptic strengthening, dendritic growth and branching, and new synapse formation in the hippocampus. In this way they induce neuroplasticity, which can reverse the neurological changes in response to stress. Since the hippocampus is primarily related to learning and memory, strengthening of its function enables us to properly process memories and learn from them. Neuroplasticity may enable the hardwiring of healthier cognitions, affective responses and behavioural expressions through the learning of healthier cognitive strategies and coping methods.

So that’s pretty cool.

However, now the drug has worked its magic on me, I’m left with the thorny problem of how to come off it without ending up in a worse place than I was to start with.

The next part is my own interpretation of the available information on the particular drug I’m on (mirtazapine 15mg), in an attempt to work out the fastest (safe) way of coming off it. This may be of interest to anyone who is in a similar predicament – but only in a general sense, as a guide to my thought process. I’m not guaranteeing that any of the charts I’ve scrounged off the web, or simply made up, are correct, and the conclusion I came to is based on one particular drug and one particular person (me!) and is unlikely to directly suit anyone else. Or in other words – please don’t try this at home!

So, first up, these pills I take reach peak concentration in about 2 hours and have a half-life of 20-40 hours (average for women 37 hours). In chart form, you get a change in concentration over time like this:

Scan_20190630 (3)

At first I thought that, because it takes a few days for the drug to clear out of my system, by taking the pills every day I might be getting ever-increasing amount of drug in my body. But apparently that’s not how it works. As long as there’s no problem with our metabolism, elimination works faster at higher concentrations, and drug concentration will reach a steady state. For mine, that should happen in about 6 days.

2_steady-state as multiples of half-life

Depending on metabolism, some people may have issues in achieving steady-state, but that usually becomes obvious by either horrible side-effects or just lack of any therapeutic effect. For myself, I’m pretty sure I’m in the normal metabolism range, and the drug seemed to work, so that was OK.

3_drug concentration and metabolism

So far so good. For the next part, I couldn’t find the right chart, so I’m making it up. I’ve drawn what I’m thinking was the intention behind the old (and wrong) tapering advice. I think the intent was for people on higher dosages to step down over periods corresponding to the times to achieve steady state, rather than going cold turkey and coming straight down from a high dosage to zero in one go.

Scan_20190630

One problem with the above approach is that it assumes there is a direct and linear relationship between drug concentrations in the blood and withdrawal symptoms. It does not recognise that withdrawal symptoms arise from steep drops in neurotransmitter concentrations in the brain, which apparently is not linearly related to the drop in dosage – hence the need for smaller dosage reductions over a longer period.

Judging by the observation that antidepressants typically take a few weeks to show an effect, perhaps this is the time it takes for neurotransmitter levels to reach steady state? Or else, there may be some other unknown effect at work, which is delaying the effect of the drug on mood – and which might also be at play on withdrawal.

Plus, we also need to recognise the down-regulation effect as the brain adjusts itself to the new levels of neurotransmitters. So rather than have a simple recovery curve-to-straight-line like this:

phases of treatment

I suggest it’s more likely to look something like this, with an improvement of mood at first, followed by the brain’s recognition that mood level is becoming too high and the implementation of a down-regulation to bring it back down.

Scan_20190630 (2)

I think this is why they aren’t supposed to give these drugs to people with bipolar or to kids. Either because of over-dosing or because of the differences in children’s brains, they are more likely to overshoot into a state of ‘activation’*.

*Symptoms of SSRI-induced activation syndrome: irritability, agitation, somatic manifestations of anxiety, panic attacks, restlessness, hostility, aggression, insomnia, disinhibition, emotional lability, impulsivity, social withdrawal, akathisia**, odd behaviour, hypomania, paranoia and other psychotic symptoms. **Akathisia: a subjective unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. Usually the legs are most prominently affected. People may fidget, rock back and forth, or pace. Prevalence rates of activation are as high as 20% in children with mental retardation, autism, Tourette’s Syndrome, panic disorder and pervasive developmental disorder.

(Just thought I’d add that in, because ‘activation’ sounds an awful lot like the issue I was having – similar to but not quite fitting anxiety or PTSD – which peaked about 3 months into my drug treatment. Just saying.)

Anyhow, to get back to the point, what I would expect to happen on discontinuing the drug would be the following:

  • Synaptic neurotransmitter levels fall
  • For drugs with a short half-life, levels fall faster than the brain can adjust. This triggers withdrawal symptoms such as dizziness, nausea, anxiety
  • Over 2 weeks or so, the brain recognises that neurotransmitter levels are lower than usual and tries to adjust by releasing more
  • For long-term users, the adjustment may not be adequate, owing to down-regulation of receptors. Withdrawal symptoms may continue.
  • Following discontinuation, if adjustment has not kept up with rate of taper, mood will drop below the normal threshold, mimicking a relapse of the original condition.

I’ve tried to illustrate this graphically like this:

Scan_20190630 (4)

What we can do to maximise success would be:

  • Don’t go cold turkey, even coming off the lowest therapeutic dose
  • To minimise withdrawal symptoms, adopt small reductions in dosage and be sure symptoms have gone before each step down
  • For long-term users and those coming down from high dosages, adopt an even longer taper, not only to ease withdrawal symptoms but to avoid apparent relapse in mood disorder

Having said all that, I’m not planning to follow the cautious 10% hyperbolic taper. I really can’t imagine myself chopping pills into smaller and smaller doses over the course of months – and I doubt I’m going to need to. Considering I’ve only been on a low dose and for less than a year, I’m thinking (hoping) I’m a low risk for an apparent relapse, and can go faster than that. So my plan is to taper by about 25% steps, based on making up dosages by combinations of half and whole pills – because the pills are tiny and half is the smallest I can easily go.

This is what I’m planning to try:

scan_20190630-5.jpg

The ‘folk wisdom’ is not to alternate half and whole pills like this, and I understand that will result in increased fluctuations in dose. I believe I can mitigate that somewhat by adjusting the times when I take the pills. At the moment I take one pill in the evening. When I’m alternating ½ and whole pills, after the ½ pill I’ll be running too low towards evening so I’ll need to bring the whole pill forward, say to mid-morning or lunchtime. Things get might get tricky when I’m on the 3-day alternations but I’ll play it by ear.

I’m also thinking to offset the final 67% reduction in dose at the end with supplements that might naturally boost levels of serotonin. St John’s Wort acts like an anti-depressant in inhibiting serotonin reuptake (but might take too long to take effect). I can’t take it earlier as it can’t be mixed with anti-depressants. 5-HTP and L-tryptophan are precursors to serotonin in the body and might work faster. The latter is a natural amino acid in food and may be safer than the former. However, I’ve never tried any of those before, so I have no idea whether that will help. Thinking there’s no harm in giving one of them a go.

Well, that’s the plan (…depending on how it goes, I may or may not let you know whether it is successful…). I’d be interested to hear others’ experiences with coming off antidepressants, too.

Wish me luck!

 

2 thoughts on “What they don’t tell you about antidepressants”

  1. I was fascinated by this for two reasons. Years ago, I went through heaven knows how many antidepressants, trying to find one that actually worked. Luckily, my impatience with getting off the ones with the worst side effects, and going off them probably faster than recommended, didn’t give me any problems. Note: none of them worked for me, at all.

    These days, I’m playing with three different blood pressure meds, trying to find the right balance to keep my blood pressure in the normal zone, and eliminating or moderating the side effects.

    Basically, it’s all guess work. The theory of brain chemistry for depression has been pretty much discarded as lacking proof, but many professionals still stick with it. Two of my meds, prescribed by a *cardiologist,* aren’t supposed to be taken together, and were the source of my abnormally (and dangerous) low heart rate, until I did the research and took things into in my own hands.

    Congratulations of being an informed rather than a compliant patient. Sometimes noncompliance can save your life.

    Liked by 1 person

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