Abstract
Food intolerance (FI) is defined as any abnormal reaction to food that is not immunologically mediated [1], so that it excludes food allergies such as IgE-mediated reactions that are most commonly observed in young children with an atopic diathesis [2]. Pharmacological FI involves adverse reactions to specific chemicals (natural or artificial) contained in foods, with individuals sometimes also reacting to fumes from products such as perfumes and household cleaning chemicals. Symptoms can involve the skin (e.g. urticaria, eczema), gastrointestinal tract (e.g. irritable bowel symptoms), upper respiratory tract (e.g. sinusitis, asthma) or the central nervous system (e.g. migraines, dizziness, fatigue, myalgia, depression). While formal epidemiological studies are lacking, some 5–10% of the population are estimated to have significant symptoms at some time [2]. Both the extent to which FI may cause or worsen depression, and its prevalence in those with typical and atypical depressive conditions, remain unestablished. As FI is rarely considered in the assessment of those with depression – even treatment-resistant depression – a case vignette is informative.
Patient history
A 25-year-old university graduate was referred with chronic dysthymic and anxiety symptoms present for 5 years, and non-responsive to cognitive behaviour therapy and a range of psychotropic drugs, including a tricyclic (doxepin), SSRIs (paroxetine and sertraline), a reversible monoamine oxidase inhibitor (moclobemide), nefazodone and buspirone. The referring psychiatrist noted the patient's vast knowledge regarding depression and its treatments, and his relentless pursuit of biological treatments, judging that referral to a specialist unit might persuade him from ‘his perpetual quest for the ideal treatment’.
History established social phobia, generalized anxiety, panic attacks and obsessive–compulsive disorder (principally manifested in checking compulsions) since childhood. His childhood was without trauma and he grew up in a stable and caring family. In his late teens, a general feeling of malaise developed and his generalized anxiety features heightened.
He experienced a clear-cut 4-week depressive episode in his early twenties. Prior and subsequent transient depressive episodes usually lasted only hours, but were judged as extremely severe, marked by anhedonia, a sense of futility, a partially non-reactive mood and suicidal ideation. While most antidepressants trialled previously and subsequently were associated with decreased anxiety, their taking was also associated with nausea and light-headedness, and commonly, a worsening in the depressed mood, usually commencing after about 2 days and with lower than recommended dosages.
Concomitant disorders included long-standing hypotension, Gilbert's syndrome (idiopathic unconjugated hyperbilirubinemia), attention deficit disorder (without hyperactivity) and motor tics (dating from mid-childhood and commencing with hair flicking), with both salt and tomatoes recognized as worsening his tics. At 21, he eliminated wheat products from his diet and noted a reduction in panic attacks and malaise, with benefits enhanced by exclusion of milk and tomato products.
Following referral, a number of additional psychotropic drugs were trialled at his request, including alprazolam, lorazepam, phenelzine, citalopram, fluvoxamine, venlafaxine, lithium and sodium valproate, as well as self-prescribed hypericum, inositol and 5-hydroxytryptophan (5HTP). Re-emergence of panic disorder with agoraphobia resulted in his inability to continue in a highly-paid consultancy position.
The pattern of rapid mood variability, resistance to antidepressant medication and sensitivity to low-dose psychotropic medication encouraged review of his Gilbert's syndrome by a specialist clinical pharmacologist, who noted that the latter was associated with reduced clearance of numerous drugs and raised platelet serotonin levels, but judged that pharmacokinetic issues did not explain the reported phenomena.
At 27, previously mild symptoms gradually worsened though varied in severity. These included gastrointestinal symptoms (constipation, diarrhoea, abdominal pains, excessive flatulence), nausea, dyspnoea, restlessness, varying energy levels including significant fatigue, myalgia and lightheadedness.
He was referred to an allergy specialist, who initiated a stringent elimination diet developed at Royal Prince Alfred Hospital, Sydney. After 4 weeks, his mood and other symptoms improved significantly, being sustained over the next month. He then commenced routine double-blind placebo capsule testing of suspect chemicals. Within a few days of taking the first (of 12) capsules, his mood and other symptoms worsened considerably. As his mood failed to return to pretest status within a week, the blind was broken and the capsule identified as containing acetylsalicylic acid – with natural salicylates being the chemicals most commonly implicated in causing adverse food reactions [2]. Because of the severity of this reaction, no more high-dose capsule challenges were undertaken, although subsequent open challenges with some foods identified high sensitivity to most chemicals implicated in food intolerance. Recommencement of the full elimination diet resulted again in a progressive improvement in mood and other symptoms and, over the next year (and till the current review) he has remained relatively symptom free, with residual symptoms either transient or mild, while he returned to full-time employment. Since adopting the diet he has occasionally trialled foods with slightly higher levels of relevant chemicals. Symptoms experienced, in rough order of frequency and likelihood, are: nausea, fatigue, depression, flatulence, constipation and diarrhoea, lightheadedness, anxiety and myalgia. There has been no worsening in his obsessive–compulsive disorder symptoms.
A subsequent review of family history established that his paternal grandfather had been on a modified diet for some 50 years (for unknown symptoms) and that his mother and two of her brothers had significant bowel symptoms that responded to dietary modification. No family members had trialled a full elimination diet.
Discussion
Natural and artificial chemicals recognized as provokers of symptoms in sensitive individuals include amines (e.g. tyramine), salicylates (e.g. aspirin), glutamate (MSG), certain food dyes and preservatives [2]. Well-recognized examples of food chemical-induced symptoms include migraines from eating chocolate [3] and salicylateinduced asthma from ingesting aspirin [4].
Depression, including severe expressions, has been noted previously as a symptom in some FI individuals [2, 5, 6]. However, unlike clinical ‘major depression’, the mood state tends to be transient and intermittent, and is rarely experienced alone, with FI symptoms usually reflected across a broad range.
As with other conditions where the feature pattern is often nebulous, FI is commonly mistaken as a manifestation of psychiatric or personality disorder. Such judgements are more likely if testing is for immunological food allergy alone [7], an elimination diet is not trialled before challenging, if elimination diets containing significant amounts of chemicals shown to be associated with symptoms (such as salicylates) are not employed [8], or if the possibility that reactions to foods can be delayed for days [2] is not recognized. Elimination diets are generally dimensionally based, so that a prototypic diet is provided to patients with the suggestion that those who have severe symptoms should adhere to it strictly, so eliminating all foods other than those with the lowest amounts of problematic chemicals. For those with less severe symptomatology, moderate adherence may be recommended; the dilemma here is that failure to improve does not then exclude the diagnostic possibility, and thus a stricter application may then need to be taken up. Such diets are available to medical practitioners and dietitians but generally are not provided to the general public, with the belief that dietary changes are best pursued under professional supervision.
One possible mechanism for explaining the diverse clinical symptoms is a disorder of neuroregulation [9]. Recognizing the common delay in symptom appearance and pharmacological features (e.g. dose dependence, cumulative and withdrawal effects, tachyphylaxis and variable tolerance), reactions may reflect abnormalities in receptor functioning or second messenger systems. This could also explain why FI individuals are more susceptible to adverse reactions when taking psychotropic drugs, both via the active drug as well as the colours and preservatives in the capsules or tablets. Nevertheless, heterogeneity in FI individuals argues against the likelihood of a single underlying mechanism.
At our tertiary referral Mood Disorders Unit we have identified several FI individuals (referred for treatment resistance), usually by a history of intolerance to low doses of multiple antidepressant drugs, their transient mood states and their response to elimination diets. We have no prevalence data, however, and suspect that the diagnosis is more commonly missed or not considered, particularly for patients whose depression is less severe and who provide vague histories – and who thus test the tolerance of their doctor. The present case is presented in some detail to alert clinicians to the possibility.
We propose to pursue the issue by studying those presenting to an allergy unit and completing elimination diets and challenge procedures, both in terms of lifetime and state depression levels. This will allow prevalence data on depression to be derived as well as assessment of the impact of successful (and unsuccessful) interventions on depression levels and episodes. In addition, as brain receptors for relevant amines have recently been identified [10], it may well be feasible to pursue the utility of genetic analyses.
While our patient was indirectly criticized by the referring psychiatrist for ‘relentlessly pursuing biological treatments’, we have no doubt that his tenacity and observant capacity to provide a detailed history brought the diagnostic possibility slowly to clarification. Thus, intolerance to antidepressant medication may be a marker of a food intolerance syndrome.
Footnotes
Acknowledgements
Supported by a National Health and Medical Research Council Program Grant (993208) and infrastructure grant from the NSW Department of Health. We thank Robert H. Loblay, Anne R. Swain, Kerrie Eyers and the Mood Disorders Unit staff for helpful advice.