by Matthew Hogg BSc (Hons)
(Originally written as coursework for a bachelor's degree in nutritional health as an academic component of Nutritional Therapist training - the contents and conclusions should be discussed with your doctor or other medical practitioner)
Depression is highly prevalent, affecting approximately 121 million worldwide; it is also the leading cause of disability and the fourth leading contributor to the global burden of disease as of the year 2000 (World Health Organization (WHO) 2010). As such, depression has a significant impact on society, affecting personal relationships and representing a burden to medical systems whilst adversely affecting economies due to lost working days. This aside from the devastating effects it has on sufferers as they struggle with symptoms including low mood, anhedonia, lack of motivation, inappropriate feelings of guilt or low self-worth and physical fatigue (WHO 2010). Conventional medicine typically treats depression using pharmaceuticals and talking therapies such as counselling and cognitive behavioural therapy (CBT) but recent research has cast doubt on the effectiveness of this approach, particularly the efficacy of selective serotonin-reuptake inhibitors (SSRIs), the most commonly prescribed class of antidepressant drugs, in mild to moderate depression (Fournier et al 2010, Kirsch et al 2008). This essay seeks to determine if Nutritional Therapy may provide effective alternative or adjunctive treatments to conventional care and offer preventative options for depression through critical appraisal of the evidence base. Focus will be placed on the role of neurotransmitters and methylation in depression since a firm theoretical basis suggests deficits in these areas might be amenable to nutritional intervention. Due to word constraints the discussion will be limited to amino acid neurotransmitter precursors and folate, vitamin B12 and S-adenosylmethionine (SAMe) as the major nutrients involved in methylation.
Aetiology and Pathophysiology of Depression
The aetiology of depression was long thought to hinge on the monoamine hypothesis which supposes the condition is caused by absolute or functional deficiencies in monoamine neurotransmitters, particularly serotonin and noradrenaline (Bear et al 2001:687). Another monoamine, dopamine, is also concentrated in regions of the brain associated with mood (Institute for Functional Medicine (IFM) 2005:639) and has been linked to depression (Dailly et al 2004). These neurotransmitters are integral to the transmission of nerve impulses; they are secreted into the synaptic cleft by pre-synaptic neurons upon the arrival of a nerve impulse and trigger a continuation of the impulse in post-synaptic neurons following binding of sufficient quantities to plasma membrane receptors which open ion channels, ultimately resulting in the establishment of a postsynaptic potential (Tortora & Derrickson 2009:441). The monoamine hypothesis postulates that insufficient serotonergic, noradrenergic and dopaminergic neurotransmission in certain emotional and behavioural centres of the brain including the limbic system results in the symptoms of depression. Recent biochemical studies have demonstrated that modulation of neural activity by monoamine neurotransmitters, rather than individual monoamines themselves, represent a significant piece in the aetiological puzzle of depression (Licinio & Wong 2005:72). [Nutritional interventions discussed in the body of the paper below.]
Another factor thought to play a substantial role in depressive pathophysiology is neuroendocrine dysfunction with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity being central (Pariante & Lightman 2008). Elevated blood cortisol levels are present in the majority of depressed patients with increased corticotropin-releasing factor (CRF) stimulation of adrenocorticotropic hormone (ACTH) secretion and blunted glucocorticoid receptor (GR) mediated negative feedback regulation among the contributing factors (Thomson & Craighead 2008). Chronically elevated cortisol levels are associated with neuronal degeneration which likely disturbs mood (Bear et al 2001:506). It may however be hypersecretion of the upstream hormone CRF that is responsible for the behavioural changes seen in depressive disorders (Bear et al 2001:691). Either way, a hyperactive HPA axis provides a biochemical explanation for the clinical connection seen between psychological stress and depression. [Nutritional interventions of potential benefit include vitamin C, pantothenic acid (vitamin B5), DHEA and adaptogenic herbs e.g. ginseng, rhodiola etc.]
Depression is also seen as an inflammatory condition. Cross-sectional studies have found elevated concentrations of pro-inflammatory cytokines such as interleukin-6 (IL-6) and C-reactive protein (CRP) (Stewart et al 2009). Whether inflammatory processes cause depression or are a consequence remains unclear. It is plausible elevated levels of pro-inflammatory cytokines bind to receptors in the brain and induce chronic sickness behaviour and symptoms characteristic of depression (Dantzer et al 2008) but a recent longitudinal study found increases in depression scores preceded increases in IL-6 and CRP suggesting depression triggers inflammation rather than the reverse (Stewart et al 2009). [Nutritional interventions of potential benefit include antioxidants and omega-3 fatty acids (specifically EPA).]
Finally, contemporary research has implicated a number of other factors including impaired ATP production due to mitochondrial dysfunction (Gardner & Boles 2008) [nutritional interventions of potential benefit include magnesium, zinc, iron, B vitamins, NADH, D-ribose and balancing blood glucose] and elevated levels of homocysteine (Almeida et al 2008, Folstein et al 2007) - the latter will be discussed in the context of nutritional therapy and methylation.
Theoretical Role of Nutritional Therapy in Neurotransmitter Metabolism, Methylation and Depression
Although more than 50 molecules that act as neurotransmitters in the brain and central nervous system (CNS) have been discovered the monoamines are still generally considered most important in neuropsychiatric conditions, including depression (Belmaker & Agam 2008, IFM 2005:638), with arguably the strongest connection to nutrition. The major building blocks of monoamine neurotransmitters are amino acids; serotonin being synthesised from L-tryptophan (IFM 2005:639) and noradrenaline and dopamine from L-tyrosine (Lake 2006:164). The biochemical reactions that lead from amino acid to monoamine neurotransmitter are catalysed by enzymes requiring various micronutrients as cofactors with niacin, pyridoxine, folate and vitamins C and D along with minerals including magnesium and copper being of vital importance (Allocca 2007:7-17, Garcion et al 2002). Production of neurotransmitters is also dependent upon the bodys ability to efficiently perform methylation reactions (Bottiglieri et al 2000).
The process of methylation involves the transfer of methyl (CH4) groups from methyl donors to acceptor molecules to form new chemical compounds. In the body the methylation cycle requires folate as the principal methyl donor and vitamin B12 as a cofactor to produce the amino acid methionine which is the immediate precursor of SAMe (Bottiglieri et al 2000) the major methyl donor in the brain (Crellin et al 1993, Reynolds et al 1984). Methylation is required for both the synthesis of monoamine neurotransmitters (Alpert et al 2008, Bottiglieri et al 2000) and the function of postsynaptic receptors due to its role in lipid metabolism and associated effects on neuronal membranes (Alpert et al 2008, IFM 2005:641); methylation deficits may thus contribute to depression by impairing monoaminergic neurotransmission. Inadequate methylation cycle function due to folate and/or vitamin B12 deficiency also results in accumulation of the toxic intermediate homocysteine and this too is a possible causal factor in depression (Almeida et al 2008, Folstein et al 2007).
Neurotransmitter metabolism and the associated methylation cycle are obvious targets for nutritional intervention in depression due to their reliance on nutrient substrates. Whether the application of Nutritional Therapy in these areas can effectively prevent and/or treat depression requires a review of the contemporary literature.
Practical Application of Nutritional Therapy in Depression
Amino Acid Precursors
The rate-limiting enzyme in the conversion of L-tryptophan to serotonin (tryptophan hydroxylase) is relatively unsaturated compared to the equivalent enzyme (tyrosine hydroxylase) that synthesises dopamine and noradrenaline from L-tyrosine (IFM 2005:639). The implication being that dietary and supplemental L-tryptophan is likely to have much greater influence on serotonin and depressive symptoms than L-tyrosine on its monoamine products and associated depression.
The literature reveals extensive study of the association between L-tryptophan depletion (TD) and depression; highly consistent associations between TD, decreased central serotonin (usually measured in cerebrospinal fluid (CSF)) and depression, particularly in people with personal or familial history of depression are evident (Moreno et al 2010, Evers et al 2009, Spring et al 2007). Individually the studies are small, perhaps due to difficulties in ensuring compliance to a TD diet with large numbers of participants, but taken as a whole they make a reasonably compelling case that ensuring people suffering from depression or with a personal or familial history are L-tryptophan-replete could be an important aspect of both treatment and relapse prevention. An important observation for Nutritional Therapists when dealing with clients with depression is that smoking appears to enhance the depressive effects of TD (Spring et al 2007).
Studies investigating L-tyrosine depletion in relation to depression are less numerous than those with L-tryptophan. Studies involving healthy individuals have had mixed results with some suggesting detrimental effects on mood (McLean et al 2004, Grevet et al 2002) while others failed to find any effect on mood or behaviour (Lythe et al 2005). All these studies were very small, limiting their power to produce statistically significant findings. In those with a history of depression, unlike with the L-tryptophan studies there appears to be no significant effect on mood and participants did not relapse despite randomised-controlled trials with crossover being employed, albeit again with limited numbers (McTavish et al 2005, Roiser et al 2005).
Epidemiological studies looking at the correlation between dietary L-tryptophan intakes and depression are surprisingly scarce. One study looking at 42 industrialised nations found countries with lower estimated average L-tryptophan intakes had higher suicide rates (Voracek & Tran 2007); the researchers controlled for factors such as wealth and alcohol intake, increasing validity. Despite the paucity of dietary intervention studies the strong association between L-tryptophan deficiency and depression in those predisposed to the condition and the fact that L-tryptophan is the least abundant amino acid in the diet (Stargrove et al 2008) provide rationale for Nutritional Therapists to ensure such clients are L-tryptophan replete by recommending foods including poultry, fish, meat, eggs and nuts (Stargrove et al 2008). Paradoxically, high carbohydrate meals/snacks may increase brain L-tryptophan and serotonin concentrations more than protein-rich equivalents since the action of insulin removes competing large neutral amino acids (LNAA) from the bloodstream to a greater degree than it does L-tryptophan leaving more available to the brain (Wurtman et al 2003). Recommending high carbohydrate intake would likely be considered counter-productive in the long-term however due to the negative effects of hyperinsulinaemia and resulting reactive hypoglycaemia on mood (McAulay et al 2001, Strachan et al 2000).
Compared to dietary intervention, there exists a somewhat greater body of research regarding the use of supplemental L-tryptophan and its metabolite and immediate serotonin precursor 5-hydroxytryptophan (5-HTP). The most recent Cochrane review (Shaw et al 2002) concluded both L-tryptophan and 5-HTP were more effective than placebo but high quality studies were lacking. RCTs incorporating frontline antidepressant medication comparison groups as well as placebo have produced promising results with both L-tryptophan (Honoré et al 1982, Thomson et al 1982) and 5-HTP (200-300mg/d) (Poldinger et al 1991, van Praag 1979) proving at least as effective as conventional medications. However, there is a lack of contemporary research and all of these studies were small. A review of double-blind, placebo-controlled trials of 5-HTP supplementation for depression by Birdsall (1998) found the sum total of participants was only 161; it is therefore hard to argue with the conclusions of Shaw et al (2002). All things considered, Nutritional Therapists may wish to consider 5-HTP supplementation in particular, perhaps when other interventions fail, but must be aware the evidence base is currently weak.
Fernstrom and Fernstrom (2007) report dietary L-tyrosine affects rate of catecholamine synthesis by activated neurons in the brain but given the abundance of L-tyrosine in the diet (Stargrove et al 2008), an adequate protein intake should provide sufficient amounts. Evidence supporting the use of supplemental L-tyrosine for depression is even weaker than for serotonin precursors. In a case report a depressed woman reported significant improvement in symptoms during L-tyrosine treatment and relapsed when placebo was substituted (Gelenberg et al 1980); such reports do not constitute robust evidence however. A subsequent double-blind, placebo-controlled trial found no evidence of an antidepressant effect with a sample size of 65 (Gelenberg et al 1990). No firm conclusions can be drawn regarding L-tyrosine supplementation given the lack of studies but no side-effects have been observed (Gelenberg et al 1990) so therapeutic trials in treatment-resistant clients may be warranted.
Substantial evidence from population, case-control and cross-sectional studies suggest poor dietary folate intake and correspondingly low folate status is associated with depression after controlling for confounding factors (Gilbody et al 2007). This evidence comes mainly from Western countries but in a cross-sectional study of the Japanese population aged 21-67 years researchers looked at associations between folate, other B vitamin and essential fatty acid (EFA) intakes and found only low folate to be associated with increased prevalence of depressive symptoms, at least in men. In a recent cross-sectional study of older Chinese serum folate concentrations were lower in individuals with depression (mean = 21.5 nmol/L) compared to those without (24.0 nmol/L) (Ng et al 2009); a linear relationship between serum folate concentration and depressive symptoms independent of homocysteine levels suggests the role of folate as a cofactor in neurotransmitter synthesis is an important mediator in depression. However, a large population study found it was elevated homocysteine (≥15.0 μmol/L or 2.02 mg/dL) along with a single nucleotide polymorphism (SNP) associated with impaired methylation that were significantly related to depression rather than folate status alone (Bjelland et al 2003). Measurement of plasma rather than serum folate concentrations in the latter study may account for the contrary findings but in practice the biochemical mechanisms are likely to be less important than therapeutic outcomes. Given the quantity and quality of the evidence base linking low folate intakes and status to depression it would seem remiss of Nutritional Therapists not to recommend consumption of a diet high in folate rich foods including legumes, nuts and seeds, okra and asparagus (Whitney et al 2002:327).
Supplemental folate is considered to have greater bioavailability than food sources (Whitney et al 2002:324) and Coppen and Bolander-Gouaille (2005) suggest 800μg/day may be efficacious. The majority of studies have investigated folate in the context of an augmentation to conventional antidepressant treatment and reviewers have come to positive conclusions but there are questions concerning whether the benefits apply equally to those with low and adequate folate status (Morris et al 2008, Mischoulon & Raab 2007, Taylor et al 2003). In one study folate (500 μg) plus fluoxetine (20mg) was compared to placebo plus fluoxetine (20mg) with the depression scores of the folate-augmented group decreasing to a much greater degree than the fluoxetine-only group (Coppen & Bailey 2000). Sufficient folate to significantly decrease plasma homocysteine concentrations was determined to be an important factor in treatment response (Coppen & Bailey 2000). Given the substantial evidence linking low folate status to depression it is surprising to find a lack of research investigating folate alone as an intervention. Only one such RCT has been conducted using oral methyltetrahydrofolate (50mg/day) and this found the intervention to be ineffective (Passeri et al 2003). However, the choice of folate form, short duration of eight weeks and use of elderly subjects with comorbid dementia make this finding all but irrelevant to the management of depression in Nutritional Therapy practice.
In the context of neurotransmitter metabolism and methylation the main role of vitamin B12 is as a cofactor for the enzyme methionine synthase (MS). In studies looking at both B12 and folate in relation to depression most have found folate to have the greatest correlation with symptoms (Ng et al 2009, Bjelland et al 2003). However, Kim et al (2008) conducted a cross-sectional and prospective study and found serum B12 to be more significantly associated with incidence of depression at follow-up. Reasons for these conflicting results may include method of nutrient status measurement (serum rather than plasma) and differences in study population (e.g. sample size, ethnicity, age). Findings of studies of dietary B12 intakes provide more insight with a large cross-sectional study finding low intakes to be associated with depression in women only (Sánchez-Villegas et al 2009) while prospective studies in the elderly tend to find no association (Skarupski et al 2010, Kamphuis et al 2008). This suggests women may be more susceptible to the effects of inadequate B12 intake on mood than men while it must be recognised that the elderly have poor B12 absorption (Whitney et al 2002:329) and thus variations in dietary intakes have more limited effects on serum/plasma status. Despite the equivocal data on B12 status and intakes and depression, plasma homocysteine is an accurate predictor of the condition (Almeida et al 2008, Folstein et al 2007, Bjelland et al 2003) and B12 is essential to reducing its concentrations through the methylation cycle (Homocysteine Lowering Trialists Collaboration 1998).
Coppen and Bolander-Gouaille (2005) suggest 1mg/day supplemental B12 may improve treatment outcomes in depression. While dietary intakes in the elderly had no effect on depression, supplemental B12 was found to be protective by Skarupski et al (2010) and in an RCT a statistically significant reduction in depressive symptoms was observed (Gariballa & Forster 2007). A cross-sectional study failed to confirm the results of this RCT but the B12 supplements were not standardised; differences in quality and bioavailability likely to have significantly influenced the overall findings (Lin et al 2009). There is an absence of data on the usefulness of B12 supplementation for depression in the general population. Ryan-Harshman and Aldoori (2008) note the difficulties in separating the effects of B12 from those of folate since the two primarily act together in biochemical reactions; they suggest however the ability of B12 to lower homocysteine levels further than folate alone may make it useful in depression treatment.
SAMe is not a dietary component but there is a substantial body of research looking at effects of supplemental SAMe on depression. A number of open label intervention studies with oral SAMe in dosages ranging 400-1600mg/d have all had favourable results with substantial improvement in Hamilton Rating Scale scores (Fava et al 1990, Rosenbaum et al 1990, Rosenbaum et al 1988). RCTs have demonstrated fast acting antidepressant effects (Berlanga et al 1992, Janicak et al 1989) and shown SAMe to be equal or superior to tricyclic antidepressants (TCAs) with lower incidence of adverse reactions (Alpert et al 2008). However in these trials SAMe was administered parenterally due to problems with formulation of oral supplements and questions regarding bioavailability (Alpert et al 2008). Regardless, subsequent RCTs have confirmed the efficacy of oral SAMe, finding it to be superior to placebo at a dose of 1600mg/d (Kagan et al 1990) and comparable to imipramine (De Vanna & Rigamonti 1992). Fava et al (1992) failed to see any benefit of 400mg/d SAMe over placebo during a six week RCT but high degradation rate of oral SAMe (Alpert et al 2008) likely means higher dosages are required to see the antidepressant effects demonstrated in the other studies. As with many of the other nutrients looked at here although the available evidence is promising participant numbers in studies to date have been small and there is a lack of contemporary research; it would be helpful for clinical practice for example for Nutritional Therapists to know how SAMe compares to more modern antidepressant drugs.
Despite clear biochemical rationale for use of the nutrients discussed in cases of depression the evidence base is generally of poor quality and in many cases contemporary studies are lacking, making it difficult to produce recommendations for Nutritional Therapy practice. With regard to amino acid neurotransmitter precursors there is no harm in ensuring clients are replete through dietary recommendations and therapeutic trials may be worth pursuing, particularly with 5-HTP at 200-300mg/d. There is strong evidence linking low folate intakes and status to depression so again dietary recommendations should ensure adequate intake; supplementing folate in those taking antidepressant medication appears likely to improve therapeutic outcomes but the Nutritional Therapist should always work cooperatively with the clients GP in such situations. Data on vitamin B12 is limited and inconclusive but the proven homocysteine-lowering effects of supplements in combination with folate suggest it may help a subset of those with depression, particularly among the elderly. Evidence of the antidepressant efficacy of SAMe supplements is dated but relatively robust with dosages of 1600mg/d eliciting the greatest therapeutic response. The need for large scale RCTs involving each of these nutrients with respect to depression is clearly evident however, given the good safety profiles ensuring adequate dietary intakes may prevent relapses whilst supplementation as described has the potential to help at least a subset of clients.