There seems to be a lot of unhappiness about: demand for antidepressant prescriptions – which were designed to treat major depressive disorders – has been increasing for decades, in some countries to alarming levels (1). This raises some pressing questions, though without easy answers. Are we less prepared to tolerate low moods? Is depression being over diagnosed? (2) Is the world becoming a darker place so that more people really need these prescriptions? Are natural responses to unpleasant events becoming more medicalised? This review will help at least to address another question: could herbs help?
We all feel down occasionally. It’s a natural response to difficult events or simply part of life’s ebb and flow, often passing within days. This is often what we mean by being depressed. However low mood is one end of a spectrum of trouble, going through stress-induced anxiety-depression, ‘mild to moderate depression’, through to very dark major disorders. Full-scale clinical depression can be a peculiar form of hell, confining sufferers to solitary torment, when nothing feels worthwhile, nothing gives any pleasure and hope disappears. Thoughts of suicide are common. People who go through this say that it is worse than any physical disease, and it can be dangerous.
So faced with a range of depressed conditions from low mood to something medically severe, a first question in herbal practice is how to understand a depressed patient: is a diagnosis of depression relevant or useful, and are there approaches suitable to herbal treatment?
Is this depression? What does that mean?
In their practices herbal practitioners often encounter patients who report they are depressed or have symptoms that suggest depression might be a diagnosis. In many cases these symptoms are linked to highly stressful situations (also to wider world events), in which anxiety may also strongly feature, or to grief or loss. Or they are confused with other problems, such as fatigue conditions, chronic viral or other infections and immunological conditions, so that it is sometimes difficult to assess whether the depression is or should be a distinct diagnosis. Sometimes patients will say that the doctor has said they have depression, while another response could be “so would I in that situation!” For the herbal practitioner the treatment of the patient’s ‘depression’ is generally more productive if it is seen as in the context of another problem. So one question often features: should there be distinct diagnosis of depression here, or is this person depressed as an obvious response to a challenging situation or other health issue?
The conventional psycho-medical definition of depression is enshrined in the current standard text DSM-5, the official manual of the American Psychiatric Association. This outlines criteria to make a clinical diagnosis. The individual must be experiencing five or more symptoms during the same 2-week period, at a level that generates clinically significant distress or impairment in social, occupational, or other important areas of functioning, and at least one of the symptoms should be 1 or 2.
- Depressed mood most of the day, nearly every day.
- Markedly diminished interest or pleasure in all, or almost all, activities (‘anhedonia’) most of the day, nearly every day.
- Significant weight loss or weight gain, or decrease or increase in appetite nearly every day.
- A slowdown of thought and a reduction of physical movement (observable by others).
- Fatigue or loss of energy nearly every day.
- Feelings of worthlessness or excessive or inappropriate guilt nearly every day.
- Diminished ability to think or concentrate, or indecisiveness, nearly every day.
- Recurrent thoughts of death, or a suicide attempt, or a specific plan for committing suicide.
This diagnosis makes the case for a distinct medical condition that should be treated separately from other factors. However, it excludes the result of substance abuse or another medical condition. In making this latter point it thus skirts over many everyday encounters in herbal practice.
Medicalising depression also overlooks a much wider conversation about its place in human history and society, its role historically in the religious path, the prominence ‘melancholics’ (from the Greek for ‘black bile’) have had in the creative arts, from cave paintings (often done in very dark places a very long way from the light) through Michelangelo and van Gogh, to British comics like Spike Milligan and Tony Hancock. How would the British fortunes through World War II have changed if Churchill had been cured of his depression? And what to make of the startling observation that biochemical and metabolic changes of depression are also found in animal hibernation?(3) It is the practitioner’s calling to reduce suffering wherever possible but the extent to which depression is woven into the human (and even animal) condition means that at the least approaches should avoid simplicity. Simple reliance on antidepressants may not meet all the needs of someone who is prone to depressive episodes.
However there is no doubt that in its most severe forms depression is a force to itself, accompanied by biochemical and metabolic changes in the body, and that direct antidepressant prescriptions may be important and even life-saving.
Clinically diagnosed depression can be unipolar or bipolar.
Unipolar depression
Unipolar depressive disorders are typically classified as follows in DSM-5:
- Major depressive disorder (MDD) characterised by deep sadness, apathy, irritability, disturbed sleep, disturbed appetite, weight loss, fatigue, poor concentration, guilt and persistent thoughts of death – lasting longer than 2 weeks and not linked to recent grief, substance abuse or a medical disorder.
- Dysthymic disorder, which consists of a pattern of chronic, ongoing mild depressive symptoms that are less severe than major depression.
- Seasonal affective disorder (SAD), which is related to seasonal changes. The prevalence increases with increasing latitude and it can be treated by light therapy. Symptoms include lack of energy, weight gain and carbohydrate craving.
Antidepressants were designed to treat patients experiencing MDD, especially with suicidal thoughts or exhibiting other forms of self-endangerment. The severity of some major depressive symptoms makes referring to specialist care a priority, with any herbal approaches in supportive mode (although also see the discussion on inflammatory mechanisms for some potentially more significant contributions). In this classification herbal medicine starts as potentially appropriate for mild to moderate manifestations, found in dysthymic disorders, and particularly in helping with the often accompanying anxiety.
Bipolar disorder
Formerly referred to as manic depression, there are different bipolar conditions. Each include phases of mania or hypomania alternating with depression, or euphoria with anhedonia.
Hypomania is a distinct period of abnormally and persistently increased activity or energy, inflated self-esteem or grandiosity, decreased need for sleep, talkability, distractibility, increased goal seeking, risky, inappropriate or even dangerous activities (eg unrestrained buying sprees, sexual indiscretions, or foolish business investments), that lasts most of the day for at least four consecutive days. These episodes include a noticeable change from usual behaviour and function, observable by others, though not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization.
Mania is diagnosed after at least a week of such symptoms and additionally when the mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
The main categories of bipolar identified in DSM-5 are as follows.
- Bipolar I disorder. There has been at least one manic episode. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes
- Bipolar II disorder. There has been at least one hypomanic episode but not full mania.
- Cyclothymic disorder. At least two years of multiple periods of hypomania symptoms and periods of depressive symptoms (though less severe than major depression).
- Other types. These include, for example, bipolar and related disorders induced by certain drugs or alcohol or due to a medical condition, such as Cushing’s disease, multiple sclerosis or stroke.
Bipolar II disorder is not a milder form of bipolar I, but a separate diagnosis. While the manic episodes of bipolar I disorder can be severe and dangerous, individuals with bipolar II can be depressed for longer periods, which can cause significant impairment and its own dangers. The timing of symptoms may include additional diagnostic labels such as mixed or rapid cycling. In addition, bipolar symptoms may occur during pregnancy or change with the seasons.
Although bipolar disorder can occur at any age, typically it is diagnosed in the teenage years or early 20s. Symptoms can vary from person to person, and may vary over time.
Mechanism of depression and antidepressant strategies
There are various theories about the causes of major depression. These include the monoamine-deficiency hypothesis (including reduced levels or excessive uptake at nerve synapses of serotonin and norepinephrine) and a dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis with an abnormal stress response and elevated cortisol, perhaps linked to earlier traumatic events (4).
Standard antidepressant medicines focus on specific mechanisms of major depressive disorders. They include selective serotonin re-uptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) mixed norepinephrine or serotonin uptake inhibitors, dopamine or norepinephrine uptake inhibitors, and norepinephrine uptake inhibitors.
SSRIs (such as citalopram, sertraline and fluoxetine or Prozac) are now front-line pharmacotherapies in the treatment of major depressive disorder. Since their formulation over 40 years ago, there have been several conflicting studies exploring their efficacy, especially in the case of bipolar disorder (5). Moreover the nature of their therapeutic effect has also remained elusive, with several hypothesises pertaining to neurotransmitter and endocrine modulation proposed. While the medications are better tolerated than their predecessors, the side effect profile of SSRIs is substantial and sometimes persisting. Other ‘second generation’ types of antidepressant prescription include serotonin–norepinephrine reuptake inhibitors (SNRIs such as venlafaxine) and norepinephrine reuptake inhibitors (NRIs – eg reboxetine). SSRIs have largely replaced ‘first generation’ tricyclic antidepressants (although amitriptyline, which inhibits reuptake of both serotonin and norepinephrine, is still widely prescribed) and monoamine oxidase inhibitors (MAOIs) that inhibit the breakdown of the brain monoamines serotonin, dopamine, and norepinephrine. All types of antidepressant are associated with potentially serious side effects and with variable levels of efficacy (6). It is worth noting that the evidence shows that antidepressant drugs are largely ineffective in patients with subthreshold to mild depression when compared to placebo. In spite of this evidence, antidepressants are increasingly prescribed for less severe forms of depression (7).
In widespread efforts to manage depression without medicines the most widely adopted option is cognitive behavioural therapy (CBT) in which sufferers are helped to shift their perceptions of their circumstances. The evidence for the benefits of ‘talking therapies’ is generally positive and comparable with antidepressants, although not perhaps as overwhelming as some advocates have claimed (8,9,10). Other psychological therapies, including simple forms of behavioural activation in community settings, and e-health apps (11,12,13) (especially with some personalisation (14)), have been found to be also helpful, especially in helping mild to moderate depression (15), anxiety with depression, and in children (16). Variations include the use of mindfulness (17), meditation (18), and creative therapies (19,20,21). The benefits of exercise in relieving depression have been posited, especially in ‘green spaces’ (22), although the evidence base here is not yet clear (23,24,25). The lessons from work with talking therapies techniques could be applied by herbal and other practitioners, and in one form or another may feature in some consultations already.
Light therapy has been found helpful for seasonal affective disorder (26).
Impaired cerebral circulation is another factor of depression (27), with evidence that cardiovascular disease is linked with depression and makes it worse (28). In a systematic review and meta-analysis a close association between depression and endothelial dysfunction was established (29). Low systolic blood pressure was also associated with depression in men aged 60 to 89 years (30). There is evidence that chronic stress leads directly to challenges to the blood-brain barrier and subsequent inflammatory changes associated with depression (see below) (31, 32)
The exact cause of bipolar disorder is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. Genetic factors are particularly important (bipolar disorder is 70% more common in people who have a first-degree relative, such as a sibling or parent, with the condition). Lithium is the gold standard mood-stabilising agent for bipolar treatment, as a metal ion that interacts with sodium function reflecting the core physiological disruptions associated with these conditions (33).
Depression as inflammation
As discussed in Herbal Reality’s article on neuroinflammation, there is considerable evidence that depression may usefully be understood as an inflammatory disorder. Recent evidence has confirmed the interaction of inflammatory changes with established neurobiological correlates of major depressive disorder: depletion of brain serotonin and dysregulation of the HPA axis (34).
Key agents inflammation in the central nervous system are the blood-brain barrier that mediates between the nervous tissue and the wider body, and a range of support cells in the nervous system (‘glia’ – particularly microglia). Depression has been notably associated with activation of microglia, even being termed a ‘microgliopathy’ (35,36). It has been demonstrated that depressed patients present neuroinflammatory alterations, including changes in T-cell population (37), and have high blood levels of inflammatory cytokines (with levels of IL-1β, IL-10, and TNF-α correlated to depression severity, with IL-8 inversely so) (38).
Depression is also strongly linked to infections, especially viral infections (39). These are likely also related to microglial activation (40).
There is a promising line of thought for the herbal practitioner faced with even severe depression. Inflammatory provocations can be linked to a leaky gut wall: to raised IgA/IgM responses to lipopolysaccharides (LPS) from Gram-negative gut bacteria (41,42). LPS are used in research to generate depressive behaviour, and their depressant effects have been confirmed in human studies. Manipulations of the gut microbiota (including microbial transplants) have been postulated as ways to prevent or treat depression (45).
However it is important to note that inflammation does not act in isolation in provoking depression. Vulnerability to inflammatory harm appears to be modified by pre-existing socio-behavioural factors. A placebo-controlled study in 115 healthy adults of the effects of an infusion of gut derived LPS (in this case an endotoxin from E. coli), showed that expected increases in proinflammatory cytokines and subsequent depressed mood were moderated by baseline levels of perceived stress, sensitivity to social disconnection, and the severity of symptoms of anxiety and depression. These background factors were associated with increased activation of pro-inflammatory transcription control pathways (e.g. NF-κB) in response to endotoxin (46).
Herbal strategies to ease depression
There is a reasonable evidence base for the benefits of herbs in ameliorating symptoms of depression. Indeed this may also hold for the consumption of more fruit and vegetables (47). in a wide ranging review of natural constituents with antidepressant activity one paper suggests that many herbal remedies may hold some modest promise (48). There are also encouraging reports for spices in general (49), saffron (50,51) and lavender (52).
The most well-known herbal remedy at least for mild to moderate depression is St John’s wort. However the mechanisms of antidepressant action remain various, even elusive, and likely linked to several different constituents. Initial biochemical studies reported that St John’s wort is a weak inhibitor of monoamine oxidase-A and -B activity, downregulates beta-adrenergic receptors, upregulates serotonin 5-HT(2) receptors, that it inhibits the uptake of serotonin, dopamine and noradrenaline (norepinephrine) at synapses. Other studies suggest that St John’s wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. Many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol hyperforin and flavonoids (53,54).
In western herbal medicine there has been a group of remedies referred to as ‘nervine tonics’ or ‘nervous trophorestoratives’. These have emerged in recognition that nervous conditions of tension, fatigue, debility and depression are all linked. This category of remedies were seen to restore energies and build up strength, hence ‘trophorestoratives’. It is worth noting that this is a modern development: in the past it seemed there was less focus on such applications, and these qualities were generally ignored in old herbals.
Plant remedies used as nervous system trophorestoratives include oatstraw, St. John’s wort, vervain (Verbena officinalis) and from the USA damiana (Turnera aphrodisiaca) and skullcap. From outside the Anglo-American traditions, gotu kola, schisandra (Schisandra chinensis), Panax ginseng, Siberian ginseng, ashwagandha and other adaptogens have been quickly adopted to this role.
Some of the remedies above can be particularly useful in managing anxiety with depression, a common presentation to the herbal practice. To these can be added valerian and passionflower to ease nervousness and anxious feelings.
Other traditional tonics and adaptogens with potential in supporting people with depression (notably when associated with fatigue and chronic stress) include, brahmi (55) and rhodiola (56).
One promising approach is to tackle the circulatory involvement in depression with herbs that improve circulation to the brain. Ginkgo started its use in Germany specifically for this purpose, and rosemary likely has similar promise.
However the most interesting and promising prospect in the long term will be to tackle the inflammatory factors in depressive illnesses. This is a much more substantial topic, covered to some extent in the piece on neuroinflammation, and deserving future development.
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