Topic of the Month

Micronutrients and mental illnesses

February 1, 2015

An increasing number of studies indicate that nutrition may play a role in the onset and treatment of mental illnesses such as depression, anxiety, and schizophrenia. Further, more recent evidence on brain metabolism suggests that nutritional habits or deficiencies of certain micronutrients can influence the development and progression of mental illnesses. A targeted intake of individual micronutrients appears to have prophylactic or therapeutic effects on certain mental illnesses. Conversely, mental illnesses such as ADHS, alcohol dependency, and eating disorders can lead to a deficiency of certain vitamins and micronutrients. Even if the evidence for dietary supplements in the treatment of mental illnesses is not sufficient to issue general recommendations, data from observational and randomized controlled studies suggest that their use appears to be practical given certain indicators.

file

For example, epidemiological studies have shown that there is a link between a low intake of polyunsaturated fatty acids and the onset of schizophrenia and depression. Intervention studies have demonstrated that a targeted intake of omega-3 fatty acids has a positive effect on these illnesses, even if this is only minimal. Likewise, folic acid appears to have antidepressant properties, while vitamin B6 can reduce the side effects of antipsychotics. A targeted intake of zinc may be useful in attention deficit hyperactivity disorder (ADHD). Certain nutritional styles such as the Mediterranean diet, consisting of lots of fish, olive oil, fruit and vegetables, can also have a protective effect against mental illnesses such as depression or dementia. Ideally, drug therapy should be complemented with nutrition advice, an exercise program, and cognitive behavioral therapy.

Vitamins

Vitamin B1 (thiamine) is essential for the function of the nervous system. Thiamine deficiency causes beriberi disease, typical symptoms of which include fatigue, lethargy, and heart, circulation, nerve, and muscle disorders. Thiamine deficiency is also the cause of memory impairment and degenerative brain disease (Wernicke-Korsakoff syndrome) in alcohol-dependent patients. This realization has led to the routine use of intramuscular and oral thiamine in the treatment of alcohol dependency (1).

While there are some indications that vitamin B6 (pyridoxine) helps combat depression among pre-menopausal women, it has not yet been found to have overall effectiveness in the treatment of depression, even if cross-sectional studies have shown an association between depression and low serum vitamin B6 concentrations (2). However, vitamin B6 does appear to be effective in treating certain movement disorders (tardive dyskinesia) that can develop as a possible consequence of lengthy use of antipsychotics. In a 26-week clinical study, inpatients suffering from schizophrenia or schizo-effective disorder and tardive dyskenesia were treated either with vitamin B6 (1200 mg/day) or a placebo. It was shown that vitamin B6 resulted in a significantly greater reduction in dyskenesia among patients compared to the placebo (3).

Numerous studies have indicated a link between folic acid deficiency and mental illnesses (4). Low serum concentrations of folic acid have been found in particular among untreated depressed patients, as well as depressed persons treated with antidepressants who did not achieve significant improvement (5). Despite multiple reports on the link between folic acid deficiency and depression, very few clinical studies have investigated the effect of treating depression with folic acid alone. Most studies in this area have used multivitamin preparations containing folic acid. To date a total of 12 clinical studies investigating folic acid or the biologically active form of folate methyltetrahydrofolate (5-MTHF) as a stand-alone treatment or as a concomitant treatment for depressed patients have been published, all of which report either of an antidepressant superiority compared to a placebo or of an effect comparable to an antidepressant (6). The treatment dose of folic acid in these studies was between 200 μg/day and 50 mg/day. All in all, treatment with a daily dose of around 400 μg folic acid/day or 50 mg 5-MTHF/day in addition to an antidepressant (serotonin reuptake inhibitor) appears to be most appropriate.

Folic acid and vitamin B12 deficiency are frequently found in the elderly. A lack of these two vitamins has been linked to an increase in plasma concentrations of homocysteine (tHcy) and a reduction in cognitive performance (7). It is assumed that high homocysteine levels cause damage to the vessels and nerve cells, and can therefore contribute to the development of dementia. Most studies on the targeted intake of folic acid for prophylaxis or treating dementia have investigated a combination of folic acid, vitamin B6, and vitamin B12. Even if such a combination therapy has been effective in reducing tHcy values, the study results have yielded an uneven picture regarding the effect of folic acid on mental and sensorimotor functions. Patients with mild cognitive impairment (MCI) and mild forms of Alzheimer’s dementia appear to benefit most from such a combination therapy (6). Vitamin B12 deficiency has also been described in the context of various other mental illnesses, such as depression, bipolar disorder, panic disorder, schizophrenia, and phobias (8). Even though studies show, for example, that low plasma levels of vitamin B12 are associated with depressive symptoms (9), or that high vitamin B12 levels correlate with greater treatment success (10), a 2-year randomized controlled study has shown that administering vitamin B12 has no effect on the severity and frequency of depressive symptoms (11).

A deficiency of vitamin D during brain development could contribute causally to the later development of schizophrenia or autism spectrum disorder. In pre-clinical studies, vitamin D deficiency led to a change in the differentiation of nerve cells, the connection strength between individual nerve cells (connectivity), and the function of nerve cell systems that produce and use dopamine as neurotransmitters (2). In a study of 104 youths suffering from severe mental illnesses, 34% exhibited vitamin D deficiency (12). A cross-sectional study of over 12,500 primary care adults showed that higher vitamin D values are associated with a significantly reduced risk of depression (13). A few small clinical studies have shown positive effects of vitamin D in the treatment of depression. However, current scientific evidence is not sufficient to justify administering vitamin D to all depressed patients. That said, there are indications that vitamin D could be useful for winter depression (seasonal affective disorder) (14), for youths lacking regular outdoor exercise (2), and for older people over the age of 65. A higher intake of vitamin D also appears to be associated with a reduced risk of Alzheimer's disease and dementia (15).

Omega-3 fatty acids

In recent years, extensive research has been carried out investigating the possible role of omega-3 fatty acids in prophylaxis and the treatment of mental illnesses – particularly unipolar depression and the transition between depression and mania (bipolar disorder). The two most frequently investigated omega-3 fatty acids have been eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are mainly found in fish and fish products. Hypotheses on the mechanism of action of omega-3 fatty acids range from the influence of membrane -bound receptors and modulation of signal transmission by neurotransmitters (serotonin, noradrenaline, and dopamine), through the impact of membrane fluidity and stability, to the regulation of calcium influx into the nerve cells (16). In depression, immunological processes such as an increased production of pro-inflammatory protein molecules (cytokines) (17) appear to play a major role (18). The administration of omega-3 fatty acids may diminish these inflammatory processes and thus have an antidepressant effect (16).

A systematic review of all traditional diets found a reduced onset of depression – particularly for the Norwegian (primarily fish and game, e.g., poultry) and Mediterranean diet (mainly vegetables, salad, fruit, fish, garlic, olive oil, and a daily glass of red wine) (19). In another review, the Mediterranean diet was also shown to have an effect against Alzheimer’s dementia (20). Equally preventive against dementia, according to this review, are a regular intake of fish and unsaturated fatty acids, social activities, and cognitive training.

More than 30 randomized controlled trials (RCT) investigating EPA, DHA, or both suggest that EPA in particular has antidepressant and mood-stabilizing effects. A meta-analysis taking the results of 15 prospective RCTs into account, with a total of 916 study participants, investigated whether EPA is the key antidepressant-like active component among omega-3 fatty acids (21). The study results showed a clear advantage when more than 60% EPA was used within the omega-3 fatty acid compound. A nutritional supplement of omega-3 fatty acids containing less than 60% EPA was ineffective. The effective dose range of EPA in this meta-analysis was between 200 and 2200 mg/day. In patients with bipolar disorder, omega-3 fatty acids appear to be more effective during depressive rather than manic episodes (16, 22). Smaller studies have investigated the effect of omega-3 fatty acids in other mental illnesses such as borderline personality disorder, schizophrenia, ADHD, compulsive disorders, and Tourette’s syndrome, but these have produced inconsistent and somewhat conflicting results (16).

Trace elements

Iron plays a significant role in energy production, the synthesis of DNA and neurotransmitters, the sheathing of nerve cell extensions by membranes (myelination), and the metabolism of phospholipids (2). Iron deficiency frequently occurs in movement disorders such as restless legs syndrome (RLS). The diagnosis of RLS caused by iron deficiency is easily overlooked as leg movements can be falsely interpreted as signs of hyperactivity, particularly in children with attention deficit hyperactivity disorder (ADHD). Iron deficiency is often found in children with ADHD (23). The results of studies on the targeted intake of iron as a treatment for RLS have proven to be inconsistent. Iron appears to be particularly effective against RLS in cases where the iron deficiency was proven by lower ferritin levels (24). It appears to be similar for ADHD, as an RCT on children with low serum concentrations of ferritin showed that iron supplementation at a dose of 80 mg/day led to a reduction of ADHD symptoms (25). As a consequence of anorexia, iron deficiency frequently occurs with anemia. This may indicate the need for an iron supplement (26).

Zinc is important for immune regulation, energy metabolism, and insulin storage, influencing protein synthesis, DNA transcription, and the metabolism of nerve modulators and neurotransmitters (2). Several studies indicate a link between zinc balance and mental illnesses involving extreme mood and drive-related symptoms (affective disorders). A systematic review identified four randomized controlled studies (RCT) investigating depressed patients (27). In two of these studies, zinc was shown to have a strong positive effect compared to a placebo when administered in combination with an antidepressant at a dose of 7–25 mg/day. The two other studies were prevention studies on mentally healthy subjects and found no effect on the mental health of the subjects or in relation to preventing the onset of depression. Zinc may also play a role in ADHD: In two RCTs where zinc was administered either as a stand-alone treatment or as a concomitant treatment at a dose of 15–150 mg/day, it was shown to significantly reduce hyperactivity and impulsiveness, but not attention deficit disorder (28). Likewise for dementia and sexual dysfunction, studies on zinc have not, as a whole, produced clear results (2).

Copper is necessary for the synthesis of dopamine and noradrenaline (2). A study has shown that around 23% of children with ADHD exhibit copper deficiency (29). Based on current evidence, however, the question as to whether copper may in future play a role in the treatment of ADHD cannot be answered.

References

  1. Hinze-Selch D. et al. Thiamine treatment in psychiatry and neurology. Fortschr Neurol Psychiatr. 2000; 68:113-120.
  2. Akhondzadeh S. et al. Nutrients for prevention and treatment of mental health disorders. Psychiatr Clin North Am. 2013; 36:25-36. 
  3. Lerner V. et al. Vitamin B6 treatment for tardive dyskinesia: a randomized, double-blind, placebo-controlled, crossover study. J Clin Psychiatry. 2007; 68:1648-1654.
  4. Crellin R. et al. Folates and psychiatric disorders: clinical potential. Drugs. 1993; 45:623-636.
  5. Morris M. S. et al. Depression and folate status in the US Population. Psychother Psychosom. 2003; 72:80-87.
  6. Bottiglieri T. Folate, vitamin B12, and S-adenosylmethionine. Psychiatr Clin North Am. 2013; 36:1-13.
  7. Clarke R. et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1988; 55:1449-1455.
  8. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006; 5:949-960.
  9. Ng T. P. et al Folate, vitamin B12, homocysteine, and depressive symptoms in a population sample of older Chinese adults. J Am Geriatr Soc. 2009; 57:871-876.
  10. Hintikka J. et al. High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry. 2003; 3:17.
  11. Ford A. H. et al. Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year, placebo-controlled, randomized trial. J Clin Psychiatry. 2008; 69:1203-1209.
  12. Gracious B. L. et al. Vitamin D deficiency and psychotic features in mentally ill adolescents: a cross-sectional study. BMC Psychiatry. 2012; 12:38 PM.
  13. Hoang M. T. et al. Association between low serum 25-hydroxyvitamin D and depression in a large sample of healthy adults: the Cooper Center longitudinal study. Mayo Clin Proc. 2011; 86:1050-1055.
  14. Dumville J. C. et al. Can vitamin D supplementation prevent winter-time blues? A randomised trial among older women. J Nutr Health Aging. 2006; 10:151-153.
  15. Annweiler C. et al. Higher vitamin D dietary intake is associated with lower risk of Alzheimer’s disease: a 7-year follow-up. J Gerontol A Biol Sci Med Sci. 2012; 67:1205-1211.
  16. Mischoulon D. and Freeman M. P. Omega-3 Fatty Acids in Psychiatry. Psychiatr Clin North Am. 2013; 36:15-23.
  17. Schmidt F. M. et al. Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity. J Psychiatr Res. 2014; 55:29–34.
  18. Lichtblau N. et al. Cytokines as biomarkers in depressive disorder: current standing and prospects. Int Rev Psychiatry. 2013; 25:592-603.
  19. Quirk S. E. et al. The association between diet quality, dietary patterns and depression in adults: a systematic review. BMC Psychiatry. 2013; 13:175.
  20. Weih M. et al. Non-pharmacologic prevention of Alzheimer’s disease: nutritional and life-style risk factors. J Neural Transm. 2007; 114:1187-1197.
  21. Sublette M. E. et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011; 72:1577-1584.
  22. Sarris J. et al. Omega-3 for bipolar disorder: metaanalyses of use in mania and bipolar depression. J Clin Psychiatry. 2012; 73:81-86.
  23. Konofal E. et al. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2004; 158:1113-1115.
  24.  Hornyak M. et al. Investigating the response to intravenous iron in restless legs syndrome: an observational study. Sleep Med. 2012; 13:732-735.
  25. Konofal E. et al. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008; 38:20-26.
  26. Himmerich H. et al. Laboratory parameters and appetite regulators in patients with anorexia nervosa. J Psychiatr Pract. 2010; 16:82-92.
  27. Lai J. et al. The efficacy of zinc supplementation in depression: systematic review of randomised controlled trials. J Affect Disord. 2012; 136:31-39.
  28. Akhondzadeh S. et al. Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial [ISRCTN64132371]. BMC Psychiatry. 2004; 4:9.
  29. Kiddie J. Y. et al. Nutritional status of children with attention deficit hyperactivity disorder: a pilot study. Int J Pediatr. 2010:767318.