Sunday, 2 June 2013

Natural Pharmacotherapies (i.e. herbs and supplements) for Depression

1. Introduction

Major Depressive Disorder (MDD; also known as clinical or unipolar depression) is a serious psychiatric illness that affects around 6.4% of the Adult US population and is characterised by reoccurring major depressive episodes. Around 20% of adults will suffer at least one major depressive episode in their lifetime. The treatment of MDD should be overseen, at all times, by a qualified mental health care professional. There are a wide range of different natural remedies for depression, many of which should be included in any medical history you give to your doctors.

2. The Herbs

2.1 St. John's wort

The most popular herbal remedy for depression is without question, St. John's wort (Hypericum perforatum). St. John's wort has, in randomised, double-blind, placebo-controlled trials demonstrated statistically significant efficacy over placebo and comparable efficacy to pharmaceutical antidepressants in the treatment of mild-moderate depression (Linde, 2008). Against moderate-severe depression it has been found, in randomised, double-blind, placebo-controlled trials to be no more effective than a placebo (Shelton, 2001).

The mechanism by which St. John's wort is purported to act is by activation of the TRPC6 ion channel, and the resulting relatively balanced (or equally potent) inhibitory effect this has on the reuptake of the neurotransmitters, serotonin, norepinephrine, dopamine, GABA, glutamate and a few others. This action appears to be mediated by means of two of its chief active constituents, hyperforin (Chatterjee, 1998) and adhyperforin (Jensen, 2001). Hyperforin and adhyperforin appear to have comparable inhibitory effects on serotonin and norepinephrine reuptake to pharmaceutical antidepressants such as venlafaxine (Effexor) and duloxetine (Cymbalta).

Similarly to many pharmaceutical antidepressants these two chemical constituents of St. John's wort have been found to elicit potent anti-inflammatory effects, in fact, in one in vitro study the anti-inflammatory effects of hyperforin were found to be around 3-18 times more potent than aspirin (Albert, 2002).

St. John's wort is definitely something you should mention when giving your medical history. It has been found to, in some cases, precipitate, when given in combination with other drugs, the potentially life-threatening complication, serotonin syndrome. It can also speed up the metabolism of other medications you might be on, reducing their efficacy in treating a wide range of different pre-existing conditions you might have.

St. John's wort, as with many herbs, is generally well-tolerated (i.e. can usually be taken with usually minimal side effects) by the human body. Common side effects include:

  • Gastrointestinal upset (e.g. dry mouth, nausea, vomiting, diarrhoea, constipation, wind, abdominal pain)
  • Fatigue
  • Headache (Shelton, 2001)
  • Dizziness
  • Drowsiness
  • Restlessness
  • Increased sensitivity to light
  • Sexual dysfunction
Figure 1: Hyperforin
Figure 2: Adhyperforin

2.2 The Others

For many years it has been known that cannabis, opium and psychedelic mushrooms can improve mood but seeing how they are illegal in much of the world, and in the case of opium, quite dangerous I will otherwise turn a blind eye to them here. Aside from these herbs/fungi there are few remaining remedies in this category. The remaining remedies are purely theoretical with little supporting evidence. For instance, Agnus Castus is a herb that appears to have dopaminergic (dopamine-acting) effects in the body and at the very least appears to improve depression in premenstural dysphoric disorder according to one study. Ginkgo biloba supplements were found in one study to be effective in the management of seasonal affective disorder (SAD; also known as winter blues). Passionflower may improve depressive symptoms due to its harmala alkaloid (e.g. harmine and harmaline) content. Harmala alkaloids are reversible inhibitors of monoamine oxidase A (RIMA), which is the exact mechanism of action of the pharmaceutical antidepressant, moclobemide. Monoamine oxidase A degrades the mood-regulating monoamine neurotransmitters serotonin, norepinephrine and dopamine in the CNS. The South African herb, Kanna, has been purported to have antidepressant effects which is supported by the finding that two of its alkaloid constituents, mesembrine and mesembrenone have been found to have selective serotonin reuptake inhibiting and phosphodiesterase (PDE) 4 inhibitory effects (Harvey, 2011). 

It would be prudent for you to mention that you are taking any of these herbs to your physician(s) if you are.

Figure 3: Harmaline

Figure 4: Harmine
Figure 5: Mesembrenone
Figure 6: Mesembrine

3. The Supplements

3.1 Omega-3 fatty acids

Omega-3 fatty acids are perhaps amongst the most popular natural remedies in modern times. Omega-3 fatty acids are purported to possess, among other things, antidepressant effects (Su, 2003). They appear to elicit antidepressant effects via competing for enzymatic conversion to prostaglandins (which when they are omega-3 in origin tend to be anti-inflammatory) with the omega-6 fatty acids that are used to create pro-inflammatory prostaglandins. Since inflammatory markers have been found to be elevated in the depressed it appears that the antidepressant effects of omega-3 fatty acids are mediated via this anti-inflammatory action. It appears as though EPA is more efficacious than DHA in the treatment of depression (Marangell, 2003).
Figure 7: DHA
Figure 8: EPA

3.2 S-adenosylmethionine (SAMe)

S-adenosylmethionine or SAMe, for short, is a compound that naturally occurs in all human cells, and is a crucial cofactor for many enzymes. Cofactors are substances that are required in order for a specific enzyme-catalysed reaction to occur that involves another substrate. SAMe is also involved in the biosynthesis of several neurotransmitters including the monoamines dopamine, norepinephrine and serotonin (Mischoulon, 2002). Consequently it was proposed and has subsequently demonstrated that SAMe is an effective and fast-acting antidepressant with comparable efficacy to pharmaceutical antidepressants (Kagan, 1990).
Figure 9: S-adenosylmethionine


3.3 Inositol

Inositol is a compound that naturally occurs in the human body and is synthesised from glucose and interacts with the second-messenger system in the body. It was once considered an essential B vitamin, but it is no longer because the body can synthesise it from glucose. See in the body, when a drug binds to a receptor it, usually, sets off a series of chemical reactions within the cell on which the receptor is expressed (which is known as the second-messenger system) that in turn lead to the biologic effects induced by the drug. The evidence for inositol as a treatment for depression is relatively limited but there was at least one randomised placebo-controlled double blind trial conducted into its effects that demonstrated its efficacy, despite the small sample size used (Levine, 1995).
Figure 10: Inositol

3.4 Folic Acid

Folic acid (or folate), similarly to SAMe, is a substance, that after a little chemical modification, is found in all human cells and, after this processing by the body, serves as a cofactor for a number of enzymes (many of which are essential for cell reproduction) and appears to play an important role in neurotransmitter synthesis. Folic acid is also known as vitamin B9 and is an essential part of the human diet. In the body folic acid is converted to dihydrofolic acid and then, by means of an enzyme known as dihydrofolate reductase, is converted to its biologically active form, tetrahydrofolic acid. Folic acid is also required for the synthesis of SAMe in the body (Coppen, 2005). Folic acid supplementation appears to improve response rates to pharmaceutical antidepressants as well (Coppen, 2005). I cannot find any randomised, double-blind, placebo-controlled trials testing the efficacy of folic acid as a monotherapy for depression, but as an adjunct it has improved response rates to the antidepressant, fluoxetine (prozac) in one randomised placebo-controlled trial (Coppen, 2000).

Folic acid supplementation has also found (albeit only one of three clinical trials performed prior to 2007 found any efficacy of folic acid supplementation in dementia [Balk, 2007]) use in the treatment of the cognitive impairments that often accompany dementia and since a common symptom caused by MDD is cognitive impairment it is possible that folic acid may, in particular, aid in the management of this common complaint in MDD. Folic acid appears to alter brain concentrations of omega-3 fatty acids and inflammatory markers and this appears to improve cognition in dementia (Das U. N., 2008).

Excessive folic acid consumption can lead to the blood-brain barrier becoming compromised and can, in turn, lead to seizures. Folic acid supplementation should be mentioned to your physician(s) because it can interact with some medications such as the dihydrofolate reductase inhibitor, methotrexate.
Figure 11: Folic acid

Figure 12: Tetrahydrofolic acid
3.5 Vitamin B12
Vitamin B12, like folic acid is an essential part of the human diet and appears to play a key role in the synthesis of SAMe and serves as a cofactor for a number of enzymes in the body and appears to be involved in neurotransmitter synthesis. A randomised, placebo-controlled trial failed to demonstrate any statistically significant improvement in depression after three months vitamin B12 supplementation (Hvas, 2004)

Figure 13: Vitamin B12

3.6 Vitamin C

Vitamin C is a vitamin that most animals can synthesise in their livers from glucose but humans and a few primates cannot. Vitamin C serves a wide range of roles in the body, including as a cofactor in the formation of the common animal protein, collagen, and also in protecting the body from free oxidative radicals by serving as an antioxidant. As an antioxidant it was proposed that it could augment conventional antidepressant treatment due to implications by the inflammatory and neurodegenerative hypothesis of depression (Maes, 2009) and this hypothesis was subsequently demonstrated (N=24; p<0.0001) in a randomised, double-blind, placebo-controlled trial in of which it was used as an adjunct to the antidepressant fluoxetine (Amr, 2013).

Figure 14: Vitamin C

Amino Acids

3.7 Phenylalanine

Phenylalanine is an essential amino acid that the body metabolises to the non-essential amino acid tyrosine and then into dopamine, norepinephrine and epinephrine. Since dopamine and norepinephrine are involved in mood regulation it is a reasonable hypothesis that phenylalanine supplementation may improve mood. In one double-blind study, forty patients were either given the tricyclic antidepressant, imipramine, or phenylalanine for thirty days and the severity of their depression was assessed and found to be roughly equivalent. There was no placebo-treated group in this study and hence it is impossible to tell whether either group statistically significantly improved compared to placebo-treated patients (Beckmann, 1979).

Figure 15: Phenylalanine

3.8 Tryptophan/5-hydroxytryptophan (5-HTP)

Tryptophan is an essential amino acid that is metabolised in the body into 5-HTP which is then converted straight to serotonin (5-HT) using the enzyme aromatic-L-amino-acid decarboxylase with the help of the cofactor vitamin B6. Some of this 5-HT is then metabolised to melatonin. Since both serotonin and melatonin appear to play key roles in mood it is a reasonable hypothesis that tryptophan and 5-HTP may improve mood. The available evidence supports the use of tryptophan and 5-HTP in the treatment of depression (Shaw, 2001). Neither which supplement is available over the counter in Australia due to a few cases of a very rare and dangerous neurological syndrome being associated with it.
Figure 16: Tryptophan

Figure 17: 5-Hydroxytryptophan

3.9 Taurine

Taurine is a non-essential amino acid that is found predominantly in animal products, although some can be derived from plant sources. It appears to play a key role in inhibitory neurotransmission, long-term potentiation in the hippocampus (Dominy, 2004), possess antioxidant effects (Das J, 2008) and reduce excitotoxicity due to the glutamate (Leon, 2009). Reduced plasma levels of taurine were found in patients with major depression (Altamura, 1995). Whether or not taurine is an effective treatment for MDD has not been elucidated by clinical trials but since long-term potentiation in the hippocampus appears to be involved in the therapeutic effects of antidepressants it is not unreasonable to theorise that taurine may be of benefit in MDD. It additionally appears to possess anxiolytic effects in animal models of anxiety which might help in anxious depression (Kong, 2006).
Figure 18: Taurine

3.10 N-acetylcysteine

N-acetylcysteine is a non-essential amino acid that possess antioxidant effects and is commonly used in medicine to counteract hepatotoxicity (liver toxicity) in paracetamol (INN; USAN: acetaminophen) overdose. It also appears capable of crossing the blood-brain barrier and influencing psychiatric states. Clinical trials have demonstrated some efficacy in treating schizophrenia (Berk, 2008) and bipolar depression (Berk, 2008). Whether or not this will translate to other forms of depression isn't entirely clear.
Figure 19: N-acetylcysteine

3.11 D-serine

D-serine is a non-essential amino acid and is the only type of amino acid that also comes in the dextrorotatory form in the human body. Most amino acids come in levorotatory form. It potently binds to and activates the glycine site on the NMDA glutamate receptor hence increasing NMDA receptor activity in the CNS upon supplementation. D-serine has been found in rodents to elicit rapid antidepressant effects. It would therefore be a reasonable enough hypothesis that this might translate to humans (Malkesman, 2012).
Figure 20: D-serine

4. Glossary

Adjunct - An add on treatment used to improve response rates to a pre-existing treatment regimen. 

Alkaloid - a plant-derived, nitrogenous (nitrogen-containing) compound that usually possesses some pharmacologic activity. 

Amino acid - the building blocks of proteins

Anxiolysis - anxiety relief.

Bipolar Disorder (BD) - Bipolar disorder is a disorder that is characterised by a continually alternating combinations of three types of mood, normally occurring at separate points in time but occasionally occurring simultaneously (a so called "mixed episode"). The first is depression, much like major depression and often just as severe. The symptoms are virtually identical to other types of depression and usually responds to antidepressants too. The second is mania which is when the patient becomes either euphoric or agitated and often has a drastic loss of impulse control (e.g. they go out on shopping sprees, or do drugs or engage in risky sexual behaviour) and sometimes they also suffer from psychosis (the "positive" symptoms of schizophrenia) during these episodes. The third is hypomania which is sort of like mania but less severe and always without hallucinations. Some patients suffer from type II bipolar disorder which is characterised by an absence of mania but with hypomanic episodes.

Blood-Brain Barrier (BBB) - A protective barrier that separates the blood in the periphery and the blood in the central nervous system. It consists of tightly held-together cells that only allow certain things, such as fat soluble small molecules to get through. 

Brain-derived Neurotrophic Factor (BDNF) - A neurotrophic factor that primarily acts on the cerebrum and hippocampus.

Central Nervous System (CNS) - The brain and spinal cord.

Cerebrum - The grey matter (outer layer) of the brain, involved in information processing. 

Cyclooxygenase (COX) - An enzyme that catalyses the formation of various prostanoids including the prostaglandins. Prostaglandins are fatty molecules that serve various roles in the body, from inflammatory responses to body temperature regulation and the protection of the stomach from the acids that churn in it. 

Dopamine - A monoamine neurotransmitter that key roles include the following:
  • Regulation of prolactin release (a hormone that stimulates lactation)
  • Voluntary movement control (Parkinson's disease, for instance, predominantly and selectively kills off dopaminergic (dopamine-signalling) cells in the substantia nigra of the brain)
  • Concentration
  • Motivation
  • Memory
  • Learning
  • Perception (psychotic disorders have been linked to excessive dopamine signalling in the mesolimbic reward pathway)
  • Reward
  • Pleasure
  • Mood
Figure 21: Dopamine

Enzyme - Usually a protein that catalyses (increases the reaction rate of) a reaction that's referred to here as the enzyme-catalysed reaction. Compounds that an enzyme catalyses a reaction for are referred to as a substrate for the enzyme.

Essential Amino Acid - An amino acid that is essential for humans to consume in order to maintain good health. 

Euthymia - A good or normal mood.

Hippocampus - A brain structure involved in the conversion of short-term memory to long-term memory. 

In Vitro - In the laboratory, not inside living organisms.

INN - International Non-proprietary Name. The name that is recognised world-wide except for when countries have their own naming conventions. 

Long-Term Potentiation (LTP) - Is a long-lasting enhancement in communication between two neurons, resulting from both neurons being stimulated simultaneously.

Monotherapy - A treatment regimen that consists of a single medication for the treatment of a particular condition. 

Neuron - The electrically signalling cells of the brain, spinal cord and peripheral nervous system.

Neurotrophic Factor - A protein that serves two purposes when neurons are exposed to said factors:
  • Protection of neurons from further damage
  • Formation of new neurons

Norepinephrine - also known as noradrenaline is a monoamine neurohormone (hormones that are secreted by special glands known as neurosecretory glands that are directly linked to the CNS. Normally have additional roles in the CNS, which norepinephrine does definitely have) that appears to play key roles in:
  • Memory
  • Learning
  • Concentration/attention
  • Pain
  • Mood
  • Anxiety
  • Vasoconstriction/vasodilation
  • Blood pressure
  • Heart rate
Figure 22: Norepinephrine

Peripheral Nervous System (PNS) - The nerves of the body. They can either be afferent (i.e. sensory, like those you require to see this post) or efferent (i.e. those involved in muscle contractions).

Phosphodiesterase (PDE) - A family of enzymes involved in the second messenger system. They degrade cyclic adenosine monophosphate (cAMP) which is an important second messenger in cells. Inhibition of PDE leads to an elevation of cAMP and an increase in second messenger activity. PDE4 is expressed in a wide range of tissues, such as immune cells and CNS cells. PDE4 inhibition leads to improvement in cognition, mood, the alleviation of psychotic symptoms (i.e. the positive symptoms of schizophrenia) anti-inflammatory effects. PDE5 inhibitors are commonly used as erectile dysfunction (ED) medication such as the notorious ED drug sildenafil (viagra). 

Premenstural Dysphoric Disorder (PDD) - A predominantly mental disorder linked with menstruation characterised by more severe anxious and depressive symptoms than those normally associated with premenstural syndrome (PMS). 

Randomised, double-blind, placebo-controlled trials - Clinical trials in of which patients with a medical condition were randomly given either a placebo or the drug being tested for efficacy in said condition and neither they nor the dispensers of the medication (e.g. doctors) knew whether they were on the real drug or on the placebo. 

Reuptake - The removal of a neurotransmitter (i.e. the one undergoing reuptake) from the synaptic cleft (the gap between neurons in of which either chemical (which are in the form of neurotransmitters released by one neuron that then attaches to the receptors on the other neuron) or electrical signals are used to carry information).

Schizophrenia - A psychiatric illness characterised, usually, by a mixture of what's known as positive, negative and cognitive symptoms. Positive symptoms are things schizophrenics have on top of what most people have, such as hallucinations, delusions, thought (e.g. inability to organise thoughts together) and movement disorders (e.g. they might continually do a pointless and unusual movement). Negative symptoms include blunted or flat affect (affect is emotional responsiveness); lack of desire for relationships; a compromised ability to feel pleasure; lack of ability to begin and sustain planned activities; speaking little, even when forced to interact. Cognitive symptoms include memory and learning impairments, difficulty paying attention and poor ability to make decisions based on available information.

Seasonal Affective Disorder (SAD) - Also known as winter blues or winter depression is an affective (or mood) disorder characterised by major shifts in mood across the different parts of the year. Most commonly euthymia occurs during the summer and depression during the winter.

Serotonin - Also known by the chemical name 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter that occurs primarily in the brain, spinal cord and peripheral nerves where it is involved in neurotrasmission associated with:

  • Memory
  • Learning
  • Temperature regulation
  • Sleep
  • Mood
  • Anxiety
  • Stress
  • Pain
  • Vasodilation & vasoconstriction (the dilation [expansion] and constriction of blood vessels, respectively)
  • Perception (e.g. LSD and psilocybin [the chief active constituent of magic mushrooms] work, or so it appears, by activating one of the serotonin receptors)
It is also found in platelets, which are cells involved in blood clotting, among other things, and appears to regulate clotting. It also appears to be involved in immune function. 

Figure 23: Serotonin

Serotonin syndrome - A condition characterised by excess serotonin in the CNS. It presents with the following symptoms:
  • Agitation or restlessness
  • Diarrhea
  • Fast heart beat and high blood pressure
  • Hallucinations
  • Increased body temperature
  • Loss of coordination
  • Nausea
  • Overactive reflexes
  • Rapid changes in blood pressure
  • Vomiting
(Perez, 2012)

Statistical Nomenclature - N is the sample size, that is how many patients were used in the study, including placebo-treated patients. p is the probability that there is no correlation between data and is given as a decimal point. e.g. p=0.01 means there is a 0.01*100%=1% change there is no correlation between the data.

USAN - US Adopted Name. The approved generic name for drugs in the US.

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