Chapter 12 Clinical depression
CLASSIFICATION, EPIDEMIOLOGY AND AETIOLOGY
Depression is associated with normal emotions of sadness and loss, and can be seen as part of the natural adaptive response to life’s stressors. True ‘clinical depression’, however, is a disproportionate ongoing state of sadness, or absence of pleasure, that persists after the exogenous stressors have abated. Clinical depression is commonly characterised by either a low mood, or a loss of pleasure, in combination with changes in, for example, appetite, sleep and energy, and is often accompanied by feelings of guilt or worthlessness or suicidal thoughts.1 The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) classifies ‘Major Depressive Disorder’ (MDD) as a clinical depressive episode that lasts longer than 2 weeks, and is uncomplicated by recent grief, substance abuse or a medical condition.2 Depression presents a significant socioeconomic burden, with the condition being projected by the year 2020 to effect the second greatest increase in morbidity after cardiovascular disease.3 The lifetime prevalence of depressive disorders varies depending on the country, age, sex and socioeconomic group, and approximates about one in six people.4,5 The 12-month prevalence of MDD is approximately 5–8%, with women approximately twice as likely as men to experience an episode.4,5
The pathophysiology of MDD is complex, and to date no unified theory explaining the biological cause exists.1 The main premise concerning the biopathophysiology of MDD centres on monoamine impairment, involving:6–10
From a holistic perspective, the biological causes of depression are unique to the individual, and can be viewed biochemically as varying impairment of monoamine
THE FOUR HUMORS
A traditional view of depression terms the condition ‘melancholia’. This is based on the humoral model, which depicts four ‘humors’ (choleric, sanguine, phlegmatic and melancholic).17
Depression falls under the auspices of the melancholic humor, being embodied as ‘black bile’.
The liver from an energetic perspective in traditional Western folkloric medicine and from traditional Chinese medicine is considered to be the organ primarily involved with depression, and is seen to regulate emotions.17,18
activity, homocysteine, cortisol and BDNF, and inflammatory interactions. Psychologically, cognitive and behavioural causes (or manifestations) of MDD are also commonly present in variations of negative or erroneous thought patterns, or schemas, impaired self-mastery, challenged social roles, and depressogenic behaviours or lifestyle choices.11–13
Several biological and psychological models theorising the causes of depression have been proposed (reviewed below). The predominant biological model of depression in the last 60 years is the monoamine hypothesis.14 Other key biological theories involve the homocysteine hypothesis,15 and the inflammatory cytokine depression theory.8 A prominent psychological model is the stress-diathesis model, which promulgates the theory that a combination of vulnerabilities (genetic, parenting, health status and cognitions) are exploited by a life stressor, for example relationship break-up, job loss and family death.13,16 These stressful events may trigger a depressive disorder. Some scholars have advanced the theory of a biopsychosocial model, which aims to understand depression in terms of a dynamic interrelation between the biological, psychological and social causes (discussed later).12
RISK FACTORS
Various factors that increase the risk of MDD exist, and such an episode may in turn cause certain health disorders/issues. Genetic vulnerability may play an important part in the development of MDD. Genetic studies have revealed that polymorphisms relevant to monoaminergic neurotransmission exist in some people who experience MDD.19 Recent hypotheses suggest that genes related to neuro-protective/toxic/trophic processes, and to the overactivation of the hypothalamic–pituitary axis may be involved in the pathogenesis of MDD.19 Early life events or proximal stressful events increase the risk of an episode.20 Twin studies provide evidence of the effect of environmental stressors on depression and many studies have revealed that a range of stressful events are involved, affecting remission and relapse of the disorder. Recurrence of depressive episodes and early age at onset present with the greatest familial risk.21 Current evidence suggests that the primary risk factors involved in MDD are a complex interplay of genetics and exposure to depressogenic life events.
A consistent theme revealed by epidemiological data is that females have higher rates of MDD than men, approximating two times higher in some community samples.4 This is associated with a higher risk of first onset, and not due to differential persistence or recurrence. It appears that hormonal factors are not responsible (for example, oestrogen levels, pregnancy or the use of oral contraceptives). Biological vulnerabilities and environmental psychosocial factors appear to be responsible for the increased incidence of depression among women. Initial psychosocial triggers may occur in early teen years upon the onset of puberty, whereby gender difference markedly presents. As Kessler states,23 it is conceivable that MDD presents more commonly in females due to social and psychological influences, such as sex-role differences and an intrinsic propensity to ruminate. Another methodological possibility is that men’s depression may present with irritability rather than anhedonia, and as depression scales place less weight on irritability this may skew the results.
Practitioners should be aware of the existence of conditions that commonly co-occur with MDD. People who are clinically depressed have a far greater risk of having co-occurring generalised anxiety, sleep disorders and substance abuse or dependency.23 It should be noted that these conditions may cause MDD and may also result from MDD. Depression is also often misdiagnosed as ‘unipolar’ when in fact it is the presentation of the depressive phase of ‘bipolar’ depression.24 Appropriate screening needs to occur in patients presenting with depression. Initial questioning should assess the length and frequency of previous and current episodes, the severity, what triggers an episode, and whether they think about death regularly or have felt so low lately that they have considered suicide. Assessment should also include a drug and alcohol screen in addition to reviewing their sleep pattern and level of anxiety and stress. To assess any bipolarity of the depression, it is important to determine whether they have ever experienced several days or more of feeling very happy or ‘high’ in addition to behavioural changes such as a decreased need for sleep, rapidity of cognition or ideas, and any increases in planning, spending money or sexual drive (the bipolar spectrum discussed further below).24 Appropriate referral in the case of suspected alcohol/substance abuse or dependency or bipolar disorder is recommended, as complementary or alternative medicine (CAM) currently lacks evidence as a primary intervention in these areas (although CAM may be adjuvantly beneficial).
SUICIDE
CONVENTIONAL TREATMENT
Current medical treatment strategies for MDD primarily involves synthetic antidepressants (for example, tricyclics, monoamine oxidase inhibitors or selective serotonin reuptake inhibitors), and psychological interventions (for example, cognitive behavioural therapy (CBT), interpersonal therapy (IPT) and behavioural therapy (BT)).1,25 Medical treatment guidelines usually involve options such as providing counselling, CBT or IPT for mild depression, antidepressants and/or CBT for moderate depression, and antidepressants and ECT (and possibly hospitalisation) for severe depression.26,27 As only 30–40% of people achieve a satisfactory response to first-line antidepressant prescription, and approximately 40% do not achieve remission after several antidepressant prescriptions, further pharmacotherapeutic developments are currently being pursued.14,28 Future novel antidepressant mechanisms of action may involve modulating cytokines, secondary messengers, and glucocorticoid, opioid, dopaminergic or melatoninergic pathways.9
KEY TREATMENT PROTOCOLS
From a clinical perspective, the goal of treating MDD is to ameliorate the depression as safely and quickly as possible. Suicide is a great concern, and is a devastating potential consequence of MDD. If suicidal ideation is significant, or if self-harm is a distinct possibility at any stage, referral to a medical practitioner or to an emergency ward of hospital for immediate psychiatric assessment is crucial. The socioeconomic cost of untreated MDD is massive, and treated depression reduces the burden on health-care systems.29 Evidence advocates early intervention to effectively treat MDD, to enhance remission, and thereby subsequently decrease human suffering and socioeconomic burden.29
Although medical research has not currently advanced to the state of tailoring pharmacotherapy prescriptions to individual neurochemical or genetic profiles, ‘whole-system’ naturopathic diagnosis and treatment has an advantage in being able to prescribe in an individualised manner. First, in order to treat depression effectively, it helps to understand the psychological and biological factors that are involved. Causes of depression are multifaceted, and individual presentations vary markedly. Because of this, tailoring the prescription for the individual may assist in compliance and recovery. Causative factors can be classified into pre-existing ‘vulnerabilities’ to depression, which may be ‘triggered’ by a stressor (commonly a series of stressors or one key event), then ‘maintaining’ factors may exacerbate or prolong the episode.
Several herbal medicines are particularly adept at affecting neuroreceptor binding and activity to achieve an antidepressant effect. Herbal medicines used to treat mental health disorders usually have central nervous system or endocrine-modulating activity.6 Common actions can involve monoamine activity modulation, stimulation or sedation of central nervous system activity, and regulation or support of healthy hypothalamic pituitary adrenal axis function (see Table 12.1).30
Table 12.1 Nervous system herbal medicine actions30
| TRADITIONAL ACTION | PROPOSED MECHANISMS | APPLICATIONS |
|---|---|---|
| Nervines (tonics, stimulants) | HPA-modulation, beta-adrenergic activity | Depression, fatigue, convalescence |
| Adaptogens, thymoleptics, antidepressants, tonics | Depression, fatigue, convalescence | |
| Anxiolytics, hypnotics, sedatives | GABA or adenosine-receptor binding or modulation | Anxiety disorders, insomnia |
| Antispasmodics, analgesics | Muscular tension (dysmenorrhoea, irritable bowel syndrome, headaches), visceral spasm, pain | |
| Cognitive enhancers | Cognitive decline, dementia |
Biopsychosocial model of depression
The most suitable model consistent with the holistic paradigm is a biopsychosocial model.12 The essence of the model is that the cause of depression is multifactorial, with many interrelated influences involved in its growth. Genetics and biochemistry (biological), cognitions and personality traits (psychological), environmental factors (environmental) and social interactions (sociological) all affect the level of a person’s ‘vulnerability’ to a depressive disorder, which is commonly triggered by chronic or acute stressors. Protective factors are considered to be good genetics, balanced positive cognitions, healthy interpersonal relations and social support, and spirituality.11,31
A balanced and integrative naturopathic treatment plan needs to address all aspects concerning the biopsychosocial model. Herbal, nutraceutical and dietary prescription can modulate the biological component of depression; psychological therapies and counselling support is advised to reconfigure negative cognitions, resolve underlying issues, and build resilience; and social concerns (for example, healthy work, lifestyle, exercise, rest balance, and sufficient family/friend/community interaction) should also be addressed. Depression may provide a context for developing meaning from the experience, thereby promoting spiritual growth. Displayed below is a model developed by the author for treating depression: the ALPS model (see Figure 12.1). This treatment model is based on the biopsychosocial model, outlining specific strategies for treating depression holistically. The model advocates a combined approach of antidepressant agents (natural or synthetic); lifestyle adjustments such as dietary improvement, and reduction of alcohol and caffeine, and increased relaxation and exercise; psychological interventions; and improved social functioning and integration.
Monoamine hypothesis
The monoamine hypothesis concerns the theory that depression is primarily caused by dysregulation of serotonin, dopamine and noradrenaline pathways (receptor activity and density, neurotransmitter production and neurochemical transport and transmission).9 Herbal and nutritional/dietary modulation may be helpful in modulating monoaminergic transmission. To date, the phytotherapy with the most evidence of monoamine modulation is Hypericum perforatum. Enough human clinical trials have been conducted for several meta-analyses to be conducted (see Table 12.2). All meta-analyses have revealed that H. perforatum provides a significant antidepressant effect compared to placebo, and an equivalent efficacy compared to synthetic antidepressants. H. perforatum has demonstrated several beneficial effects on modulating monoamine transmission. Although initial in vitro experiments suggested monoamine oxidase-inhibition by H. perforatum, further conducted experiments have not confirmed this activity.32 In vivo and in vitro studies have, however, revealed non-selective inhibition of the neuronal reuptake of serotonin, dopamine and norepinephrine.33 This activity is likely to occur in part via modulation of neurotransmitter transport systems (for example, via Na+ gradient membranes). Increased dopaminergic activity in the prefrontal cortex has been documented.34 A decreased degradation of neurochemicals and a sensitisation of and increased binding to various receptors (for example, GABA, glutamate and adenosine) have also been observed.35–37 It should be noted that some of the pharmacodynamic studies used intraponeal rather than oral administration; caution in extrapolating to humans is advised.
Aside from SJW, Rhodiola rosea and Crocus sativus currently possess the most evidence as monoamine and neuroendocrine modulators, and have provided preliminary human clinical evidence of efficacy in treating MDD.38,39 R. rosea is a stimulating adaptogen, which possesses antidepressant, anti-fatigue and tonic activity.39,40 A 6-week, phase III, three-arm randomised controlled trial (RCT) involving 91 subjects comparing R. rosea SHR-5 standardised extract (680 mg and 340 mg/day) with placebo demonstrated significant dose-dependent improvement on depression.41 It should be noted that the effect size was small, with a low response in comparison to a very low placebo response (usually there is a 20–50% reduction of depression in a placebo group); further studies need to be conducted to confirm efficacy. The phytochemicals salidroside, rosvarin, rosarin, rosin and tyrosol are considered to be the active constituents.42 In animal models, R. rosea has been documented to increase noradrenaline, dopamine and serotonin in the brainstem and hypothalamus, and to increase the blood–brain permeability to neurotransmitter precursors.43 Crocus sativus is developing clinical evidence as an effective antidepressant (reviewed later). Crocin and safranal are currently regarded as the constituents responsible for C. sativus’s antidepressant action.38 The mechanisms responsible for the antidepressant actions are purported to be mediated via reuptake inhibition of dopamine, norepinephrine and serotonin, and NMDA receptor antagonism.38 Safranal is posited to exert selective GABA-α agonism, and possible opioid receptor modulation, as demonstrated via intracerebroventricular administration in an animal model.44
Other herbal medicines that have been documented to exert monoamine modulation include Bacopa monnieri, Ginkgo biloba, Panax ginseng and Convolvulus pluricaulis; however, to date insufficient clinical trials have confirmed antidepressant effects in humans.45,46
HPA-axis modulation
In the last two decades, cortisol has achieved increased attention in the study of the pathogenesis of depression. Substantial evidence exists for the role of cortisol and the HPA axis in depression.47 Postmortem studies and cerebral spinal fluid sampling have found that corticotrophin-releasing hormone (CRF) can be elevated in samples from depressed patients.48 A combination of vulnerability factors (genetic, age and early life events) and precipitating factors (psychological, physiological stressors, substance misuse and comorbid disease) may provoke an increase in CRF. This stimulates the secretion of adrenocorticotropin hormone (ACTH), and subsequent cortisol release from the adrenal glands (see Section 5 on the endocrine system). In vitro and animal models have demonstrated that HPA-axis dysfunction and increased cortisol attenuate the production of BDNF in the brain.9 BDNF is an important growth factor that nourishes nerve cells, and lower BDNF is correlated with depressive states.1,19 Synthetic antidepressants and electroconvulsive therapy appear to regulate the HPA axis and increase the production of BDNF.47 In animal models, hypericin and the flavonoid derivatives have demonstrated to down-regulate plasma ACTH and corticosterone levels.31 In particular, an animal model demonstrated that 8 weeks of H. perforatum or hypericin administration decreased the expression of genes involved in the regulation of the HPA axis, and significantly decreased levels of CRH mRNA by 16–22% in the hypothalamic paraventricular nucleus (PVN) and serotonin 5-HT(1A) receptor mRNA by 11–17% in the hippocampus. Human studies have, however, found that H. perforatum increases salivary and serum cortisol levels.49,50 Importantly, while in vivo studies have shown that synthetic antidepressants can increase BDNF, H. perforatum does not prevent a decrease in stress-reduced BDNF.51 It should be noted that while evidence does suggest that HPA modulation does occur with H. perforatum administration, the complex pharmacodynamics of the effect has not been fully elucidated to date, with variables such as differing human or animal models, stress study methodology and types of H. perforatum extracts obfuscating the conclusion.
Herbal adaptogens and tonics may play a beneficial role in modulating ACTH (refer further to Section 5 on the endocrine system). Stimulating adaptogens such as Eleutherococcus senticosus, Schisandra chinensis and Rhodiola rosea have demonstrated significant adaptogenic effects, posited as occurring from HPTA modulation.42 Although E. senticosus, S. chinensis and other adaptogens such as Panax ginseng and Withania somnifera have not demonstrated specific antidepressant activity, they may provide a supportive role in depressive presentations with HPA-axis dysregulation.
Homocysteine hypothesis
The homocysteine hypothesis centres on the theory that genetic and environmental factors elevate levels of homocysteine, which in turn provokes changes in neuronal architecture and neurotransmission, resulting in depression.15,52 The sulfur compound homocysteine (formed from methionine) has been demonstrated to be directly toxic to neurons, and can induce DNA strand breakage. Higher serum levels of homocysteine have been noted in depressive populations compared to healthy controls.52 Metabolism of homocysteine to S-adenosyl methionine (SAMe) or back to methionine requires folate, B6 and B12. Folate is involved with the methylation pathways in the ‘one-carbon’ cycle, and is responsible for the metabolism and synthesis of various monoamines.52 Folate is also most notably involved with the synthesis of SAMe, an endogenous antidepressant formed from homocysteine. Folate deficiency is implicated in causing increased homocysteine levels, and has been consistently demonstrated in depressive populations and in poor responders to antidepressants.53,54 Folate deficiency has been reported in approximately one-third of people suffering from depressive disorders.54 Finally, a correlation has been discovered between methylenetetrahydrofolate reductase (a folate-metabolising enzyme) polymorphisms and depression, indicating a genetic link.55
Several studies exist assessing the antidepressant effect of folic acid in humans with concomitant antidepressant use.1,56,57 All of these studies yielded positive results with regard to enhancing antidepressant response rates or increasing the onset of response. An example of folic acid’s antidepressant activity is reflected in a controlled study using 500 μg of folic acid or placebo adjuvantly with 20 mg fluoxetine in 127 subjects with a Hamilton Depression Rating Scale (HDRS) of ≥ 20.57,58 The study demonstrated a statistically significant reduction after 10 weeks on the HDRS for women. This effect was not, however, replicated in the male sample. Along with a good dietary intake of folate-rich leafy vegetables or folic acid supplementation, a multivitamin high in B vitamins (especially B6 and B12) may assist in reducing homocysteine, and maintaining adequate levels of SAMe. This will also assist in maintenance of energy production, adrenal function and the creation of neurotransmitters.
Inflammatory factors causing depression
A cytokine-mediated pro-inflammatory event has been considered as a factor involved with the pathophysiology of MDD.8 Studies have demonstrated that otherwise healthy patients with depression have presented with activated inflammatory pathways.59 It has been posited that pro-inflammatory cytokines produced from inflammation may influence neuroendocrine function via entry through the ‘leaky regions’ of the brain (for example, the circumventricular organs), and subsequent modulation of cytokine specific transport molecules, or cytokine stimulation of vagal afferent fibres.8 Modulation of both CRT and neurotransmitters is known to be effected by cytokines. The main pro-inflammatory cytokines implicated in depressogenesis centres on IFN-α producing IL-1β, IL-6 and TNF-α cytokines (see Chapter 28 on autoimmunity). In laboratory studies, animals exposed to a variety of stressors have demonstrated an increase in these pro-inflammatory cytokines. Synthetic antidepressants have been shown to inhibit the production of various inflammatory cytokines, and to stimulate the production of anti-inflammatory cytokines.8 Although in its infancy, nascent research is evolving towards developing synthetic medicines that modulate cytokines with a regard to ameliorating depression.9
Attenuation of pro-inflammatory cytokines may be of benefit in individuals who present with either a preceding or comorbid inflammatory condition, or a chronic latent infection. Appropriate screening to determine any infections, or inflammatory process, with reference to the chronology of the onset of depression is advised. If an association is plausible, herbal medicines and nutrients that dampen the inflammatory cascade and attenuate the production of pro-inflammatory cytokines may be advised (see Section 2 on the respiratory system and and Section 1 on the gastrointestinal system). In brief, herbal and nutritional medicines that may potentially benefit the treatment of pro-inflammatory evoked MDD include Albizzia spp., Echinacea spp., vitamin C and bioflavonoids, and zincAlbizzia spp. (in particular A. lebbeck) have been documented to exert anti-inflammatory and antiallergic activity.60 In addition to this activity, anxiolytic and antidepressant effects have been demonstrated in animal models, and in the case of Albizzia julibrissan, the plant curiously is known as ‘happy bark’ in traditional Chinese medicine.61–63
Aside from the previously mentioned herbal and nutritional medicines, omega-3 fatty acids also have a role in reducing inflammation-based MDD.59 Epidemiological studies have demonstrated that a rise in depressive symptoms may be correlated with lower dietary omega-3 fish oil (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)).64–67 Studies have also demonstrated that people with depression have a tendency towards a higher ratio of serum arachidonic acid to essential fatty acids, and an overall lower serum level of omega-3 compared to healthy controls.59,68–70 Urbanised Western cultures tend to have a far higher ratio of dietary omega-6 oils compared to omega-3 oils, and this has been regarded as a possible factor in the rise of depression over the last several decades.64,67 The pathophysiology occurring from a pro-omega-6 diet may involve an increased promotion of inflammatory eicosanoids, a lessening of BDNF and a decrease in neuronal cell membrane fluidity and communication.67,71 Evidence currently suggests that omega-3 fatty acids exert antidepressant activity via beneficial effects on neurotransmission.72 This may occur via modulation of neurotransmitter (norepinephrine, dopamine and serotonin) reuptake, degradation, synthesis and receptor binding.73,74 Animal models have demonstrated that omega-3 fatty acids increase serotonin and dopamine concentrations in the frontal cortex, and that a diet deficient in the nutrient decreases catecholamine synthesis.73,75,76 A recent human clinical trial demonstrated a significant increase in plasma concentrations of norepinephrine in healthy humans.74
Several human clinical trials have been conducted assessing the efficacy of EPA, DHA or a combination of both of these essential fatty acids.77 Clinical evidence regarding the use of essential fatty acids as a monotherapy is equivocal, with a mixture of positive and negative trials (see Table 12.2 at the end of the chapter for a review of the evidence).
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