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Depression can be classified generally as either unipolar, characterised by depression, or bipolar, characterised by both depression and mania. Unipolar disorders include major depression, dysthymia, a milder but persistent form, and the annual seasonal affective disorder (SAD). Major depression presents with depressed mood, diminished interest or pleasure, feelings of guilt or worthlessness, disturbed sleep or appetite, and low energy and concentration levels. Depression can become chronic or recurrent and severe cases may also lead to suicide (WHO, 2010).
This essay will first discuss the range of biochemical and physiological factors that can contribute to depression. It will also explain some of the more relevant diagnostic signs, symptoms and tests that could help elucidate which factor(s) may be contributing to a client's depression. Secondly, it will discuss nutritional factors/imbalances pertinent to depression and the role of nutrition in addressing the range of factors involved.
Whilst environmental factors, for example, psychosocial stress, are highly significant in the aetiology of depression, a biological predisposition to mood disorders is also moderately heritable (Sullivan et al., 2000). Multiple gene polymorphisms, especially those involving monoaminergic neurotransmission, have been studied, however, research is conflicting and genetic factors are multiple and complex (Levinson, 2006).
The brain and neuroplasticity
Abnormalities in several prefrontal and limbic structures and their interconnections involved in mood regulation and stress response, have been implicated in depression (Davidson, 2003). For example, hyperactivity in the ventromedial prefrontal cortex (vmPFC), associated with increased sensitivity to pain, anxiety, and depressive thoughts, and hypoactivity in the dorsolateral prefrontal cortex (dlPFC), primarily concerned with 'cognitive' and 'executive' functions, are demonstrated in depression. Abnormal activity levels decrease with symptom remission (Maletic et al., 2007; Koenigs & Grafman, 2009). These anomalies are, however, not pathognomic and it is unclear whether they are a cause or a consequence of depression (Koenigs & Grafman, 2009).
Stress-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is known to be associated with mood disorders (McEwan, 2005). The pre-frontal cortex, together with the hippocampus and amygdala of the limbic system are also targets for stress hormones. In long-term depression, the hippocampus and PFC undergo atrophy, whereas the amygdala becomes hyperactive and may undergo hypertrophy in acute depression and atrophy on long-term depression (McEwan, 2005;Alexopoulos, 2005).
With particular reference to the hippocampus, stress-induced hypercortisolaemia may induce atrophy and compromise neuroplasticity, through both inhibition of neurogenesis and neurotoxic effects (Sapolsky, 2001). Other possible mechanisms include an imbalance between glucocorticoid and mineralocorticoid receptors influencing neurotoxic susceptibility (de Kloet et al. 2007).
Further, cortisol-induced alterations in cellular plasticity via downregulation of growth factors, including brain-derived neurotrophic factor (BDNF) (Maletic et al., 2007) and receptor sensitivity (Duman & Monteggia, 2006) could compromise the structure and function of the limbic system, particularly the hippocampus. To further complicate matters, the BDNF precursor, pro-BDNF can also degrade neural networks via processes regulated by various neurotransmitters including serotonin, noradrenaline, GABA and glutamate (Lu et al., 2005).
Additionally, evidence for dysregulation of cortisol signalling in depression also comes from the fact that both brain atrophy and depression are also apparent in Cushing's disease (Patil, 2007) which features hypercortisolism. Furthermore, depression often features in hypocortisolism, as seen in Addison's disease and 'adrenal fatigue'. The mechanisms for hypocortisolism in the pathogenesis of depression are, however, less clear (Buckingham, 2009, p.101).
Table 1 displays various signs and symptoms that could help identify if one of these conditions is a factor contributing to depression.
Table 1: Table to show signs and symptoms for adrenal fatigue, hyper and hypo-cortisolism
Signs & Symptoms
Upper body obesity with thin arms and legs, muscle wasting and weakness â-ª 'buffalo hump' â-ª red 'moon face' â-ª acne or skin infections â-ª poor wound healing â-ª hirsuitism â-ª hypertensionâ-ª high blood sugar â-ª fatigue â-ª anxiety (Kumar & Clark, 2005, p.947).
Weight loss â-ª muscle weakness â-ª fatigue â-ª postural hypotension â-ª increased skin pigmentation â-ª anorexia â-ª nausea â-ª vomiting (Kumar & Clark, 2005, p..945)
History of chronic stress. Difficulty concentrating â-ª brain fog â-ª fatigue, poor immune function â-ª poor digestion â-ª cold intolerance â-ª reliance on stimulants â-ª sugar cravings â-ª salt cravings â-ª postural hypotension â-ª paradoxical papillary response (Lam, 2009).
Abnormal cortisol levels, due to either stress, adrenal fatigue, Cushings or Addison's disease, could be detected through tests including blood cortisol, 24-hour urinary cortisol and the saliva-based Adrenal Stress Profile (Lord & Bralley, 2008, p.627).
Other tests that could help identify adrenal dysfunction include the Paradoxical Pupillary Response Test which measures the pupils' ability to respond to light, a mechanism strongly influenced by the adrenal hormones (Weatherby & Ferguson, 2002, p.95-97).
Thyroid hormone dysregulation
Cortisol is required in the conversion of thyroxine (T4) to the active form, triiodothyronine (T3), however both hyper- and hypocortisolism can lead to hypothyroidism, also commonly associated with depression (Holshoer, 2008, p.159). Further, chronic elevation of adrenalin, as seen in stress can lead to reduced T4 via negative feedback, also producing hypothyroid symptoms (Jones, 2005). Symptoms of hypothyroidsm are outlined in table 2, below.
Table 2: Table to show common signs and symptoms of hypothyroidism
Common signs & symptoms of hypothyroidism:
Hoarse voice â-ª goitre â-ª slow speech â-ª poor circulation â-ª bradycardia â-ª fluid retention â-ª coarse, dry skin and hair â-ª scaly skin â-ª delayed tendon reflexes â-ª cold intolerance â-ª constipation â-ª memory and concentration problems â-ª slow thinking â-ª menorrhagia â-ª weight gain with decreased food intake (Kumar & Clark, 2005, p.933).
Private lab tests are superior to the standard as they test not only TSH (thyroid-stimulating hormone), total T4 and free-T4 serum levels, but also free-T3, reverse-T3 and auto-antibodies, providing a fuller picture of thyroid function. However, 24-hour urine tests measuring free-T3 and T4 tend to be more sensitive (Thyroid UK, 2009).
A simple home-test which can act as a guide to thyroid function is the Barnes temperature test which involves measuring temperature on waking. Temperatures consistently below 36.5°C may indicate hypothyroidism.
Amine dysregulation theories
These theories postulate that diminished neurotransmission of monoamines, particularly serotonin (5-HT), noradrenalin and dopamine, is central to depression (Hindmarch, 2002). Almost all effective pharmacological anti-depressants directly increase levels of one or more of these monoamines, for example, by inhibiting their reuptake e.g. selective serotonin reuptake inhibitors (SSRIs) or inhibiting enzymes involved in their breakdown e.g. monoamine oxidase inhibitors (Rucker & McGuffin, 2008). Indeed, monoamine oxidase, the primary enzyme for 5-HT breakdown has been found in significantly higher levels in untreated depressives, compared to healthy controls (Meyer et al., 2006). Further evidence comes from the fact that serotonin depletion, via a diet lacking its precursor, the amino acid tryptophan, induces depressive relapse in recovered depressives, however, not in healthy controls (Ruhe et al., 2007). Despite the evidence, monoamine depletion is neither necessary to induce depression, nor sufficient to explain it. Indeed, it is likely that multiple systems and mechanisms are involved in the pathogenesis of depression (Hindmarch, 2002).
The Role of Cytokines
Fortunately, a growing volume of research into the role of cytokines and inflammation in depression is further elucidating the complex links between brain plasticity, stress, neurotransmitters, neuro-endocrine function and the wide-ranging medical conditions which feature depression (Loftis et al, 2009). It appears that stress activates pro-inflammatory cytokines, including interleukin-1(beta)(IL-1Î²), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-Î±) and nuclear factor kappa-B (NF-KB), and their signalling pathways in brain regions including those involved in emotional regulation (Miller et al., 2009).
Whilst cytokines in the central nervous system can have neuroprotective or neurodegenerative functions, research indicates that chronic disruption of cytokine balance due to stress, disease (including infectious, autoimmune, cardiovascular, neurodegenerative and arthritic conditions), medication/substance use or brain injury can impair neuroplasticity, thereby contributing to depression (Farmer, 2008; McAfoose & Baune, 2009; Anisman et al., 2008). Mechanisms of damage may also involve oxidative stress (Wichers & Maes, 2004).
Cytokines can be regulated by non-immune factors including neurotransmitters and hormones. Conversely, evidence also suggests that cytokines or cytokine inducers can profoundly affect the metabolism of serotonin, noradrenalin, dopamine, cortisol and other compounds and factors involved (Anisman et al., 2008, Miller et al., 2009). For example, pro-inflammatory cytokines such as IFN influence serotonin metabolism by stimulating indoleamine-pyrrole 2,3-dioxygenase (IDO) which degrades tryptophan, thereby diminishing serotonin availability and contributing to depression (Dantzer et al, 2008).
Nutrition & Depression
Food Allergies/Intolerances & Intestinal Permeability
There exists a wealth of anecdotal reports suggesting a link between food intolerances and depression. Some studies (e.g. LeBovidge et al., 2009) make this association without examining biological factors while others (e.g. Ortolani & Pastorello, 2006) consider the immunological factors of food intolerance without tying this to mental health. Thus far, no studies have directly examined a pathophysiological link between the two.
However, it is recognised that chronic stress can result in intestinal permeability (e.g. Gareau et al., 2008) and the link between intestinal permeability, inflammation and food allergies is gaining recognition (e.g. Sampson, 2004). Further, intestinal permeability has been associated with depression via immune activation and inflammatory mediators (Maes et al., 2008). DespitÂe the lack of specific studies, it perhaps follows that the link between food intolerance and depression is also scientifically plausible explaining another important aetiological factor in depression.
Signs and symptoms of food intolerances and intestinal permeability can be seen in table 3.
Table 3: Table to show common signs and symptoms of intestinal permeability and food intolerances
Common signs & symptoms
Mood swings â-ª frequent infections â-ª insomnia â-ª discoloured circles around the eyes â-ª hyperactivity â-ª bloating â-ª IBS â-ª fatigue â-ª itchy skin â-ª headaches (Manners, n.d.)
Bloating â-ª flatulence â-ª abdominal discomfort â-ª signs and symptoms of nutrient deficiencies, despite adequate diet (malabsorption) â-ª fatigue â-ª diarrhoea â-ª arthralgia â-ª skin rashes â-ª food intolerances (Galland, 2007)
Intestinal permeability can be detected using the Lactulose and Mannitol test which indicates the intestines ability to absorb these two sugars of differing size. As measured by a subsequent urine test, mannitol should be easily absorbed but raised lactulose levels would indicate intestinal permeability (Lord & Bralley, 2008, p.423).
The gold-standard test for food intolerance detection is through 'food challenges' whereby a food is avoided for a period of time and then re-introduced and symptom recurrence or significant changes in pulse noted (Sampson, 2004). Subsequent avoidance of culprit foods may ameliorate depression.
Deficiencies, imbalances and Treatment
Depression has been associated with a number of nutritional deficiencies including zinc, magnesium, vitamin B6 and B12, folic acid, vitamin D, chromium, tryptophan and omega-3 polyunsaturated fatty acid (PUFA) deficiencies, although findings are not always consistent (Rao et al., 2008). These and other imbalances shall be briefly discussed below, followed by table 4 which outlines the corresponding deficiency-associated symptoms and signs and food sources.
Zinc & Magnesium
Zinc and magnesium deficiencies contribute to depression via pathways including hyper-excitability of NMDA glutamate receptors (Eby & Eby, 2009). Zinc deficiency can also cause abnormal glucocorticoid secretion, to which the hippocampus is particularly susceptible (Takeda & Tamano, 2009). Both have been hypothesised to positively impact on depression via various complex pathways involving BDNF potentiation and inhibition of NMDA-receptor function, involved in synaptic plasticity (Szewczyk et al., 2008). Correspondingly, both zinc and magnesium have demonstrated anti-depressant activity in numerous studies (ibid.).
Calcitriol, the active form of vitamin D, has been strongly implicated in brain development and function, however, research is limited and contradictory regarding its links to depression (McCann & Ames, 2008). However, it is known that calcitriol regulates brain neurotrophic factors, and is involved in neurogenesis, immunomodulation (Berk et al., 2007), and the synthesis and secretion of thyroid hormones (Garcion et al., 2002; Abreu et al., 2009), all of which could potentially play a role in the pathogenesis of depression. Vitamin D supplementation, particularly important in inadequate sunlight exposure, has indeed demonstrated anti-depressant effects (Jorde et al., 2009).
Chromium and blood sugar
Chromium may positively influence depression via mechanisms including 5HT2A receptor down-regulation and increasing insulin sensitivity (Davidson et al., 2003). It is an important mineral in blood sugar regulation, dysregulation of which has been linked to depression (Cox et al., 2007). Interestingly, it appears to be particularly beneficial in atypical depression which also features carbohydrate craving (Davidson et al., 2003).
Blood sugar dysregulation can also be ameliorated through well-known nutritional therapy measures including regular eating patterns, consumption of low, rather than high glycaemic foods and avoidance of stimulants. This is thought to, in turn, help support the adrenals and ameliorate stress and depression and further, potentially ameliorate thyroid hormone imbalances, however, no studies exist to support this.
B-vitamins & serotonin
Vitamin B6, B12 and folate deficiencies are implicated in depression via homocysteine, raised levels of which have been linked to depression in some studies (Folstein et al., 2007). Homocysteine levels can be reduced via two pathways - remethylation, which involves synthesising s-adenosylmethionine (SAMe), and transsulfuration, which involves conversion to the anti-oxidant, glutathione. These pathways require zinc, folate, vitamin B12 and B2, or trimethyl-glycine (TMG) and B2, B6 and zinc, respectively. While a Cochrane review supports a role for folate in the treatment of depression (Taylor et al., 2004), there is a general lack of studies considering the therapeutic effects of the B-vitamins and TMG.
Serotonin & Tryptophan
Vitamin B6 is also important as a cofactor in the tryptophan-serotonin pathway (Turner et al., 2006) and vitamin B12 and folate too, are involved in monoamine synthesis (Robinson, 2009).
Serotonin synthesis can also be facilitated by eating tryptophan-rich foods, such as chicken, turkey and eggs, alongside carbohydrates to assist tryptophan in crossing the blood-brain barrier, counter to other competing amino acids. However, there is little consensus within the literature on the therapeutic efficacy of tryptophan loading (Silber & Schmidt, 2009).
Omega-3 PUFA deficiencies and high omega-6:omega-3 ratios have been associated with depression (Tiemeier et al., 2003). However, whilst one review reported consistently therapeutic effects (Sontrop & Campbell, 2006), not all studies support this (Appleton et al., 2006). Possible mechanisms linking PUFAs and depression include their well-established impact on inflammatory cytokine production (see Dinan et al., 2009) and their positive effects on hippocampal BDNF (Wu et al., 2004). Furthermore, the omega-3 PUFA, docosahexaenoic acid (DHA), is essential to the maintenance of neuronal membrane integrity and fluidity and changes in structure could compromise protein function and cellular signalling, leading to depression (Parker et al, 2006).
Nutritional deficiencies can be detected through urine and blood tests (Lord & Bralley, 2008, p.601). Further, zinc deficiency can be ascertained through the zinc taste test which consists of drinking an aqueous zinc mixture, which has a varying degree of taste according to level of deficiency (Weatherby, 2003, p.52).
Deficiencies can also be ascertained through consideration of the diet, in correlation with signs and symptoms, as outlined in table 4.
Table 4: Table to show deficiency signs and symptoms and food sources of vitamins and minerals implicated in depression ((Webb, 2008).
Deficiency signs & symptoms
â-ª Tremors/ spasms/ convulsions â-ª Muscle weakness â-ª Irregular heartbeat â-ª Constipation â-ª Insomnia / nervousness/ anxiety â-ª Hyperactivity â-ª behavioural disturbances â-ª personality changes â-ª
Anorexia â-ª Ca deposition (e.g. kidney stones)
Nuts, legumes, unmilled grains, beans, green leafy vegetables, avocados, banana, Dairy, milk, fish, meat
Impaired wound healing â-ª Impaired night vision & growth â-ª Anorexia â-ª Failure to grow â-ª Frequent infections â-ª Impaired taste/smell â-ª Decreased fertility â-ª Hair loss â-ª Acne/greasy skin â-ª Pallor â-ª Behavioural disturbances â-ª White marks on fingernails.
Oysters, meat, shellfish, eggs, Ginger, pecans, almonds, beans, nuts, seeds and wholegrain cereals (e.g. rye & oats)
Impaired glucose tolerance â-ª Dizziness/irritability after 6 hrs without food â-ª Need for frequent meals
Cold hands â-ª Excessive sleepiness â-ª Sweet food cravings â-ª Excessive or cold sweats
Oysters, Egg, Liver, Chicken Brewers yeast, Rye bread, , Apples
Wholegrain cereals, Pulses, Onions
Wheat germ, Potatoes, Green peppers
Diarrhoea â-ª insomnia â-ª burning sensation in mouth â-ª myopia
Fish, especially herring, mackerel, salmon, meat, dairy, Fortified cereals or soy/rice milk
Skin and nervous system changes â-ª Irritability â-ª insomnia â-ª Fatigue â-ª anorexia â-ª Mouth lesions â-ª Muscle tremors/cramps â-ª Tingling hands & feet â-ª nervousness
Liver, chicken, fish, pork, Bananas, watercress, seeds and nuts, soybeans, avocado, cabbage, red kidney beans, cauliflower,
Pernicious anaemia - Weakness & fatigue â-ª pale skin â-ª Irritability â-ª anxiety/tension â-ª Eczema or dermatitis â-ª tender or sore muscles (arms & legs) â-ª Constipation â-ª Impaired memory
Meat, sardines, tuna, eggs, oysters, dairy, chlorella.
Anaemia - irritability â-ª weakness â-ª sleep problems â-ª pallor â-ª Anxiety/tension â-ª Fatigue â-ª Neurological changes
Milk, egg yolks, kidney, liver, Wheatgerm, broccoli, sprouts, spinach, peanuts, asparagus, sesame seeds, cabbage, kiwi, papaya, parsnips, asparagus
Excessive thirst â-ª fatigue â-ª dry â-ª rough skin â-ª dry hair â-ª loss of hair or dandruff â-ª eczema â-ª asthma â-ª joint pain â-ª premenstrual syndrome
Oily fish - e.g. salmon, mackerel, sardines, kippers.
Depression is a deeply complex condition involving, in addition to environmental circumstances, a wide range of interlinking biochemical, physiological and nutritional factors, mechanisms and imbalances. Nutrition can play an important role in addressing depression through a number of fundamental mechanisms, thereby helping to correct the causative imbalances involved. However, depression is still poorly understood and studies are often conflicting, thus further research is required to elucidate both its aetiology and the role of nutrition in its treatment.
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