There is a strong association of migraine with serious depression, encompassing the linked domains of genetics, patho-physiology and treatment response. A careful personal and family history of both disorders should be sought and will determine the treatment of those with migraine and depression in their family or personal history. It is interesting that drugs working in several different ways (re-uptake inhibitors like TCAs, MAOIs and GABA-ergic drugs like valproate) are clearly efficacious for both conditions — a sure indication of shared patho-physiology. This commentary integrates recent research findings and considers the Bayesian rationale for considering several drugs (guidelines are somewhat discrepant) and partly reprises the role of older drugs, including MAOIs, that have been lost in the shadows for decades.
It has been my view for decades that the association between migraine and manic-depressive illness (Bipolar disorder) is closer than is generally recognised, and I paid special attention to a history of both when assessing cases. Evidence has continued to accumulate that this closeness of association includes the genetics, the patho-physiology and the treatment of these two conditions.
The effectiveness of the ‘TCAs’ in migraine prophylaxis has withstood the test of time, despite the different recommendations in the burgeoning multitude of guidelines*** — lumping TCAs together is not valid, researchers have persistently failed take account of the completely different properties of individual TCAs, e.g. doxepin and trimipramine are simply antihistamines, and desipramine is as close to being a selective NRI as any new drug like reboxetine (see my TCA review paper (1)). Lumping the TCAs together constitutes an elementary error of pharmacology and logic. It is highly unlikely that they are all equally effective.
***They all rely on meta-analysis of much the same sets of data – it appears no one does original research any more, everybody just employs themselves in endless pointless meta-analyses of biased and unrepresentative data. It is called progress, apparently.
The only TCA with potent activity as a 5-HT reuptake inhibitor is clomipramine. Paradoxically, amitriptyline, which has very little effect on 5-HT, is the TCA most commonly used for migraine. Where is the sense in that?
The irony of this is compounded by the evidence indicating a major patho-physiological role for low 5-HT in the vulnerability to migraine, and acute 5-HT release from platelets in the triggering of acute episodes — clomipramine remedies both those abnormalities. How serendipitous, the theoretically ideal drug.
Bayesian reasoning impels one to the view that the prime choice from the TCAs has to be clomipramine: and yet, even after 50 years, there are only a couple of inadequate trials. There is no good reason for this — quite the reverse — it is just a historical accident, similar to the accident of its use as a drug for OCD rather than depression, when in fact it is the best AD of all the TCAs.
Disabuse yourself of the notion that science determines what treatments we use: that is determined by society, culture, politics, fashion, and money (2).
In the original version of this commentary, more than 20 years ago, I observed that recent research substantiated a significant genetic relationship, especially with manic-depressive illness (bipolar disorder). That is now more firmly established, and indicates clearly that the link is also strong with unipolar depression, in particular the form showing ‘melancholic’ depression characteristics (see below for discussion of this).
Biochemical studies of migraine indicate that patients have alterations of serotonin ‘handling’ compared to non-migraineurs, and probably have a lower 5-HT level between attacks — that may be a CNS reduction, as opposed to alterations in platelet 5-HT content, which decreases early in a migraine attack, as serum levels increase. Early in an attack there is a massive depletion of platelet 5-HT (which returns to normal within 72 hours (3, 4)), causing a short-lived increase in plasma 5-HT, and a rise in urinary 5-HIAA. An inverse correlation between the urinary levels of 5-HIAA and platelet 5-HT seems to be well replicated (5, 6), which indicates that, as expected, the source of 5-HT is the platelet-release, not neuronal activity (cf. serotonin toxicity).
An infusion of a 5-HT-releaser such as reserpine (note it is non-specific releaser, being more potent as a dopamine releaser) induces migraine-like headaches (7) — it is therefore interesting that there seem to be no reports of migraine following the ingestion of the widely used and more specific 5-HT releaser, MDMA (8). Other 5-HT releasers have also been reported to precipitate migraine (5, 9).
However, in relation to the CNS, migraine is not a feature of serotonin toxicity. This can be stated very reliably because they have now been an enormous number of well-documented cases, of all degrees of severity, examined by expert toxicologists — no migraine, end of story, surely?
We can conclude confidently that large increases of CNS serotonin do not trigger migraine.
Intravenous infusion of 5-HT has been reported to reduce the pain in migraine patients (10), presumably a peripheral effect, since serotonin does not cross the BBB***.
***There appears to be little discussion of this apparent paradox: but note this ‘fact’ seems to be substantiated by Anthony (5, 11), but it is contradicted by Ostfeld (12), see Panconesi for detailed discussion (9).
When will medical science come to terms with the requirement for the independent replication of results? It is astonishing that such a central & fundamental finding, in such an important condition, has been brushed aside almost un-replicated, as if facts don't matter (does that remind you of someone?).
These observations would seem to indicate that it is release of 5-HT by platelets which plays a key role in triggering an attack and initiating the vasoconstriction. A subsequent stage of reactive vasodilation may be the severe headache phase during which additional intravenous serotonin is capable of re-establishing vasomotor tone and lessening the headache.
A triggering of 5-HT release by platelets also fits with the important observation that aspirin, and other platelet drugs, have a prophylactic effect in migraine. This would be presumed to work by inhibiting platelet aggregation, and thus platelet 5-HT release.
These, and other aspects of recent research, are reviewed in detail by Deen et al. (13).
At this point we may remind ourselves that clomipramine substantially depletes platelet 5-HT — amitriptyline only a little. Platelets express the 5-HT transporter (aka SERT, or SER-T, or 5-HTT) on their outer membrane and utilise it to garner 5-HT from the serum and accumulate it in vesicles, where it then plays a role in platelet aggregation and blood clotting. This is evidenced by the fact that all potent 5-HT reuptake inhibitors increase the bleeding tendency, this is an aspect of SSRI side-effects which has received only belated attention until quite recently (14-17).
In the days before in vitro human cloned receptor assays, which can estimate the affinity of drugs at the 5-HT transporter, one of the bio-assays of these drugs was the extent to which they depleted platelet 5-HT. Amitriptyline is rather weak in this regard, but does have minimal platelet 5-HT diminishing potency, but nowhere near as great as that of clomipramine (18, 19): that difference is, of course, reflected in their relative potencies at the 5-HT transporter, where clomipramine is 50 times more potent (1). It is also notable that these drugs increase central CNS 5-HT levels — their proposed mechanism of antidepressant action — which would be posited to lessen, or nullify, the hypothesised CNS 5-HT deficit in migraine. This central 5-HT under-activity being an obvious putative link between migraine and depressive illness.
The above is congruent with my own extensive experience, from clinical practice, where I frequently switched people from amitriptyline to clomipramine, for the improved treatment of their depressive illness (CMI is a much more potent anti-depressant drug than AMI), and at the same time observed a great lessening of the frequency of migraine attacks, over the medium to long term (one to six months). Indeed, it was not unusual to see patients who reported complete absence of migraine attacks once established on a therapeutic dose of clomipramine.
Those who favour Bayesian reasoning will hardly be surprised by any of the above facts or logic.
When I read discussions about mechanisms of action I am reminded of the pitfalls of theorising on these matters without fully understanding the various aspects of clinical medicine and pharmacology — ultracrepidarianism, to wit. In reviewing various papers for this commentary, I came across various examples of fallacies which are educative to examine. In discussing the mechanisms that might link depression and migraine, Baska et al. make a common class of reasoning error involving the categories of reasoning of ‘over-inclusiveness’ and ‘invalid analogy’ (20). They make the following statement:
‘In addition, the first-line antidepressant drugs in the treatment of major depression, the SSRIs, are not effective in preventing migraine attacks. In contrary, the most effective migraine prophylactic drugs, the beta-blockers, have pro-depressive side effects.’
This is a statement and line of reasoning that is dubious because, although in principle it makes a potentially useful point, it is off-target: first, the SSRIs are not an effective treatment for melancholic-type depression, which is the type of depression most closely associated with migraine. Second, beta-blockers do not, in any meaningful sense, have ‘pro-depressive’ side-effects. That is a meaningless association because beta-blockers cause a syndrome of apathy and tiredness, not a picture of melancholic depression, and they do not precipitate depression in those with a depressive diathesis. The comparisons are superficial and invalid.
Incidentally, I expect other accepted statements about aspects of migrainemay fall into the same category: for instance, the statement that reserpine precipitates attacks of migraine. It is not well replicated, and are such headaches really migraine? or just migraine-like?
Methodology and replication are the neglected sine qua non for good science.
It is appropriate to give such ideas attention, because mistakes of fact, analogy and reasoning, such as the above, pervade many false arguments used by researchers, both clinical and non-clinical. There are many drugs that are called ‘antidepressant drugs’ that have only a small effect on reducing the scores on non-specific symptom questionnaires used to assess the severity of ‘depression’, but which do not, by any stretch of the imagination, constitute drugs that substantially improve or cure melancholic depression. When researchers compare the behavioural-pharmacology of drugs in animals, and draw conclusions therefrom, the validity and value of such reasoning is commonly non-existent.
Yet such reasoning is ubiquitous. This is a similar argument to one recently discussed by Clare Stanford from UCL (21). She points out in her editorial that a substantial proportion of the animal models used for ‘depression’ are un-validated. As she says, ‘interpretation of results from many of these procedures is dubious’, to the extent that it is ‘undermining confidence in behavioural neuroscience’; I quote her abstract in full:
‘Preclinical (predictive) screens for psychotropic drugs are often used, incorrectly, as animal ‘models’ of psychiatric disorders, or to study ‘disorder-like’ behaviours. This misunderstanding is contributing to poor translation and is undermining confidence in behavioural neuroscience. In this editorial, I discuss some of the reasons why the interpretation of results from many of these procedures is dubious because the criteria for validity of the test, as a model of the disorder, have been ignored. Arising from this, I propose that the description of any abnormal behaviour of rodents as a ‘model’ of a psychiatric disorder, or even ‘disorder-like’, without evidence-based justification, should be regarded as unacceptable in this journal.’
Journals of Psychopharmacology, and associated bodies, have also recently promoted another major change in thinking, one that I have espoused for many years, for which I heartily applaud them — the idea of ‘Neuroscience-based Nomenclature (NbN), viz. classifying drugs by their pharmacological effects (22, 23). You can be excused from wondering why this is a revolutionary idea! This is relevant to my comment above about the TCAs being lumped together when considering conditions like migraine and depression. Lumping a class of drugs defined by their structure — not their pharmacological properties — is completely irrational, they have hugely different pharmacological properties. I have been railing about this in my writing for decades and I find it astonishing that it has taken so long for this view to begin its ascendancy: the path is yet long.
This means that the use of the terms like ‘second-generation’ or ‘atypical antipsychotic’, have now been declared illegitimate, they are bastards — stop using them, or I will start abusing you and deriding your intellectual prowess (see my commentary about this, and my paper (24).
This Neuroscience-based Nomenclature (NbN) approach officially endorses many things I have been saying ever since Elliot Richelson’s first receptor data paper (25)***: e.g. doxepin is not a bloody TCA, it is an anti-histamine, probably the most selective and potent one on the market (1). I have come across plenty of psychiatrists who have convinced themselves it is an AD and used it as such over many years. I shall say no more.
Doxepin is referred to in standard texts as a TCA. Caveat lector.
Elliot’s paper was so poorly cited that I wrote to him asking why he thought so few people understood the importance and significance of it — we have been corresponding ever since.
So, NbN has made its stage debut, better late than never! Sadly, for many psychiatrists it will probably be ‘never’. Perhaps, just perhaps, neurologists will be a little more susceptible to being influenced by science.
Epidemiological & genetic studies
Migraine is now conceptualised as a neuro-vascular disorder with a strong genetic basis — some cases are caused by single genes — common migraine exhibits definite familial clustering (26).
There are causal mutations in ion channel genes (CACNA1A, ATP1A2, and SCN1A), which effect glutamatergic neurotransmission and the threshold for cortical spreading depression. In common polygenic migraine, genome-wide association studies have identified SNPs at many loci that are associated with migraine risk.
A recent Australian study shows the risk for migraine in relatives of probands reporting depression is considerably higher than the risk for depression in relatives of probands reporting migraine (27). Yang’s results indicate that the observed comorbidity between migraine and depression is explained almost entirely by shared genetic mechanisms (28). Indications are that migraine in depressed patients represents a bipolar trait (29), cf. ‘The link’ below.
Oedegaard’s study further substantiates that unipolar cases with comorbid migraine resemble bipolar II patients (30).
The link: depression and migraine
At this point, a quick refresher concerning the genetics and classification of depression is pertinent. The form of depression that shows classic endogenous features, often now referred to as melancholic depression — to help separate it from the over-inclusive DSM category of major depressive disorder (MDD) — shows the classic biological features of anergia and anhedonia, combined with early-morning awakening, diurnal variation etc.; these demarcate a form of depression which is more likely to transmute, in time, into a picture of bipolar disorder (31). Therefore, the genetic commonality between melancholic-type ‘unipolar’ depression and classic manic-depressive illness (now referred to as bipolar disorder) is very significant, and it is this form of depression which is most strongly linked to migraine. The point to remember is that many index cases of depression, with the above melancholic characteristics, (and especially those who also suffer migraine) will turn out in time to exhibit a more typical manic-depressive course (31).
That observation has huge implications for optimum treatment strategies — like avoiding mono-therapy with TCAs if patients are potentially manic-depressive (cf. MAOIs & valproate, below). These considerations are not addressed in any guidelines I have seen.
It is also noteworthy that migraineurs, even without diagnosed depression, have a substantially increased risk of suicide (32, 33). This is hardly surprising, since we would expect many missed cases of depression in people who are treated for migraine. They are unlikely to be examined carefully for depressive symptoms in all cases. This serves as an indication of how important detecting depressive symptoms in migraineurs actually is.
DSM has been a profoundly negative influence on classification, and drug trials, especially in the field of depressive illness. DSM may have been a boon for pharmaceutical companies, but it has not been a positive influence on clinical research.
Pharmacology and presumed pathophysiology as a guide
For those who do not already have an intricate knowledge of psycho-pharmacology this is a particularly interesting area, because amitriptyline — the most commonly used TCA in migraine prophylaxis — actually has only a feeble serotonergic effect. Its benefits, in conditions thought to be influenced by altering 5-HT, are minimal or non-existent. I have discussed this elsewhere, and detailed that the only TCA antidepressant that has clinically relevant effects on 5-HT reuptake — and well-established clinical effects in 5-HT responsive conditions such as obsessive-compulsive disorder & narcolepsy — is clomipramine; so, there are powerful reasons, especially if one is a Bayesian, for expecting it to be particularly effective in migraine (1).
There are only two studies of clomipramine, both poor, that I know of (34, 35), and a recent review of the treatment of migraine specifically stated that there were no further studies of clomipramine in migraine (36). The patients in the Langohr trial had once weekly attacks on entry, and took CMI for 4 weeks (this is a prophylaxis trial, not one of acute efficacy) and they concluded it did not work. It doesn’t get much sillier than that, especially when we know ADs take weeks, not days, to take effect. Talk about dumb and dumber.
TCAs have been used for migraine for fifty years (36, 37), yet there is still lack of agreement about their efficacy: that does not say much about the methodology and quality of clinical trials in this area.
A recent meta-analysis (38) — for the benighted ones who still think meta-analysis is a useful activity —- found no difference in prophylactic efficacy between amitriptyline, SSRIs, and SNRIs. If correct (it probably is not), this would make a nonsense out of any notion of a 5-HT-mediated mechanism of action. It would obviously be very important to look at the differences in platelet 5-HT content with these different treatments, and to look for differences between different TCAs, among which there are huge differences (orders of magnitude) in affinity at the 5-HT transporter.
Others may share my surprise that a competent effort has not been made to test the premise that CMI is effective — not many people want to be bothered to do a trial that lasts 3 to 6 months, which is what is necessary to establish true prophylaxis, especially when there is no money in it, as is the case with clomipramine (see ‘MAOIs’ below).
The two poor short-term trials of clomipramine for migraine prophylaxis (34, 35) are clearly inadequate to justify any assumption that it is ineffective.
My experience in routine clinical practice, where I saw many patients with both depression and migraine, is that patients who had experienced improvement with amitriptyline, having previously had trials of various drugs, would almost always notice a decrease in frequency of migraine when they were changed to clomipramine. I would do that frequently because I was primarily treating their depression, and because clomipramine is a better antidepressant amitriptyline. I therefore saw a great many patients who responded to clomipramine and some remained completely migraine-free for a long time (years).
SSRIs appear to be of equivocal effectiveness: opinion is still not unanimous on that point. However, if release of 5-HT from platelets is a key mechanism in triggering attacks, then one would expect them to be clearly effective.
These issues highlight the ambiguity surrounding the role of 5-HT in migraine and the obviously inadequate testing of key hypotheses. As pointed out above, the TCAs have 5-HTT affinity that varies, from non-existent, to potent. Note: many of them are also are fairly potent 5-HT2A antagonists (1). If it were shown that amitriptyline and nortriptyline were equally effective that would tend to support the idea that it is their blockade of 5-HT2A receptors that mediates their effectiveness. However, if as I assert, clomipramine is more effective, that would support an increase of central 5-HT, along with a decrease of platelet 5-HT, as being more likely mediators of improvement. That is because clomipramine is about equally potent as a 5-HT2A antagonist, but 50 times more potent at the 5-HTT.
Since it is incontrovertibly true that there are a number of different mechanisms creating vulnerability to migraine, including multiple SNP variations, and ion channel abnormalities, we are clearly dealing with a patho-physiologically heterogeneous clinical syndrome.
It is illogical to expect double-blind trials to reveal much about differences between different treatments in groups that are heterogeneous.
Unless the treatment concerned has a dramatic effect on one particular subset of patients, enough to influence the whole result, such methodologies are doomed to fail.
If the condition is patho-physiologically heterogeneous then different trial methodologies are required to elucidate treatment response. A-B-A treatment comparisons are appropriate, as well as treatment discontinuation-re-institution. This, as if such were needed for any real scientist, is another attestation to how poorly much research is conceived. A few thousand words on that is a task for another day! If there is anybody out there who is an expert in clinical science methodology this would be an excellent example to explain the usefulness of different methodologies. Will anyone step up to the plate?
And what about MAOIs!
Anyone, with even a passing acquaintance with my writing, will know my views about the regrettable underuse of MAOIs in serious depression (39). It will come as no surprise to learn that there are a number of studies indicating an excellent effect of MAOIs on severe migraine, although one would hardly think that from the current migraine literature, most of which fails to mention them at all. Because of my frequent use of MAOIs, and my long-standing interest in migraine and its connection with manic-depressive illness, I have observed many patients who, once put on tranylcypromine (TCP), had complete long-term remission of previously long-standing and troublesome migraine headaches.
Allow me to give a little detail by way of an anecdote. Most published medical research is wrong (40), and one only has to go back a few years and check, to find a myriad of new treatments which never subsequently enjoyed independent replication or validation. The false prophet of the double-blind trial continually proves that drug A > B > C > A — Penrose stairs with drugs, as I have previously described it — and its dominant weighting in the assessment of evidence is quite unjustified by its proven inadequacy as a methodology, both in theory and practice. However, it is a methodology which serves the purposes of pharmaceutical companies getting easy approval for, and marketing, new and expensive drugs.One does not need a double-blind trial for an effective migraine prophylactic treatment any more than for a trial of whether penicillin or parachutes work (41). If one needs statistics to do that analysis, then the treatment is obviously of only marginal efficacy.
For many years it has been my habit to contact researchers, who have published subsequently un-replicated new treatment reports, to ask why they have not published anything else since then. Many of them simply decline to answer such questions, the honest ones admit further work was a failure — but, the subsequent failures are almost never published.
The earliest paper that I was aware of (when I wrote the original commentary concerning MAOIs & migraine 20 years ago), was published by an eminent Australian neurologist, Prof James Lance (42). When I saw that he had not written anything for many years after that paper, I contacted him, in his retirement, to ask why. His reply was handwritten with a fountain pen — the last such letter that I remember receiving. He told me that he had continued to use them over many years and found them of considerable efficacy, but that he had, regrettably, simply not got around to doing any more formal work or trials, or writing more about it.
There are a couple of more recent reports using MAOIs (43, 44), as well as more older ones (10, 45-48).
I would not hesitate to use MAOIs for prophylaxis in severe migraine. And since these drugs are safer and easier to use than most people imagine, as I have discussed elsewhere (39), they would seem to be the underused ammunition in the therapeutic armamentarium. For patients who are bipolar they represent an especially good choice since many people are of the opinion MAOIs are a good option for the depressive phase of BPD. Furthermore, elderly patients tolerate them particularly well.
GABA and Valproate
Valproate enhances the action of GABA, which is the major inhibitory neurotransmitter in the CNS, and seems to be of firmly established efficacy for migraine. One imagines this indicates that another of the contributing mechanisms involved in the poly-genic susceptibility to both migraine and BPD, involves some kind of sensitivity and over-reactiveness of the CNS. In that context, it is notable that Valproate is an extremely effective anti-manic drug, also with useful prophylactic activity, for bipolar disorder itself. It therefore has a special place in patients who are bipolar. How good is that.
Guideline recommendations for migraine prophylaxis
It is appropriate to preface any comment about guidelines by noting their often undeclared conflicts of interest (49), and biases (50, 51), and the considerably discrepant recommendations by different groups compiling guidelines, which attests to their inherent problems. Nonetheless, it is of use to be aware of what drugs are, and are not, recommended in such sources. Anyone familiar with my writing will know of my considerable scepticism about the backbone of guidelines, meta-analysis, which I refer to as the ‘phrenology of the new millennium’.
As examples, the following guidelines are not exactly in full agreement!
Canadian Headache Society, 2012: ‘Based on our review, 11 prophylactic drugs received a strong recommendation for use (topiramate, propranolol, nadolol, metoprolol, amitriptyline, gabapentin, candesartan, butterbur, riboflavin, coenzyme Q10, and magnesium citrate) and 6 received a weak recommendation (divalproex sodium, flunarizine, pizotifen, venlafaxine, verapamil, and lisinopril) (52).
The ‘Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society’, 2012: (53) opine: ‘Divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A).’
A UK perspective from ‘NICE’ may be found here:
They suggest: topiramate or propranolol & to consider amitriptyline (according to the person's preference, comorbidities and risk of adverse events).
It is important not to allow guidelines to become a substitute for thought and clinical judgement. Even more insidiously, some doctors seem to be using guidelines as an excuse to be intellectually lazy and dictatorial about the treatment they offer to patients: one hears increasingly frequently that patients have been told they cannot have a treatment because ‘it is not in the guidelines’. That is utterly disgraceful, totally inappropriate, and a significant transgression of medical ethics. It seems that we are moving towards medical totalitarianism. That is, incidentally, a deadly serious and non-hyperbolic comment.
I suggest clomipramine is a forgotten gem, and is the drug of choice when anxiety or depression are co-morbid, which is frequently. However, caution is required if bipolarity is suspected.When that is the case, MAOIs and valproate deserve serious consideration and they are compatible with each other and with lithium.
If lithium is not required or desired, valproate may be considered for possible or definite bipolar cases, and MAOIs may be the treatment of choice for depressed bipolar migraineurs.
For severe bipolar disorder accompanied by migraine, lithium and valproate, with tranylcypromine as the antidepressant when required, may be seriously considered as the optimum combination.
The frequent co-occurrence of depression and anxiety means beta-blockers need to be used with due consideration of the possibility of their immediate or future presence.This is especially so in the knowledge that even migraineurs without diagnosed depression have a substantially elevated suicide rate.
In view of the evidence concerning the genetics and patho-physiology, and that amitriptyline has been used and recommended for 50 years —so much accumulated experience can hardly be completely wrong — clomipramine is an anachronism that is crying out for explanation.Having read most of the reviews of this subject published in the last decade, I cannot recall a single one that discusses the possibility that depleting platelet serotonin may prevent the triggering of an attack. I suspect it is because most authors either do not know, or have forgotten, that platelet serotonin depletion is a property of serotonin reuptake inhibitors.
When patients manifest both depression and migraine, as they so commonly do, it is important to be aware of, and treat, both conditions. It is essential to screen migraineurs & depressives for both past and family history of depression (especially bipolar disorder) and panic attacks and migraine. This will guide treatment. The association of migraine with bipolar disorder will determine antidepressant choice.
Some are of the opinion that magnesium deficiency may be relevant: it is common, and all one has to do to remedy that is to use sea salt, as opposed to ordinary table salt, which has less magnesium. See ‘Why all migraine patients should be treated with magnesium’ (54) and re the surprisingly high frequency of magnesium deficiency see (55-57).
I find it remarkable that none of the guidelines contain any substantive comment or discussion about the relevance of the common co-occurrence of migraine and melancholic-type depression and bipolar disorder (it is mentioned en passant at best). These are obviously very important factors, perhaps the most important factors, in determining treatment. It is difficult not to think, in this context, of the old comment about committees — a camel is a horse designed by a committee.
The considerable discrepancies between different guidelines must reflect on the unsatisfactory quality of research, and the procedures by which it is assessed and translated into everyday practice — at which point one must note that most patients, including children, females, and the elderly, who we treat in everyday practice, are excluded from entry into clinical trials, which are therefore difficult, if not impossible to extrapolate to everyday practice.As if the problems with meta-analysis were not already bad enough. And, did I mention fraud and bias …?
What logical thinker can rely on, or even give credence to, guidelines when they are unquestionably tainted with confected science? I suggest it is appropriate to grow up, learn to think for yourself, avoid being a slave to guidelines, and think outside the square.Good clinical science ought not to play second-fiddle to randomised controlled trials.
1. Gillman, PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol, 2007. 151(6): p. 737-48.
2. Lewontin, RC, Biology as Ideology. The Doctrine of DNA. 1991: HarperCollins.
3. Izzati-Zade, KF, The role of serotonin in the pathogenesis and clinical presentations of migraine attacks. Neurosci. Behav. Physiol., 2008. 38(5): p. 501-5.
4. Borgdorff, P and Tangelder, GJ, Migraine: possible role of shear-induced platelet aggregation with serotonin release. Headache, 2012. 52(8): p. 1298-318.
5. Lance, J, 5-Hydroxytryptamine and its role in migraine. Eur. Neurol., 1991. 31(5): p. 279-281.
6. Dalsgaard-Nielsen, J, le Fevre Honore, P, and Zeeberg, I, Changes in platelet function and blood serotonin level in migraine patients during treatment with femoxetine. Acta Neurol. Scand., 1982. 66(2): p. 191-8.
7. Iversen, HK and Olesen, J, Experimental headache, in The headaches., J Olesen, PC Tfelt-Hansen, and K Welch, Editors. 1993, Raven Press: New York. p. 145–151.
8. Partilla, JS, Dempsey, AG, Nagpal, AS, Blough, BE, et al., Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther, 2006. 319(1): p. 237-46.
9. Panconesi, A and Sicuteri, R, Headache induced by serotonergic agonists--a key to the interpretation of migraine pathogenesis? Cephalalgia, 1997. 17(1): p. 3-14.
10. Kimball, RW, Friedman, AP, and Vallejo, E, Effects of Serotonin in Migrainous Patients. Neurology 10:107-111 (Feb) 1960., 1960.
11. Anthony, M, Hinterberger, H, and Lance, JW, Plasma serotonin in migraine and stress. Arch. Neurol., 1967. 16(5): p. 544-52.
12. Ostfeld, AM, Migraine headache: its physiology and biochemistry. JAMA, 1960. 174: p. 1188-90.
13. Deen, M, Christensen, CE, Hougaard, A, Hansen, HD, et al., Serotonergic mechanisms in the migraine brain - a systematic review. Cephalalgia, 2017. 37(3): p. 251-264.
14. Anglin, R, Yuan, Y, Moayyedi, P, Tse, F, et al., Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am. J. Gastroenterol., 2014. 109(6): p. 811-9.
15. Jiang, HY, Chen, HZ, Hu, XJ, Yu, ZH, et al., Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clin Gastroenterol Hepatol, 2015. 13(1): p. 42-50 e3.
16. Laporte, S, Chapelle, C, Caillet, P, Beyens, MN, et al., Bleeding Risk under Selective Serotonin Reuptake Inhibitor (Ssri) Antidepressants: A Meta-Analysis of Observational Studies. Pharmacol. Res., 2016.
17. Roose, SP and Rutherford, BR, Selective Serotonin Reuptake Inhibitors and Operative Bleeding Risk: A Review of the Literature. J Clin Psychopharmacol, 2016. 36(6): p. 704-709.
18. Lingjaerde, O, Inhibition of platelet uptake of serotonin in plasma from patients treated with clomipramine and amitriptyline. Eur. J. Clin. Pharmacol., 1979. 15(5): p. 335-40.
19. Lingjaerde, O, Inhibitory effect of clomipramine and related drugs on serotonin uptake in platelets: more complicated than previously thought. Psychopharmacology, 1979. 61(3): p. 245-9.
20. Baska, D, Why are migraineurs more depressed? A review of the factors contributing to the comorbidity of migraine and depression. Neuropsychopharmacologia Hungarica 2017. XIX. évf. 1. szám, 2017.
21. Stanford, SC, Confusing preclinical (predictive) drug screens with animal ‘models’ of psychiatric disorders, or ‘disorde r-like’ behaviour, is undermining confidence in behavioural neuroscience. J Psychopharmacol, 2017. 31: p. 641-643.
22. Zohar, J, Stahl, S, Moller, HJ, Blier, P, et al., A review of the current nomenclature for psychotropic agents and an introduction to the Neuroscience-based Nomenclature. Eur. Neuropsychopharmacol., 2015. 25(12): p. 2318-25.
23. Nutt, DJ and Blier, P, Neuroscience-based Nomenclature (NbN) for Journal of Psychopharmacology. J Psychopharmacol, 2016. 30(5): p. 413-5.
24. Gillman, PK, Atypical antipsychotics: where is the science, where is the evidence. The Carlat Psychiatry Report, 2013. 11(1): p. 3-5.
25. Richelson, E and Pfenning, M, Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol, 1984. 104(3-4): p. 277-86.
26. Sutherland, HG and Griffiths, LR, Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders. Headache, 2017. 57(4): p. 537-569.
27. Yang, Y, Zhao, H, Heath, AC, Madden, PA, et al., Familial Aggregation of Migraine and Depression: Insights From a Large Australian Twin Sample. Twin Res Hum Genet, 2016. 19(4): p. 312-21.
28. Yang, Y, Zhao, H, Heath, AC, Madden, PA, et al., Shared Genetic Factors Underlie Migraine and Depression. Twin Res Hum Genet, 2016. 19(4): p. 341-50.
29. Ligthart, L, Hottenga, JJ, Lewis, CM, Farmer, AE, et al., Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders. Hum. Genet., 2014. 133(2): p. 173-86.
30. Oedegaard, KJ and Fasmer, OB, Is migraine in unipolar depressed patients a bipolar spectrum trait? J Affect Disord, 2005. 84(2-3): p. 233-42.
31. Angst, J, Sellaro, R, Stassen, HH, and Gamma, A, Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Affect Disord, 2005. 84(2-3): p. 149-57.
32. Breslau, N, Davis, GC, and Andreski, P, Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. Psychiatry Res., 1991. 37(1): p. 11-23.
33. Wang, SJ, Migraine and suicide. Expert Rev Neurother, 2007. 7(9): p. 1069-71.
34. Langohr, HD, Gerber, WD, Koletzki, E, Mayer, K, et al., Clomipramine and metoprolol in migraine prophylaxis--a double-blind crossover study. Headache, 1985. 25(2): p. 107-13.
35. Noone, JF, Clomipramine in the prevention of Migraine. J. Int. Med. Res., 1980. 8: p. s 49-52.
36. Jackson, JL, Shimeall, W, Sessums, L, Dezee, KJ, et al., Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ, 2010. 341: p. c5222.
37. Couch, JR and Hassanein, RS, Amitriptyline in migraine prophylaxis. Arch. Neurol., 1979. 36(11): p. 695-9.
38. Xu, XM, Liu, Y, Dong, MX, Zou, DZ, et al., Tricyclic antidepressants for preventing migraine in adults. Medicine (Baltimore). 2017. 96(22): p. e6989.
39. Gillman, PK, “Much ado about nothing”: Monoamine oxidase inhibitors, drug interactions and dietary tyramine. CNS Spectr, 2017: p. http://dx.doi.org/10.1017/S1092852916000651.
40. Ioannidis, JP, Why most published research findings are false. PLoS Med, 2005. 2(8): p. e124.
41. Smith, GC and Pell, JP, Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ, 2003. 327(7429): p. 1459-61.
42. Anthony, M and Lance, JW, Monoamine oxidase inhibition in the treatment of migraine. Archives of Neurology, 1969. 21: p. 263-268.
43. Corser, B, Guarino, RA, and A, Z, Safety and tolerability of the MAO inhibitor isocarboxazid (Marplan) in the prophylactic treatment of migraine. Cephalalgia, 2009. 29((suppl)): p. 1-166.
44. Merikangas, KR and Merikangas, JR, Combination monoamine oxidase inhibitor and beta-blocker treatment of migraine, with anxiety and depression. Biol Psychiatry, 1995. 38(9): p. 603-10.
45. Dalsgaard-Neilson, A, Migraene-patienter med niamid. Ugeskr Laeg, 1962. 124: p. 10-11.
46. Michelacci, S and Franchi, G, Treatment of Vascular Headaches With Nialamide, a Monoamine Oxidase Inhibitor. Minerva Med 53:1521-1523 (May), 1962.
47. Blumenthal, LS and Fuchs, M, Current Therapy for Headache. Southern Med J 56:503-508 (May) 1963, 1963.
48. Perrault, M, Migraines Severes, I.M.A.O. et Methysergide. Progr Med 91:413-414 (June), 1963.
49. Bindslev, JBB, Schroll, J, Gøtzsche, PC, and Lundh, A, Underreporting of conflicts of interest in clinical practice guidelines: cross sectional study. BMC medical ethics, 2013. 14(1): p. 19.
50. Sniderman, AD, LaChapelle, KJ, Rachon, NA, and Furberg, CD, The necessity for clinical reasoning in the era of evidence-based medicine. Mayo Clin. Proc., 2013. 88(10): p. 1108-14.
51. Bastian, H, Nondisclosure of Financial Interest in Clinical Practice Guideline Development: An Intractable Problem? PLoS Med, 2016. 13(5): p. e1002030.
52. Pringsheim, T, Davenport, W, Mackie, G, Worthington, I, et al., Canadian Headache Society guideline for migraine prophylaxis. Can. J. Neurol. Sci., 2012. 39(2 Suppl 2): p. S1-59.
53. Silberstein, SD, Holland, S, Freitag, F, Dodick, DW, et al., Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology, 2012. 78(17): p. 1337-45.
54. Mauskop, A and Varughese, J, Why all migraine patients should be treated with magnesium. J Neural Transm (Vienna), 2012. 119(5): p. 575-9.
55. Ismail, AA, Ismail, Y, and Ismail, AA, Clinical assessment of magnesium status in the adult: an overview, in Magnesium in Human Health and Disease. 2013, Springer. p. 3-34.
56. Sun-Edelstein, C and Mauskop, A, Foods and supplements in the management of migraine headaches. Clin. J. Pain, 2009. 25(5): p. 446-52.
57. Bilbey, DL and Prabhakaran, VM, Muscle cramps and magnesium deficiency: case reports. Can. Fam. Physician, 1996. 42: p. 1348-51.