Date Created: about 1998

Preface to ‘old edition’

Most of the SNRIs that have been on the market have failed to show antidepressant effect in most trials. This drug is a reminder of that, it was initially developed as an antidepressant before those failed trials and its subsequent resurrection as an anti-obesity drug. It was removed from the market for reasons that were probably somewhat spurious.

Another example is duloxetine which was developed around the same time, failed as an antidepressant, was shelved, was resurrected as incontinence prevention drug, and then eventually recycled successfully as an antidepressant!

Milnacipran was developed by a small French company (in the 1980s I think) and never gained acceptance as an effective antidepressant anywhere else, I do not know what trials were done unsuccessfully, one never does, and it was only after a company takeover that the levo-isomer was successfully marketed in the USA in 2013 as ‘Fetzima’. I do not know what kind of strange image that name might conjure up to you, I'm certainly not going to admit to the image I see!

So I suspect if one aggregated all the trials on SNRIs that would demonstrate no antidepressant effect. Those who have read much of my work will know that I almost never used those drugs, because I preferred the combination of sertraline and nortriptyline instead., If, as is my view, that works better than these SNRIs them the possible explanation is the other effects possessed by tricyclics, which may make a greater contribution to the antidepressant effect that is generally recognised.

One interpretation of that is that standard double-blind trials comparing drugs to other antidepressants or placebo are an extremely blunt instruments for detecting drugs that benefit depressive syndromes.

Here is the old note for the record, from around the year 1998.

Introduction

Sibutramine is an interesting serotonin and noradrenalin reuptake inhibitor compound developed by the old "Boots" company as an antidepressant in the late 1980s. It was developed as an anti-obesity agent after company take-overs in the 1990s.

No studies of this drug as an antidepressant have ever been published in peer reviewed journals. It was trialed as an antidepressant in USA and UK with, it is said, negative results. That is perhaps unfortunate because it was one of the first, and most potent, serotonin and noradrenalin reuptake inhibitors (SNRIs) devoid of TCA-like side effects (cf. clomipramine). Also it was strongly positive in nearly all animal models that are thought to predict human antidepressant effectiveness.

It would be expected to possess the superior (at least over selective serotonin reuptake inhibitors) antidepressant effects that are probably significant for serotonin and noradrenalin reuptake inhibitor (SNRI) treatment strategies; viz combinations of eg sertraline with nortriptyline, clomipramine, milnacipran, venlafaxine and duloxetine (possibly coming to the market soon).

If sibutramine eventually proves not to be an effective antidepressant that would be of considerable relevance and importance for the 40 year old mono-amine theory of depression and also the animal models used to predict the effectiveness of putative antidepressant drugs. This makes it especially regrettable that such potentially significant results, not only have never been formally published, but also seem to be unheard of by most psycho-pharmacologists with whom I have been in contact.

The frequent co-morbidity of depression and obesity and the synergistic effect they have on each other and on heart disease make this subject intriguing both from a theoretical and therapeutic standpoint. It is also worth noting the close association between satiety and relaxation and anorexia and anxiety: these may reveal evolutionary factors of survival value. Oligo-peptides may have a role in modulating such pathways, but that is another story.

Interactions; serotonin syndrome interactions are possible

The product information makes it clear that the drug is a "SNRI" with the important consequence of that action being emphasised in relation to serotonin syndrome.

As an SNRI sibutramine is likely to have the same risk of serotonin syndrome as all serotonin reuptake inhibitors (see other notes) such as selective serotonin reuptake inhibitors (SSRIs) as well as venlafaxine, milnacipran, tramadol, pethidine etc.

The drug company are clearly emphasising this in the PI and marketing.

However, I still see a potential danger. Doctors' mental set will equate "serotonin reuptake inhibitor" with a risk of serotonin syndrome. But, being marketed as a weight reduction drug, sibutramine may not easily become conceptualised in everyone's mind as a serotonin reuptake inhibitor.

So, do think of this drug as a serotonin reuptake inhibitor: that will reduce the chance of absent-mindedly adding it to moclobemide or tranylcypromine (MAOIs are the only likely serious interactions). I know of know of no reports of such serious reactions as yet.

Note: it is unlikely that serious serotonergic toxicity (or serotonin syndrome) will result from combining sibutramine with another serotonin reuptake inhibitor antidepressant. The risk of toxicity from serotonin syndrome is primarily with MAOIs, including RIMAs such as moclobemide.

See section on serotonin syndrome (www.psychotropical.com home page) as well as various 'Psychopharmacology Update Notes PUN_2002' notes re serotonin syndrome for fuller coverage.

Pharmacology

Sibutramine is a mono-cyclic compound with a branched carbon side chain; it is somewhat similar in structure to amphetamine and tranylcypromine. However its pharmacological activity is very different in that it is not a pre-synaptic transmitter releaser, nor a monoamine oxidase inhibitor, but a reuptake inhibitor.

Sibutramine itself seems from current research to have little inherent pharmacological activity (it is a 'pro-drug', like codeine). Current information indicates it is rapidly broken down by cytochrome P450 enzyme 3A4 into two metabolites (referred to as M1 and M2). Current research indicates that each of these is fairly specific as, respectively, a serotonin reuptake inhibitor and a noradrenalin reuptake inhibitor (and these properties are ~3 x more potent than any dopamine reuptake inhibitor capacity). Sibutramine and its two metabolites are said to have no affinity for:-- serotonergic, adrenergic, dopaminergic, muscarinic, histaminic, benzodiazepine or NMDA receptors.

The time to maximum concentration (Tmax) for the metabolites is 3 - 4 hours (sibutramine itself ~ one hr). Their half life (t1/2) is ~16 hours and they seem to exhibit linear kinetics (at doses of 10 - 30 mg). They are conjugated to inactive hydroxy-metabolites and so far have not been shown to have significant effect on blocking or inducing cytochrome P450 enzymes. However, 3A4 inhibitors like ketaconazole do slightly (probably to a clinically insignificant degree) increase plasma concentrations. So, exact P450 involvement in further elimination remains incompletely defined.

It seems a rude irony that this drug has more of the characteristics that might define the ideal antidepressant agent than most drugs marketed as 'antidepressants'. (see note 736 "Antidepressants Pharmacology").

Weight loss

The benchmark preferred measures for weight loss are a combination of long term dietary modification and an increased level of physical exercise. There is no drug treatment that has yet been demonstrated to have efficacy on the longer term morbidity or mortality from excess weight.

If the above approaches are insufficiently helpful then some may consider it is reasonable to treat patients with a body mass index (BMI) >30 (without concomitant risk factors) or patients with a BMI >27 with concomitant risk factors.

The treatment of lifestyle-related conditions with medications attracts debate. Perhaps treatment of type II diabetes, hyperlipidemia or hypertension is little different from the treatment of obesity itself.

Weight increase leads to increased sympathetic and decreased parasympathetic activity. Weight decrease leads to the opposite effect. Inhibition of noradrenaline reuptake is expected to increase blood pressure and pulse rate.

There is some evidence that sibutramine has thermogenic properties (as, incidentally, does tranylcypromine), probably via activation of the sympatho-adrenal system producing increased activity at the beta3-adrenoceptor (which activate 'brown' fat cells to produce heat, if you have enough of them remaining 'post-weaning').

As might be hypothesised, other (so-called) serotonin and noradrenalin reuptake inhibitors (SNRI) that have been tested, eg venlafaxine and duloxetine, similarly decreased food intake (in rats). I say 'so-called' because there remains significant doubt that either venlafaxine or duloxetine do act as sufficiently potent noradrenalin reuptake inhibitors in humans. However, milnacipran does not reduce weight in humans for reasons that, I presume, no-one can yet explain.

A recent meta-analysis of medications for obesity reviewed 108 studies. Four drugs produced large effect sizes: amphetamine, benzphetamine, fenfluramine and sibutramine. The maximum weight loss over placebo was 4.0 kg.

The Lancet paper suggests changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride (but not LDL cholesterol) exceed those expected from weight loss alone.

I interpret the current evidence as indicating that sibutramine may be the drug of choice for obesity. It may possibly have a place in the treatment of the obese patient with refractory depression. Present knowledge makes that impossible to be sure about, or what it is best to do; especially because of the uncertain interactions and the potential for serotonin syndrome with other antidepressant agents noted in the product information PI (which may be legalistically, rather than pharmacologically, influenced).

Side effects

Most frequent side-effects are dry mouth and constipation, mild increased heart rate and blood pressure with tachycardia and palpitations. Also flushing, insomnia, nausea, sweating, irritability, impatience, excitation. In larger doses sibutramine 25 mg seems subjectively indistinguishable from placebo; at 75 mg it gave unpleasant effects, such as "anxiety, confusion, and decreased vigor". Sibutramine alone is associated with improved cognitive function and there is no significant interaction with alcohol.

Seizures were reported in <0.1%. (cf. Bupropion ~1.0% and TCAs ~ 0.1%).

Some anorectic drugs (the serotonin releasing agents like fenfluramine) have been implicated in the development of heart valve lesions. Evidence from both theory and practice indicates sibutramine does not have this problem.

It could possibly induce / precipitate a manic episode in bipolar patients. A check for any history of Bipolar Disorder, personal or close family, would be smart: if present referral may be wise; but the degree of risk is probably low.

Despite lack of anti-muscarinic activity the noradrenergic activity makes it liable to aggravate benign prostatic hypertrophy and narrow angle glaucoma: ie either increased noradrenalin or decreased acetylcholine activity may precipitate these problems.

Treatment of depressive illness in obese patients

A significant proportion of patients suffering from depression are obese. Antidepressant treatment often causes weight gain. All the old tricyclic antidepressants (TCAs), and some new drugs like mirtazapine do too, probably related to their anti-histaminic properties (blockade of H1 receptors).

The selective serotonin reuptake inhibitors (SSRIs) do not usually cause much weight gain or loss; but, especially in refractory cases of depression, they may be inadequate to induce full remission.

Psychiatrists have generally paid scant attention to weight gain (probably because of limited knowledge of the pharmacological mechanisms relating to appetite). Very few papers published before the new "atypical" neuroleptics came on the scene actually weighed the patients. Some papers (published in peer-reviewed journals) considering weight gain used the subjective impressions of the patients as evidence, but failed to actually weigh them. I consider that bizarre in the extreme when one is dealing with such a simple and objective physical measurement. It may be worth contemplating what that tells us about the heritage of psychiatry as a discipline and the depth and security of its roots in the methodology of science.

Note in this context that, contrary to what many texts state, the monoamine oxidase inhibitor tranylcypromine does not cause weight gain (phenelzine definitely does). Tranylcypromine is one of the few antidepressants suitable for serious refractory cases that does not cause weight gain. As a bonus, it lowers blood pressure also; whereas the serotonin and noradrenalin reuptake inhibitors (SNRIs) and the noradrenalin reuptake inhibitors (NRIs) tend to raise blood pressure.

Other drugs likely to be useful in this important high morbidity group are venlafaxine (which seems to promote weight loss) and milnacipran (which is not associated with weight decrease, it seems to be neutral).

In my experience the perennial residual clinical problem is often poor sleep that is refractory to benzodiazepines. Suggestions please !

Patients already on an antidepressant drug

There is no database of experience for combinations with, or change-overs to, sibutramine. This is a specialist area and those with insufficient knowledge of the potential pharmaco-dynamic and pharmaco-kinetic interactions may prefer to refer or consult.

Note: despite absence of positive (or negative) published evidence of the antidepressant effects of sibutramine it may yet prove to be an effective SNRI antidepressant agent.

Selective serotonin reuptake inhibitors (SSRIs): there is no reason to expect any major pharmacokinetic interactions with either selective serotonin reuptake inhibitors (SSRIs) or other antidepressants (ie they probably will not greatly interfere with each-others blood levels / breakdown). The 3A4 blockade from fluoxetine or nefazodone may elevate sibutramine levels, but probably not to a dangerous degree. It would be prudent to take more care with known cytochrome P450 enzyme inhibitors, viz fluoxetine, fluvoxamine, paroxetine, nefazodone (see other notes re cytochrome P450 enzymes).

Clearly added effects at the re-uptake site are to be expected; this is like giving a larger dose of one drug. So sibutramine and 100 mg of sertraline together may be equivalent to giving 300 or 400 mg of sertraline. A commensurate increase in side effects may occur; but toxicity or serious serotonin syndrome can be considered as unlikely.

The above suggests that swapping over by dove-tailing the doses of each drug is unlikely to produce serious problems. Since sibutramine is a potent serotonin reuptake inhibitor one presumes there would be little point in, or advantage from, using both other serotonin reuptake inhibitors and sibutramine together (the same would probably apply to other types of antidepressant). But there is no sound evidence about this as yet.

Any drug with anti-histamine effects, not just all old TCAs, may negate the weight loss effects of sibutramine because H1 blockade promotes increased appetite and weight gain. SNRIs that have H1 blocking properties, viz clomipramine, definitely cause weight gain, not loss. The same may be true of all neuroleptics, old and new; so it is probably pointless, and often contra-indicated, to combine them with sibutramine.

Combinations with serotonergic drugs acting via mechanisms other than serotonin reuptake inhibition (such as will inevitably be used by some 'adventurous'*** doctors who have an impression of their own breadth and depth of erudition that may not be warmly embraced by their medical defence organisation's legal team) may throw up some problematic and odd side effects. E.g. mirtazapine, nefazodone, tryptans, buspirone, L-tryptophan. However, I interpret current knowledge as suggesting they are not likely to cause serious serotonin syndrome.

An important naturalistic experiment will be taking place, perhaps without even being noticed. If sibutramine is used in obese patients who have already been treated with antidepressants then any improvement, or worsening, of the depression after the change-over will constitute evidence about the extent of any antidepressant action of sibutramine. This is valuable data that will probably be both ignored and lost.

Please email me if you have observations about treating anyone with previous depression with sibutramine.

*** This is a "Yes, Minister' irregular verb.

The declension below has come from Sir Humphrey's private papers via an impeccable source:

"I cautiously try new strategies

You are a daring innovator

He takes undue risks."