Tag: Serotonin

Yes or No: Is there a Link Between Depression and Serotonin?

Published on by Andrew Marshall1 Comment

Every year many suffering with depression are prescribed antidepressants to manage their condition, with antidepressants being described – by a spokesperson for the Royal College of Psychiatrists – as “an effective evidence-based treatment” (The Pharmaceutical Journal, 2022).

Within England, UK, “From 2021-22, there was a 5% rise in the number of adults receiving them – from 7.9 million in the previous 12 months to 8.3 million. [… with …] “An estimated 83.4 million antidepressant drug items were prescribed between 2021 and 2022, which marks a 5% increase from the previous year.” (BBC, 2022).

Within the US, Brody and Gu (2020) reported that “During 2015–2018, 13.2% of adults aged 18 and over used antidepressant medications in the past 30 days. [… and … ] In 2018, an estimated 7.2% of American adults had a major depressive episode in the past year. Carey and Geberloff reported in 2018 that “Nearly 25 million adults, like Ms. Toline, have been on antidepressants for at least two years, a 60 percent increase since 2010.”

Now it is important to remember that:

  • Depression is associated with diminished quality of life and increased disability;
  • Antidepressants are one of the primary treatments for depression;
  • Antidepressants are among the most frequently used therapeutic medications in the UK and US; and
  • There is research to suggest antidepressants work, at least in some people.

However, a new major analysis (by Moncrief et al., 2022) reported in the New Scientist suggests there is no link between serotonin levels and depression, raising questions about antidepressants that focus on this brain-signalling molecule (Wild, 2022, p.20).

Although this analysis suggests antidepressants might not be as effective as previously stated, brain electrodes might be. Read our next post about brain electrodes and depression here.

References

BBC (British Broadcasting Corporation). (2022) Nearly Half a Million More Adults on Antidepressants in England. Available from World Wide Web: https://www.bbc.co.uk/news/health-62094744. [Accessed: 17 November, 2022].

Carey, B. & Gebeloff, R. (2018) Many People Taking Antidepressants Discover They Cannot Quit. Available from World Wide Web: https://www.nytimes.com/2018/04/07/health/antidepressants-withdrawal-prozac-cymbalta.html. [Accessed: 17 November, 2022].

Moncrief, J., Cooper, R.E., Stockman, T., Amendola, S., Hengartner, M.P. & Horowitz, M.A. (2022) The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence. Molecular Psychiatry. doi.org/gqh6nd.

The Pharmaceutical Journal. (2022) Antidepressant Prescribing Increases by 35% in Six Years. Available from World Wide Web: https://pharmaceutical-journal.com/article/news/antidepressant-prescribing-increases-by-35-in-six-years. [Accessed: 17 November, 2022].

Wild, S. (2022) No Link between Depression and Serotonin, Finds Major Analysis. New Scientist. 30 July 2022, pp.20.

An Overview of the Biology of Obsessive-Compulsive Disorder

Published on by Andrew Marshall2 Comments

Introduction

The biology of obsessive-compulsive disorder (OCD) refers biologically based theories about the mechanism of OCD.

Cognitive models generally fall into the category of executive dysfunction or modulatory control. Neuroanatomically, functional and structural neuroimaging studies implicate the prefrontal cortex (PFC), basal ganglia (BG), insula, and posterior cingulate cortex (PCC). Genetic and neurochemical studies implicate glutamate and monoamine neurotransmitters, especially serotonin and dopamine.

Refer to Obsessive-Compulsive Spectrum.

Neuroanatomy

Models

The cortico-basal ganglia-thalamo-cortical loop (CBGTC) model is based on the observation that the basal ganglia loops related to the OFC and ACC are implicated in OCD by neuroimaging studies, although the directionality of volumetric and functional changes is not consistent. Causal evidence from OCD secondary to neuropsychiatric disorders supports the CBGTC model. Obsessions may arise from failure of the circuit to gate information that is normally implicitly processed, leading to representation in explicit processing systems such as the dlPFC and hippocampus, and thereby resulting in obsessions.

Abnormal affect in OCD has been hypothesized to result from dysfunction in the OFC, ventral striatum, and amygdala. OCD is characterised by high levels of anxiety, high rates of comorbidity with major depressive disorder, and blunted response to reward. This is reflected by reduced amygdala and ventral striatum response to positive stimuli, and elevated amygdala response to fearful stimuli. Furthermore, deep brain stimulation of the nucleus accumbens is an effective treatment of OCD, and symptom improvement correlates with reduced binding of dopamine receptors. The reduced binding, due to the ability of the radioligand tracers to be displaced by endogenous dopamine, is taken to reflect increased basal dopamine release. Affective dysregulation due to blunted reward, and elevated fear sensitivity may promote compulsivity by assigning excessive motivational salience to avoidance behaviour.

The ventral striatum is important in action selection, and receives inputs from the medial OFC that signal various aspects of value for stimulus association outcomes. By assigning abnormal values to certain behaviours, OFC may lead to compulsive behaviour through modulating action selection in the ventral striatum. A number of abnormalities have been found in the OFC, including reduced volume, increased resting state activity, and reduced activity during cognitive tasks. The difference between resting and cognitive paradigms may be due to increased signal to noise ratio, a possible mechanism of aberrant valuation. OFC-striatum connectivity also predicts symptom severity, although the opposite has been found in some studies.

Besides abnormal valuation of stimuli or tasks, compulsions may be driven by dysfunction in error monitoring that leads to excessive uncertainty.

OCD has also been conceptualised as resulting from dysfunction in response inhibition, and fear extinction. While hyperactivation of the OFC as a whole during resting is observed in OCD, hyperactivation of the lateral OFC and hypoactivation of the mOFC is seen. This is congruent with the localization of fear/avoidance behaviours to the lOFC and emotional regulation to the mOFC. Hyperactivity of the dACC during monitoring task, along with hyperactivity of the lOFC and amygadala may all contribute to generating obsessions, reduced regulation by the mOFC may enable them.

One model suggests that obsessions do not drive compulsions, but are rather byproducts of compulsions, as evidenced by some studies reporting excessive reliance on habit. Dysfunctional habit based learning may be a driver behind neuroimaging studies of memory reporting increased hippocampus activity. The conscious processing of information that is normally implicitly processing may be the underlying cause of obsessions.

Functional Neuroimaging

Functional neuroimaging studies have implicated multiple regions in OCD. Symptom provocation is associated with increased likelihood of activation in the bilateral orbitofrontal cortex (OFC), right anterior PFC, left dorsolateral prefrontal cortex (dlPFC), bilateral anterior cingulate cortex (ACC), left precuneus, right premotor cortex, left superior temporal gyrus (STG), bilateral external globus pallidus, left hippocampus, right insula, left caudate, right posterior cingulate cortex (PCC), and right superior parietal lobule. The medial portion of the orbitofrontal cortex connects with the paralimbic-limbic system, including the insular cortex, cingulate gryus, amygdala, and hypothalamus. This area is involved in encoding the representation of the value of an expected outcome, which is used to anticipate positive and negative consequences that are likely to follow a given action. During affective tasks hyperactivation has been observed in the ACC, insula and head of the caudate and putamen, regions implicated in salience, arousal, and habit. Hypoactivation during affective tasks is observed in the medial prefrontal cortex (mPFC) and posterior caudate, which are implicated in behavioural and cognitive control. During non-affective tasks, hyperactivation has been observed in the precuneus and PCC, while hypoactivation has been observed in the pallidum, ventral anterior thalamus and posterior caudate. An older meta analysis found hyperactivity in the OFC and ACC. An ALE meta analysis of various functional neuroimaging paradigms observed various abnormalities during Go/no go, interference, and task switching paradigms. Decreased likelihood of activation in right putamen and cerebellum was reported during Go/no go. During interference tasks, likelihood of activation was reported in the left superior frontal gyrus, right precentral gyrus, and left cingulate gyrus, to be decreased, and in the right caudate to be increased. Task switching was associated with extensive decreased likelihood of activation in the middle, medial, inferior, superior frontal gyri, caudate, cingulate and precuneus. A separate ALE meta analysis found consistent abnormalities in orbitofrontal, striatal, lateral frontal, anterior cingulate, middle occipital and parietal, and cerebellar regions.

Structural Neuroimaging

Differences in grey matter, white matter and structural connectivity have been observed in OCD. One meta-analysis reported grey matter increases in the bilateral lenticular nuclei, and grey matter decreases in the ACC (anterior cingulate cortex) and mPFC (medial prefrontal cortex).[14] Another meta-analysis reported that global volumes are not decreased, but the left ACC and OFC demonstrate decreased volume, while the thalamus but not basal ganglia have increased volumes. An ALE meta analysis found increased grey matter in the left postcentral gyrus, middle frontal region, putamen, thalamus, left ACC, and culmen, while decreased grey matter was reported in the right temporal gyrus and left insula extending to the inferior frontal gyrus.

Overlapping abnormalities in white matter volume and diffusivity have been reported. Increased white matter volume and decreased Fractional anisotropy has been observed in anterior midline tracts, interpreted as indicating increased crossings. However, given these effects were most pronounced in medicated adults, it is possible that medication plays a role An ALE meta analysis has observed increased FA in the superior longitudinal fasiculus and corpus callosum, and decreased FA in inferior longitudinal and cingulum fibres.

Neurochemistry

Glutamate, an excitatory neurotransmitter has been implicated in OCD. MRS studies have observed decreased Glx (glutamate, glutamine and GABA) in the striatum. However, increased Glx has been reported in the ACC. Furthermore, increased cerebrospinal fluid (CSF) glutamate and glycine have been found. Various preclinical models have supported glutamate signalling dysfunction in OCD, and treatment with glutamatergic agents such as the glutamate-inhibiting riluzole has been reported to be efficacious.

Reduced dopamine D1 receptors and dopamine D2 receptors in the striatum have been reported in people with OCD, along with both increased and decreased reports of dopamine transporter (DAT) binding. While antipsychotics are sometimes used to treat refractory OCD, they frequently fail in treating or exacerbate OCD symptoms. Treatment with deep brain stimulation is effective in OCD, and response correlates with increased dopamine in the nucleus accumbens. Combined this evidence suggests that OCD may be associated with both increased and decreased dopamine signalling, or that a unidirectional model may not be adequate.

Drug challenge studies have implicated 5-HT2A and 5-HT2A in OCD. Administration of meta-Chlorophenylpiperazine (mCPP), a non selective serotonin (5-HT) release and receptor agonist with a preference for 5-HT2C has been reported to exacerbate OCD symptoms. Psilocybin, a 5-HT2C, 5-HT2A and 5-HT1A receptor agonist has been associated with acute improvement of OCD symptoms. In vivo neuroimaging has found abnormalities with 5-HT2A and serotonin transporter (5-HTT). Inconsistent binding potentials have been observed for 5-HT2A, with both decreased and increased and binding potentials being reported. Inconsistent results have been reported in with respect to 5-HTT as well, with increased, decreased and no changes being reported.

Oestrogen and OCD

Aromatase is an enzyme expressed in several gonadic tissue sites. It is the rate limiting step in the conversion of androgens to oestrogen. This conversion can significantly impact oestrogen levels in brain areas. These OCD-linked effects have been demonstrated by Aromatase knockout mice (ArKO), who lack a functional enzyme to convert androgens to oestrogen. This ArKO knockout strategy has provided a model to examine the physiological impact of lower than normal amounts of oestrogen.

Studies with ArKO mice have been used to show that varying levels of oestrogen affect the onset of OCD behaviours. Lower amounts of oestrogen are associated with an increase of OCD behaviours in males more than females.

Variation in oestrogen can lead to increased levels of OCD symptoms within women as well. The disorder itself has a later onset in women, and tends to show two distinct peaks of onset. The first peak occurs around puberty and the second around the age of childbearing. These peaks correlate with time periods where oestrogen levels are highest in women.

What is Serotonin Syndrome?

Published on by Andrew Marshall9 Comments

Introduction

Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs.

Not to be confused with Antidepressant Discontinuation Syndrome.

The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include high blood pressure and a fast heart rate; usually without a fever. Symptoms in moderate cases include high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhoea. In severe cases body temperature can increase to greater than 41.1 °C (106.0 °F). Complications may include seizures and extensive muscle breakdown.

Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs. This may include selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), monoamine oxidase inhibitor (MAOI), tricyclic antidepressants (TCAs), amphetamines, pethidine (meperidine), tramadol, dextromethorphan, buspirone, L-tryptophan, 5-HTP, St. John’s wort, triptans, ecstasy (MDMA), metoclopramide, or cocaine. It occurs in about 15% of SSRI overdoses. It is a predictable consequence of excess serotonin on the central nervous system (CNS). Onset of symptoms is typically within a day of the extra serotonin.

Diagnosis is based on a person’s symptoms and history of medication use. Other conditions that can produce similar symptoms such as neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, heat stroke, and meningitis should be ruled out. No laboratory tests can confirm the diagnosis.

Initial treatment consists of discontinuing medications which may be contributing. In those who are agitated, benzodiazepines may be used. If this is not sufficient, a serotonin antagonist such as cyproheptadine may be used. In those with a high body temperature active cooling measures may be needed. The number of cases of serotonin syndrome that occur each year is unclear. With appropriate treatment the risk of death is less than one percent. The high-profile case of Libby Zion, who is generally accepted to have died from serotonin syndrome, resulted in changes to graduate medical education in New York State.

Signs and Symptoms

Symptom onset is usually rapid, often occurring within minutes of elevated serotonin levels. Serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may consist of increased heart rate, shivering, sweating, dilated pupils, myoclonus (intermittent jerking or twitching), as well as overresponsive reflexes. However, many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin; not an effect of elevated serotonin itself. Tremor is a common side effect of MDMA’s action on dopamine, whereas hyperreflexia is symptomatic of exposure to serotonin agonists. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, high blood pressure and hyperthermia; a temperature as high as 40 °C (104 °F). The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental changes include hypervigilance or insomnia and agitation. Severe symptoms include severe increases in heart rate and blood pressure that may lead to shock. Temperature may rise to above 41.1 °C (106.0 °F) in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, kidney failure, and disseminated intravascular coagulation; these effects usually arising as a consequence of hyperthermia.

The symptoms are often described as a clinical triad of abnormalities:

  • Cognitive effects: headache, agitation, hypomania, mental confusion, hallucinations, coma.
  • Autonomic effects: shivering, sweating, hyperthermia, vasoconstriction, tachycardia, nausea, diarrhoea.
  • Somatic effects: myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor.

Cause

A large number of medications and street drugs can cause serotonin syndrome when taken alone at high doses or in combination with other serotonergic drugs. The table below lists some of these drugs.

ClassDrugs
AntidepressantsMAOIs, TCAs, SSRIs, SNRIs, nefazodone, and trazodone.
OpioidsDextropropoxyphene, tramadol, tapentadol, pethidine (meperidine), fentanyl, pentazocine, buprenorphine oxycodone, and hydrocodone.
Central Nervous System StimulantsMDMA, MDA, methamphetamine, lisdexamfetamine, amphetamine, phentermine, amfepramone (diethylpropion), serotonin releasing agents like hallucinogenic substituted amphetamines, sibutramine, methylphenidate, and cocaine.
5-HT1 AgonistsTriptans
Psychedelics5-Methoxy-diisopropyltryptamine, alpha-methyltryptamine, and LSD.
HerbsSt John’s Wort, Syrian rue, Panax ginseng, Nutmeg, and Yohimbe.
OthersTryptophan, L-Dopa, valproate, buspirone, lithium, linezolid, dextromethorphan, 5-hydroxytryptophan, chlorpheniramine, risperidone, olanzapine, ondansetron, granisetron, metoclopramide, ritonavir, and metaxalone.

Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin. It may also occur due to an overdose of a single serotonergic agent. The combination of MAOIs with precursors such as L-tryptophan or 5-HTP pose a particularly acute risk of life-threatening serotonin syndrome. The case of combination of MAOIs with tryptamine agonists (commonly known as ayahuasca) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as the “cheese effect”. Many MAOIs irreversibly inhibit monoamine oxidase. It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors. With respect to tricyclic antidepressants only clomipramine and imipramine have a risk of causing SS.

Many medications may have been incorrectly thought to cause serotonin syndrome. For example, some case reports have implicated atypical antipsychotics in serotonin syndrome, but it appears based on their pharmacology that they are unlikely to cause the syndrome. It has also been suggested that mirtazapine has no significant serotonergic effects, and is therefore not a dual action drug. Bupropion has also been suggested to cause serotonin syndrome, although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome. In 2006 the United States Food and Drug Administration (FDA) issued an alert suggesting that the combined use of SSRIs or SNRIs and triptan medications or sibutramine could potentially lead to severe cases of serotonin syndrome. This has been disputed by other researchers as none of the cases reported by the FDA met the Hunter criteria for serotonin syndrome. The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine.

The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. Serotonin syndrome has been reported in patients of all ages, including the elderly, children, and even newborn infants due to in utero exposure. The serotonergic toxicity of SSRIs increases with dose, but even in over-dose it is insufficient to cause fatalities from serotonin syndrome in healthy adults. Elevations of central nervous system serotonin will typically only reach potentially fatal levels when drugs with different mechanisms of action are mixed together. Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (e.g. tramadol, amphetamine, and MDMA) and are associated with severe cases of the syndrome.

Although the most significant health risk associated with opioid overdoses is respiratory depression, it is still possible for an individual to develop serotonin syndrome from certain opioids without the loss of consciousness. However, most cases of opioid-related serotonin syndrome involve the concurrent use of a serotergenic drug such as antidepressants. Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression.

Cases where opioids alone are the cause of serotonin syndrome are typically seen with tramadol, because of its dual mechanism as a serotonin-norepinephrine reuptake inhibitor. Serotonin syndrome caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating the condition.

Pathophysiology

Serotonin is a neurotransmitter involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting. In humans the effects of excess serotonin were first noted in 1960 in patients receiving a monoamine oxidase inhibitor (MAOI) and tryptophan. The syndrome is caused by increased serotonin in the central nervous system. It was originally suspected that agonism of 5-HT1A receptors in central grey nuclei and the medulla was responsible for the development of the syndrome. Further study has determined that overstimulation of primarily the 5-HT2A receptors appears to contribute substantially to the condition. The 5-HT1A receptor may still contribute through a pharmacodynamic interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes. Additionally, noradrenergic CNS hyperactivity may play a role as CNS norepinephrine concentrations are increased in serotonin syndrome and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role; NMDA receptor antagonists and GABA have been suggested as affecting the development of the syndrome. Serotonin toxicity is more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects of overdose.

Spectrum Concept

A postulated “spectrum concept” of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The dose-effect relationship is the effects of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug which may produce large elevations in serotonin levels. Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of poisoning.

Diagnosis

There is no specific test for serotonin syndrome. Diagnosis is by symptom observation and investigation of the person’s history. Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach. Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have better sensitivity and specificity, 84% and 97%, respectively, when compared with the gold standard of diagnosis by a medical toxicologist. As of 2007, Sternbach’s criteria were still the most commonly used.

The most important symptoms for diagnosing serotonin syndrome are tremor, extreme aggressiveness, akathisia, or clonus (spontaneous, inducible and ocular). Physical examination of the patient should include assessment of deep-tendon reflexes and muscle rigidity, the dryness of the mucosa of the mouth, the size and reactivity of the pupils, the intensity of bowel sounds, skin colour, and the presence or absence of sweating. The patient’s history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription and over-the-counter drugs, illicit substances, and dietary supplements, as all these agents have been implicated in the development of serotonin syndrome. To fulfil the Hunter Criteria, a patient must have taken a serotonergic agent and meet one of the following conditions:

  • Spontaneous clonus, or
  • Inducible clonus plus agitation or diaphoresis, or
  • Ocular clonus plus agitation or diaphoresis, or
  • Tremor plus hyperreflexia, or
  • Hypertonism plus temperature > 38 °C (100 °F) plus ocular clonus or inducible clonus.

Differential Diagnosis

Serotonin toxicity has a characteristic picture which is generally hard to confuse with other medical conditions, but in some situations it may go unrecognized because it may be mistaken for a viral illness, anxiety disorders, neurological disorder, anticholinergic poisoning, sympathomimetic toxicity, or worsening psychiatric condition. The condition most often confused with serotonin syndrome is neuroleptic malignant syndrome (NMS). The clinical features of neuroleptic malignant syndrome and serotonin syndrome share some features which can make differentiating them difficult. In both conditions, autonomic dysfunction and altered mental status develop. However, they are actually very different conditions with different underlying dysfunction (serotonin excess vs dopamine blockade). Both the time course and the clinical features of NMS differ significantly from those of serotonin toxicity. Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs like chlorpromazine and cyproheptadine. Dopamine receptor blockade (NMS) has a slow onset, typically evolves over several days after administration of a neuroleptic drug, and responds to dopamine agonists such as bromocriptine.

Differential diagnosis may become difficult in patients recently exposed to both serotonergic and neuroleptic drugs. Bradykinesia and extrapyramidal “lead pipe” rigidity are classically present in NMS, whereas serotonin syndrome causes hyperkinesia and clonus; these distinct symptoms can aid in differentiation.

Management

Management is based primarily on stopping the usage of the precipitating drugs, the administration of serotonin antagonists such as cyproheptadine, and supportive care including the control of agitation, the control of autonomic instability, and the control of hyperthermia. Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with activated charcoal if it can be administered within an hour of overdose. The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving benzodiazepines for myoclonus, and waiting for the symptoms to resolve. Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists. The serotonin antagonist cyproheptadine is the recommended initial therapy, although there have been no controlled trials demonstrating its efficacy for serotonin syndrome. Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine. Animal experiments also suggest a benefit from serotonin antagonists. Cyproheptadine is only available as tablets and therefore can only be administered orally or via a nasogastric tube; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases. Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed.

Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such as olanzapine. Critically ill people should receive the above therapies as well as sedation or neuromuscular paralysis. People who have autonomic instability such as low blood pressure require treatment with direct-acting sympathomimetics such as epinephrine, norepinephrine, or phenylephrine.[6] Conversely, hypertension or tachycardia can be treated with short-acting antihypertensive drugs such as nitroprusside or esmolol; longer acting drugs such as propranolol should be avoided as they may lead to hypotension and shock. The cause of serotonin toxicity or accumulation is an important factor in determining the course of treatment. Serotonin is catabolized by monoamine oxidase A in the presence of oxygen, so if care is taken to prevent an unsafe spike in body temperature or metabolic acidosis, oxygenation will assist in dispatching the excess serotonin. The same principle applies to alcohol intoxication. In cases of serotonin syndrome caused by monoamine oxidase inhibitors oxygenation will not help to dispatch serotonin. In such instances, hydration is the main concern until the enzyme is regenerated.

Agitation

Specific treatment for some symptoms may be required. One of the most important treatments is the control of agitation due to the extreme possibility of injury to the person themselves or caregivers, benzodiazepines should be administered at first sign of this. Physical restraints are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometric muscle contractions that are associated with severe lactic acidosis and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacological sedation. The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called rhabdomyolysis.

Hyperthermia

Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with vecuronium, intubation, and artificial ventilation. Suxamethonium is not recommended for muscular paralysis as it may increase the risk of cardiac dysrhythmia from hyperkalaemia associated with rhabdomyolysis. Antipyretic agents are not recommended as the increase in body temperature is due to muscular activity, not a hypothalamic temperature set point abnormality.

Prognosis

Upon the discontinuation of serotonergic drugs, most cases of serotonin syndrome resolve within 24 hours, although in some cases delirium may persist for a number of days. Symptoms typically persist for a longer time frame in patients taking drugs which have a long elimination half-life, active metabolites, or a protracted duration of action.

Cases have reported persisting chronic symptoms, and antidepressant discontinuation may contribute to ongoing features. Following appropriate medical management, serotonin syndrome is generally associated with a favourable prognosis.

Epidemiology

Epidemiological studies of serotonin syndrome are difficult as many physicians are unaware of the diagnosis or they may miss the syndrome due to its variable manifestations. In 1998 a survey conducted in England found that 85% of the general practitioners that had prescribed the antidepressant nefazodone were unaware of serotonin syndrome. The incidence may be increasing as a larger number of pro-serotonergic drugs (drugs which increase serotonin levels) are now being used in clinical practice. One post-marketing surveillance study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone. Additionally, around 14 to 16 percent of persons who overdose on SSRIs are thought to develop serotonin syndrome.

Notable Cases

The most widely recognised example of serotonin syndrome was the death of Libby Zion in 1984. Zion was a freshman at Bennington College at her death on 05 March 1984, at age 18. She died within 8 hours of her emergency admission to the New York Hospital Cornell Medical Centre. She had an ongoing history of depression, and came to the Manhattan hospital on the evening of 04 March 1984, with a fever, agitation and “strange jerking motions” of her body. She also seemed disoriented at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her for hydration and observation. Her death was caused by a combination of pethidine and phenelzine. A medical intern prescribed the pethidine. The case influenced graduate medical education and residency work hours. Limits were set on working hours for medical postgraduates, commonly referred to as interns or residents, in hospital training programmes, and they also now require closer senior physician supervision.

What is a Serotonergic Drug?

Published on by Andrew Marshall1 Comment

Introduction

Serotonergic means “pertaining to or affecting serotonin”.

Background

Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron produces serotonin. A substance is serotonergic if it produces its effects via interactions with the serotonin system, such as by stimulating or blocking neurotransmission.

A serotonergic or serotoninergic agent is any chemical that modifies the effects of serotonin in the body. Some different types of serotonergics drugs include the following:

  • Serotonin receptor agonists and antagonists;
  • Serotonin reuptake inhibitors; and
  • Serotonin releasing agents.

What is a Serotonin-Norepinephrine Reuptake Inhibitor?

Published on by Andrew Marshall16 Comments

Introduction

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs that treat major depressive disorder (MDD), anxiety disorders, obsessive-compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin only.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane transport proteins that are responsible for the reuptake of serotonin and norepinephrine from the synaptic cleft back into the presynaptic nerve terminal. Dual inhibition of serotonin and norepinephrine reuptake can offer advantages over other antidepressant drugs by treating a wider range of symptoms. They can be especially useful in concomitant chronic or neuropathic pain.

SNRIs, along with SSRIs and norepinephrine reuptake inhibitors (NRIs), are second-generation antidepressants. Over the past two decades, second-generation antidepressants have simply replaced first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), as the drugs of choice for the treatment of MDD due to their improved tolerability and safety profile.

Medications

There are eight FDA approved SNRIs in the United States, with venlafaxine being the first drug to be developed in 1993 and levomilnacipran being the latest drug to be developed in 2013. The drugs vary by their other medical uses, chemical structure, adverse effects, and efficacy.

  • Atomoxetine.
  • Desvenlafaxine.
  • Duloxetine.
  • Levomilnacipran.
  • Milnacipran.
  • Sibutramine.
  • Tramadol.
  • Venlafaxine.

Brief History

Refer to Development and Discovery of SSRI Drugs.

In 1952, iproniazid, an antimycobacterial agent, was discovered to have psychoactive properties while researched as a possible treatment for tuberculosis. Researchers noted that patients given iproniazid became cheerful, more optimistic, and more physically active. Soon after its development, iproniazid and related substances were shown to slow enzymatic breakdown of serotonin, dopamine, and norepinephrine via inhibition of the enzyme monoamine oxidase. For this reason, this class of drugs became known as monoamine oxidase inhibitors, or MAOIs. During this time development of distinctively different antidepressant agents was also researched. Imipramine became the first clinically useful tricyclic antidepressant (TCA). Imipramine was found to affect numerous neurotransmitter systems and to block the reuptake of norepinephrine and serotonin from the synapse, therefore increasing the levels of these neurotransmitters. Use of MAOIs and TCAs gave major advances in treatment of depression but their use was limited by unpleasant side effects and significant safety and toxicity issues.

Throughout the 1960s and 1970s, the catecholamine hypothesis of emotion and its relation to depression was of wide interest and that the decreased levels of certain neurotransmitters, such as norepinephrine, serotonin, and dopamine might play a role in the pathogenesis of depression. This led to the development of fluoxetine, the first SSRI. The improved safety and tolerability profile of the SSRIs in patients with MDD, compared with TCAs and MAOIs, represented yet another important advance in the treatment of depression.

Since the late 1980s, SSRIs have dominated the antidepressant drug market. Today, there is increased interest in antidepressant drugs with broader mechanisms of action that may offer improvements in efficacy and tolerability. In 1993, a new drug was introduced to the US market called venlafaxine, a SNRI. Venlafaxine was the first compound described in a new class of antidepressive substances called phenylethylamines. These substances are unrelated to TCA and other SSRIs. Venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine in the central nervous system. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action mainly due to a subsequent norepinephrine reuptake inhibition.

Mechanism of Action

Monoamines are connected to the pathophysiology of depression. Symptoms may occur because concentrations of neurotransmitters, such as norepinephrine and serotonin, are insufficient, leading to downstream changes. Medications for depression affect the transmission of serotonin, norepinephrine, and dopamine. Older and more unselective antidepressants like TCAs and MAOIs inhibit the reuptake or metabolism of norepinephrine and serotonin in the brain, which results in higher concentrations of neurotransmitters. Antidepressants that have dual mechanisms of action inhibit the reuptake of both serotonin and norepinephrine and, in some cases, inhibit with weak effect the reuptake of dopamine. Antidepressants affect variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle, leading to decreased cardiac conduction and cardiotoxicity {source needed}. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression. Drugs that selectively block the reuptake of serotonin and norepinephrine effectively treat depression and are better tolerated than TCAs. TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity.

Tricyclic Antidepressants

TCAs were the first medications that had dual mechanism of action. The mechanism of action of tricyclic secondary amine antidepressants is only partly understood. TCAs have dual inhibition effects on norepinephrine reuptake transporters and serotonin reuptake transporters. Increased norepinephrine and serotonin concentrations are obtained by inhibiting both of these transporter proteins. TCAs have substantially more affinity for norepinephrine reuptake proteins than the SSRIs. This is because of a formation of secondary amine TCA metabolites.

In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for increased availability of norepinephrine in or near the synaptic clefts. Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of norepinephrine transport and variable blockade of serotonin transport.

Norepinephrine interacts with postsynaptic α and β adrenergic receptor subtypes and presynaptic α2 autoreceptors. The α2 receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in the central nervous system. Formation of norepinephrine is reduced by autoreceptors through the rate-limiting enzyme tyrosine hydroxylase, an effect mediated by decreased cyclic AMP-mediated phosphorylation-activation of the enzyme. α2 receptors also cause decreased intracellular cyclic AMP expression which results in smooth muscle relaxation or decreased secretion.

TCAs activate a negative feedback mechanism through their effects on presynaptic receptors. One probable explanation for the effects on decreased neurotransmitter release is that, as the receptors activate, inhibition of neurotransmitter release occurs (including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents). Repeated exposure of agents with this type of mechanism leads to inhibition of neurotransmitter release, but repeated administration of TCAs finally leads to decreased responses by α2 receptors. The desensitization of these responses may be due to increased exposure to endogenous norepinephrine or from the prolonged occupation of the norepinephrine transport mechanisms (via an allosteric effect). The adaptation allows the presynaptic synthesis and secretion of norepinephrine to return to, or even exceed, normal levels of norepinephrine in the synaptic clefts. Overall, inhibition of norepinephrine reuptake induced by TCAs leads to decreased rates of neuron firing (mediated through α2 autoreceptors), metabolic activity, and release of neurotransmitters.

TCAs do not block dopamine transport directly but might facilitate dopaminergic effects indirectly by inhibiting dopamine transport into noradrenergic terminals of the cerebral cortex. Because they affect so many different receptors, TCAs have adverse effects, poor tolerability, and an increased risk of toxicity.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin and are a widely used group of antidepressants. With increased receptor selectivity compared to TCAs, undesired effects such as poor tolerability are avoided. Serotonin is synthesized from an amino acid called L-tryptophan. Active transport system regulates the uptake of tryptophan across the blood-brain barrier. Serotonergic pathways are classified into two main ways in the brain: the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord.

Selective Norepinephrine Reuptake Inhibitors

Noradrenergic neurons are located in two major regions in the brain. These regions are locus coeruleus and lateral tegmental. With administration of SNRIs, neuronal activity in locus coeruleus region is induced because of increased concentration of norepinephrine in the synaptic cleft. This results in activation of α2 adrenergic receptors, as discussed previously.

Assays have shown that SNRIs have insignificant penchant for mACh, α1 and α2 adrenergic, or H1 receptors.

Dual Serotonin and Norepinephrine Reuptake Inhibitors

Agents with dual serotonin and norepinephrine reuptake inhibition (SNRIs) are sometimes called non-tricyclic serotonin and norepinephrine reuptake inhibitors. Clinical studies suggest that compounds that increase the concentration in the synaptic cleft of both norepinephrine and serotonin are more successful than single acting agents in the treatment of depression, but the data is not conclusive whether SNRIs are a more effective treatment option over SSRIs for depression. Dual reuptake inhibitors have low affinity at neuronal receptors of the other neurotransmitters, which have low adverse effects compared with the TCAs. Nontricyclic antidepressants have improved potency and onset action acceleration in antidepressant response than SSRIs alone, which give the impression that synergism is an efficient property in mediating antidepressant activity.

The non-tricyclic SNRIs have several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions, and the half-life of the nontricyclic SNRIs.

Combination of mechanisms of action in a single active agent is an important development in psychopharmacology.

Structure Activity Relationship (SAR)

Aryloxypropanamine Scaffold

Several reuptake inhibitors contain an aryloxypropanamine scaffold. This structural motif has potential for high affinity binding to biogenic amine transports. Drugs containing an aryloxypropanamine scaffold have selectivity profile for norepinephrine and serotonin transporters that depends on the substitution pattern of the aryloxy ring. Selective NRIs contain a substituent in 2′ position of the aryloxy ring but SSRIs contain a substituent in 4′ position of the aryloxy ring. Atomoxetine, nisoxetine and reboxetine all have a substitution group in the 2′ position and are selective NRIs while compounds that have a substitution group in the 4′ position (like fluoxetine and paroxetine) are SSRIs. Duloxetine contains a phenyl group fused at the 2′ and 3′ positions, therefore it has dual selective norepinephrine and serotonin reuptake inhibitory effects and has similar potencies for the both transporters. The nature of the aromatic substituent also has a significant influence on the activity and selectivity of the compounds as inhibitors of the serotonin or the norepinephrine transporters.

Cycloalkanol Ethylamine Scaffold

Venlafaxine and desvenlafaxine contain a cycloalkanol ethylamine scaffold. Increasing the electron-withdrawing nature of the aromatic ring provides a more potent inhibitory effect of norepinephrine uptake and improves the selectivity for norepinephrine over the serotonin transporter. Effects of chloro, methoxy and trifluoromethyl substituents in the aromatic ring of cycloalkanol ethylamine scaffold were tested. The results showed that the strongest electron-withdrawing m-trifluoromethyl analogue exhibited the most potent inhibitory effect of norepinephrine and the most selectivity over serotonin uptake. WY-46824, a piperazine-containing derivative, has shown norepinephrine and dopamine reuptake inhibition. Further synthesis and testing identified WAY-256805, a potent norepinephrine reuptake inhibitor that exhibited excellent selectivity and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.

Milnacipran

Milnacipran is structurally different from other SNRIs. The SAR of milnacipran derivatives at transporter level is still largely unclear and is based on in vivo efficacy that was reported in 1987. N-methylation of milnacipran in substituent group R4 and R5 reduces the norepinephrine and serotonin activity. Researches on different secondary amides in substitution groups R6 and R7 showed that π electrons play an important role in the interaction between transporters and ligands. A phenyl group in substituent R6 showed effect on norepinephrine transporters. Substituent groups in R6 and R7 with allylic double bond showed significant improved effect on both norepinephrine and serotonin transporters. Studies show that introducing a 2-methyl group in substituent R3, the potency at norepinephrine and serotonin transporters are almost abolished. Methyl groups in substituent groups R1 and R2 also abolish the potency at norepinephrine and serotonin transporters. Researchers found that replacing one of the ethyl groups of milnacipran with an allyl moiety increases the norepinephrine potency. The pharmacophore of milnacipran derivatives is still largely unclear.

The conformation of milnacipran is an important part of its pharmacophore. Changing the SAR in milnacipran changes the stereochemistry of the compound and affects the norepinephrine and serotonin concentration. Milnacipran is marketed as a racemic mixture. Effects of milnacipran reside in the (1S,2R)-isomer and substitution of the phenyl group in the (1S,2R)-isomer has negative impact on norepinephrine concentration. Milnacipran has low molecular weight and low lipophilicity. Because of these properties, milnacipran exhibits almost ideal pharmacokinetics in humans such as high bioavailability, low inter-subject variability, limited liver enzyme interaction, moderate tissue distribution and a reasonably long elimination half-life. Milnacipran’s lack of drug-drug interactions via cytochrome P450 enzymes is thought to be an attractive feature because many of the central nervous system drugs are highly lipophilic and are mainly eliminated by liver enzymes.

Future Development of SAR

The application of an aryloxypropanamine scaffold has generated a number of potent MAOIs. Before the development of duloxetine, the exploration of aryloxypropanamine SAR resulted in the identification of fluoxetine and atomoxetine. The same motif can be found in reboxetine where it is constrained in a morpholine ring system. Some studies have been made where the oxygen in reboxetine is replaced by sulfur to give arylthiomethyl morpholine. Some of the arylthiomethyl morpholine derivatives maintain potent levels of serotonin and norepinephrine reuptake inhibition. Dual serotonin and norepinephrine reuptake inhibition resides in different enantiomers for arylthiomethyl morpholine scaffold. Possible drug candidates with dual serotonin and norepinephrine reuptake inhibitory activity have also been derived from piperazine, 3-amino-pyrrolidine and benzylamine templates.

Clinical Trials

Depression

Several studies have shown that antidepressant drugs which have combined serotonergic and noradrenergic activity are generally more effective than SSRIs, which act upon serotonin reuptake by itself. Serotonergic-noradrenergic antidepressant drugs may have a modest efficacy advantage compared to SSRIs in treating major depressive disorder (MDD), but are slightly less well tolerated. Further research is needed to examine the possible differences of efficacy in specific MDD sub-populations or for specific MDD symptoms, between these classes of antidepressant drugs.

Analgesic

Data from clinical trials have indicated that SNRIs might have pain relieving properties. Although the perception and transmission of pain stimuli in the central nervous system have not been fully elucidated, extensive data support a role for serotonin and norepinephrine in the modulation of pain. Findings from clinical trials in humans have shown these antidepressants can to reduce pain and functional impairment in central and neuropathic pain conditions. This property of SNRIs might be used to reduce doses of other pain relieving medication and lower the frequency of safety, limited efficacy and tolerability issues. Clinical research data have shown in patients with GAD that the SNRI duloxetine is significantly more effective than placebo in reducing pain-related symptoms of GAD, after short-term and long-term treatment. However, findings suggested that such symptoms of physical pain reoccur in relapse situations, which indicates a need for ongoing treatment in patients with GAD and concurrent painful physical symptoms.

Indications

SNRIs have been tested for treatment of the following conditions:

Pharmacology

Route of Administration

SNRIs are delivered orally, usually in the form of capsules or tablets. It is recommended to take SNRIs in the morning with breakfast, which does not affect drug levels, but may help with certain side effects. Norepinephrine has activating effects in the body and therefore can cause insomnia in some patients if taken at bedtime. SNRIs can also cause nausea, which is usually mild and goes away within a few weeks of treatment, but taking the medication with food can help alleviate this. The drugs themselves are usually a fine crystalline powder that diffuses into the body during digestion.

Dosage

Dosages vary depending on the SNRI used due to varying potencies of the drug in question as well as multiple strengths for each drug.

Mode of Action

The condition for which SNRIs are mostly indicated, major depressive disorder, is thought to be mainly caused by decreased levels of serotonin and norepinephrine in the synaptic cleft, causing erratic signalling. Based on the monoamine hypothesis of depression, which asserts that decreased concentrations of monoamine neurotransmitters leads to depressive symptoms, the following relations were determined: “Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life.” SNRIs work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in increased extracellular concentrations of serotonin and norepinephrine and, consequently, an increase in neurotransmission. Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for norepinephrine than serotonin. Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older tricyclic antidepressants (TCAs), but not with the SSRIs.

Recent studies have shown that depression may be linked to increased inflammatory response, thus attempts at finding an additional mechanism for SNRIs have been made. Studies have shown that SNRIs as well as SSRIs have significant anti-inflammatory action on microglia in addition to their effect on serotonin and norepinephrine levels. As such, it is possible that an additional mechanism of these drugs that acts in combination with the previously understood mechanism exist. The implication behind these findings suggests use of SNRIs as potential anti-inflammatories following brain injury or any other disease where swelling of the brain is an issue. However, regardless of the mechanism, the efficacy of these drugs in treating the diseases for which they have been indicated has been proven, both clinically and in practice.

Pharmacodynamics

Most SNRIs function alongside primary metabolites and secondary metabolites in order to inhibit reuptake of serotonin, norepinepherine, and marginal amounts of dopamine. For example, venlafaxine works alongside its primary metabolite O-desmethylvenlafaxine to strongly inhibit serotonin and norepinephrine reuptake in the brain. The evidence also suggests that dopamine and norepinepherine behave in a co-transportational manner, due to the inactivation of dopamine by norepinephrine reuptake in the frontal cortex, an area of the brain largely lacking in dopamine transporters. This effect of SNRIs results in increased dopamine neurotransmission, in addition to the increases in serotonin and norepinephrine activity. Furthermore, because SNRIs are extremely selective, they have no measurable effects on other, unintended receptors, in contrast to monoamine oxidase inhibition. Pharmaceutical tests have determined that use of both SNRIs or SSRIs can generate significant anti-inflammatory action on microglia, as well.

Pharmacokinetics

The half-life of venlafaxine is about 5 hours, and with once-daily dosing, steady-state concentration is achieved after about 3 days, though its active metabolite desvenlafaxine lasts longer. The half-life of desvenlafaxine is about 11 hours, and steady-state concentrations are achieved after 4 to 5 days. The half-life of duloxetine is about 12 hours (range: 8-17 hours), and steady-state is achieved after about 3 days. Milnacipran has a half-life of about 6 to 8 hours, and steady-state levels are reached within 36 to 48 hours.

Contraindications

SNRIs are contraindicated in patients taking MAOIs within the last two weeks due to the increased risk of serotonin syndrome, which can be life-threatening.[65] Other drugs and substances that should be avoided due to increased risk of serotonin syndrome when combined with an SNRI include: other anti-depressants, anti-convulsants, analgesics, antiemetic agents, anti-migraine medications, methylene blue, linezolid, Lithium, St. John’s worts, ecstasy, and LSD. Signs and symptoms of serotonin syndrome include: hyperthermia, rigidity, myoclonus, autonomic instability with fluctuating vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

Due to the effects of increased norepinephrine levels and, therefore, higher noradrenergic activity, pre-existing hypertension should be controlled before treatment with SNRIs and blood pressure periodically monitored throughout treatment. Duloxetine has also been associated with cases of liver failure and should not be prescribed to patients with chronic alcohol use or liver disease. Studies have found that Duloxetine can increase liver function tests three times above their upper normal limit. Patients suffering from coronary artery disease should caution the use of SNRIs. Furthermore, due to some SNRIs’ actions on obesity, patients with major eating disorders such as anorexia nervosa or bulimia should not be prescribed SNRIs. Duloxetine and milnacipran are also contraindicated in patients with uncontrolled narrow-angle glaucoma, as they have been shown to increase incidence of mydriasis.

Side Effects

Because the SNRIs and SSRIs act in similar ways to elevate serotonin levels, they share many side effects, though to varying degrees. The most common side effects include nausea/vomiting, sweating, loss of appetite, dizziness, headache, increase in suicidal thoughts, and sexual dysfunction. Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. However, norepinephrine-selective antidepressants, such as reboxetine and desipramine, have successfully treated anxiety disorders. People at risk for hypertension and heart disease should monitor their blood pressure. The side effects of upset stomach may be decreased by taking SNRIs with food.

Sexual Dysfunction

SNRIs, similarly to SSRIs, can cause several types of sexual dysfunction, such as erectile dysfunction, decreased libido, sexual anhedonia, and anorgasmia. The two common sexual side effects are diminished interest in sex (libido) and difficulty reaching climax (anorgasmia), which are usually somewhat milder with SNRIs compared to SSRIs. To manage sexual dysfunction, studies have shown that switching to or augmenting with bupropion or adding a PDE5 Inhibitor have decreased symptoms of sexual dysfunction. Studies have shown that PDE5 Inhibitors, such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra), have sometimes been helpful to decrease the sexual dysfunction, including erectile dysfunction, although they have been shown to be more effective in men than women.

Serotonin Syndrome

A serious, but rare, side effect of SNRIs is serotonin syndrome, which is caused by an excess of serotonin in the body. Serotonin syndrome can be caused by taking multiple serotonergic drugs, such as SSRIs or SNRIs. Other drugs that contribute to serotonin syndrome include MAO inhibitors, linezolid, tedizolid, methylene blue, procarbazine, amphetamines, clomipramine, and more. Early symptoms of serotonin syndrome may include nausea, vomiting, diarrhoea, sweating, agitation, confusion, muscle rigidity, dilated pupils, hyperthermia, rigidity, and goose bumps. More severe symptoms include fever, seizures, irregular heartbeat, delirium, and coma. If signs or symptoms arise, discontinue treatment with serotonergic agents immediately. It is recommended to washout 4 to 5 half-lives of the serotonergic agent before using an MAO inhibitor.

Bleeding

Some studies suggest there are risks of upper gastrointestinal bleeding, especially venlafaxine, due to impairment of platelet aggregation and depletion of platelet serotonin levels. Similarly to SSRIs, SNRIs may interact with anticoagulants, like warfarin. Currently, there is more evidence of SSRIs having higher risk of bleeding than SNRIs. Studies have suggested caution when using SNRIs or SSRIs with high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or naproxen due to an increased risk of upper GI bleeding.

Precautions

Starting an SNRI Regimen

Due to the extreme changes in noradrenergic activity produced from norepinephrine and serotonin reuptake inhibition, patients that are just starting an SNRI regimen are usually given lower doses than their expected final dosing to allow the body to acclimate to the drug’s effects. As the patient continues along at low doses without any side-effects, the dose is incrementally increased until the patient sees improvement in symptoms without detrimental side-effects.

Discontinuation Syndrome

As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal, or “discontinuation syndrome“, which could include states of anxiety and other symptoms. Therefore, it is recommended that users seeking to discontinue an SNRI slowly taper the dose under the supervision of a professional. Discontinuation syndrome has been reported to be markedly worse for venlafaxine when compared to other SNRIs. As such, as tramadol is related to venlafaxine, the same conditions apply. This is likely due to venlafaxine’s relatively short half-life and therefore rapid clearance upon discontinuation. In some cases, switching from venlafaxine to fluoxetine, a long-acting SSRI, and then tapering off fluoxetine, may be recommended to reduce discontinuation symptoms. Signs and symptoms of withdrawal from abrupt cessation of an SNRI include dizziness, anxiety, insomnia, nausea, sweating, and flu-like symptoms, such as lethargy and malaise.

Overdose

Causes

Overdosing on SNRIs can be caused by either drug combinations or excessive amounts of the drug itself. Venlafaxine is marginally more toxic in overdose than duloxetine or the SSRIs. Risk of overdose is increased in patients taking multiple serotonergic agents or interacting agents.

Symptoms

Symptoms of SNRI overdose, whether it be a mixed drug interaction or the drug alone, vary in intensity and incidence based on the amount of medicine taken and the individuals sensitivity to SNRI treatment. Possible symptoms may include:

  • Somnolence.
  • Coma.
  • Serotonin syndrome.
  • Seizures.
  • Syncope.
  • Tachycardia.
  • Hypotension.
  • Hypertension.
  • Hyperthermia.
  • Vomiting.

Management

Overdose is usually treated symptomatically, especially in the case of serotonin syndrome, which requires treatment with cyproheptadine and temperature control based on the progression of the serotonin toxicity. Patients are often monitored for vitals and airways cleared to ensure that they are receiving adequate levels of oxygen. Another option is to use activated carbon in the GI tract in order to absorb excess neurotransmitter. It is important to consider drug interactions when dealing with overdose patients, as separate symptoms can arise.

Comparison to SSRIs

Because SNRIs were developed more recently than SSRIs, there are relatively few of them. However, the SNRIs are among the most widely used antidepressants today. In 2009, Cymbalta and Effexor were the 11th- and 12th-most-prescribed branded drugs in the United States, respectively. This translates to the 2nd- and 3rd-most-common antidepressants, behind Lexapro (escitalopram), an SSRI. In some studies, SNRIs demonstrated slightly higher antidepressant efficacy than the SSRIs (response rates 63.6% versus 59.3%). However, in one study escitalopram had a superior efficacy profile to venlafaxine.

Special Populations

Pregnancy

Currently, no antidepressants are FDA approved during pregnancy. All SSRIs and SNRIs are Category C, except paroxetine, which is Category D since it has shown association with congenital heart disorders. Use of antidepressants during pregnancy may result in foetus abnormalities affecting functional development of the brain and behaviour. Untreated depression may also affect birth outcomes, so it is recommended to discuss options with a provider to weigh the risks and benefits.

Paediatrics

SSRIs and SNRIs have been shown to be effective in treating major depressive disorder and anxiety in paediatric populations. However, there is a risk of increased suicidality in paediatric populations for treatment of major depressive disorder, especially with venlafaxine. Fluoxetine is the only antidepressant that is approved for child/adolescent major depressive disorder.

Geriatrics

Most antidepressants, including SNRIs, are safe and effective in the geriatric population. Decisions are often based on co-morbid conditions, drug interactions, and patient tolerance. Due to differences in body composition and metabolism, starting doses are often half that of the recommended dose for younger adults.

Exercise for Mental Health

Published on by Andrew MarshallLeave a comment

1.0 Introduction

“Lifestyle modifications can assume especially great importance in individuals with serious mental illness. Many of these individuals are at a high risk of chronic diseases associated with sedentary behavior and medication side effects, including diabetes, hyperlipidemia, and cardiovascular disease. An essential component of lifestyle modification is exercise. The importance of exercise is not adequately understood or appreciated by patients and mental health professionals alike. Evidence has suggested that exercise may be an often-neglected intervention in mental health care.” (Sharma, Madaaan & Petty, 2006).

This article provides an overview of exercise for mental health.

It is now a well-known ‘secret’ that exercise (and, let us not forget, physical activity) has an important part to play in both our physical health and mental health.

I think we can safely state that you (the reader) almost certainly already know that an inactive lifestyle contributes to chronic miseries such as obesity, diabetes, heart disease, cancer, osteoporosis, and an earlier death. You may also be one of the third of people who have resolved to exercise more (well, maybe get Christmas out the way first!).

However, how often do people consider the contribution of physical exercise to their mental health? And, with an expected rise in the number of people with mental health issues, it is more important than ever to extol the benefits of exercise.

“It is estimated there will be nearly 8 million more adults in the UK by 2030. If prevalence rates for mental disorders stay the same (at around one in four), that is some 2 million more adults with mental health problems than today. It is also estimated that there will be one million more children and young people in the UK by 2030. Again, if prevalence rates for mental disorders stay the same (at around one in ten), that is some 100,000 more children and young people with mental health problems than today.” (Mental Health Foundation, 2013, p.2).

Exercising releases natural chemicals, such as serotonin, dopamine and endorphins into the body, which help to boost mood. High levels of serotonin are linked to elevated mood while low levels are associated with depression. Exercise can also help reduce the amount of harmful chemicals in the body that are produced when an individual is stressed.

2.0 Benefits of Exercise

In simple terms, exercise provides a variety of short- and long-term, and obvious and less obvious, benefits.

  • Exercising benefits nearly all aspects of a person’s health (CDC, 2019) – In addition to aiding control weight, it can improve the chances of living longer, maintaining/improving the strength of bones and muscles, and an individual’s mental health.
  • When an individual does not get enough exercise, they are at increased risk for health problems – these include cardiovascular disease, high blood pressure (hypertension), type 2 diabetes, some cancers, and metabolic syndrome (CDC, 2019).
  • Exercise also increases a variety of substances that play an important role in brain function (Section 4.0).
  • Exercise can help prevent (certain) mental illnesses and is an important part of treatment.

Exercise is well-known to stimulate the body to produce our natural feel-good hormones which can make problems seem more manageable.

The simple act of focusing on exercise can give an individual a break from current concerns and damaging self-talk. Further, depending on the activity, individuals may benefit from calming exercises, be energised, and get outside or interact with others, all of which are known to improve mood and general health.

With this in mind, the health benefits from regular exercise that should be emphasised and reinforced by every professional (e.g. mental health, medical, nursing, physiotherapist, fitness/exercise) to individuals include:

  • Improved sleep;
  • Increased interest in sex;
  • Better endurance;
  • Stress relief;
  • Improvement in mood;
  • Increased energy and stamina;
  • Reduced tiredness that can increase mental alertness;
  • Weight reduction;
  • Reduced cholesterol; and
  • Improved cardiovascular fitness.

2.1 What is the Importance of Exercise for those with Mental Health Problems?

Having a mental health problem can put an individual at a higher risk of developing a serious physical health problem. For example, individuals with mental health problems are:

  • Twice as likely to die from heart disease (Harris & Barraclough, 1998).
  • Four times as likely to die from respiratory disease (Phelan et al., 2001).
  • On average, likely to die between 10 and 17 years earlier than the general population, if they have schizophrenia or bipolar disorder.
    • This may be due to a number of factors including poor diet, exercise and social conditions. People may also be slower to seek help, and doctors can sometimes fail to spot physical health problems in people with severe mental health problems.

3.0 Linking Physical Health and Mental Health

It is still very common for physical health and mental health, aka mind and body, to be treated separately (both medically and in general), although attitudes are slowly changing.

There is an increasing pool of evidence that suggests that exercise is not only necessary for the maintenance of good mental health, but it can be used to treat even chronic mental illness.

For example, it is now clear that exercise reduces the likelihood of depression and also maintains mental health as people age. On the treatment side, exercise appears to be as good as existing pharmacological interventions across a range of conditions, such as mild to moderate depression, dementia, and anxiety, and even reduces cognitive issues in schizophrenia.

The question you might now be asking is, how?

3.1 Exercise directly affects the Brain

Aerobic exercises (such as jogging, swimming, cycling, walking, gardening, and dancing) have been proved to reduce anxiety and depression (Guzszkowska, 2004). These improvements in mood are proposed to be caused by exercise-induced increase in blood circulation to the brain and by an influence on the hypothalamic-pituitaryadrenal (HPA) axis and, thus, on the physiologic reactivity to stress (Guszkowska, 2004). It has been suggested that this physiologic influence is probably mediated by the communication of the HPA axis with several regions of the brain, including:

  • The limbic system, which controls motivation and mood;
  • The amygdala, which generates fear in response to stress; and
  • The hippocampus, which plays an important part in memory formation as well as in mood and motivation.

However, it is important to note that other hypotheses that have been proposed to explain the beneficial effects of physical activity on mental health which include (Peluso & Andrade, 2005):

  • Distraction;
  • Self-efficacy; and
  • Social interaction.

In 2017, Firth and colleagues suggested that regular exercise increases the volume of certain brain regions – in part through:

  1. Better blood supply that improves neuronal health by improving the delivery of oxygen and nutrients; and
  2. An increase in neurotrophic factors and neurohormones that support neuron signaling, growth, and connections.

They also stated that of critical importance for mental health is the hippocampus (an area of the brain involved in memory, emotion regulation, and learning). Studies in other animals show convincingly that exercise leads to the creation of new hippocampal neurons (neurogenesis), with preliminary evidence suggesting this is also true in humans.

“Aerobic exercise interventions may be useful for preventing age-related hippocampal deterioration and maintaining neuronal health.” (Firth et al., 2017, p.230).

There is an accumulating evidence base that various mental health conditions are associated with reduced neurogenesis in the hippocampus.

The evidence is particularly strong for depression and, interestingly, many anti-depressants – that were once thought to work through their effects on the serotonin system – are now known to increase neurogenesis (Anacker et al., 2011) in the hippocampus.

Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. It has a popular image as a contributor to feelings of well-being and happiness, though its actual biological function is complex and multifaceted, modulating cognition, reward, learning, memory, and numerous physiological processes. It sends signals between nerve cells. Serotonin is found mostly in the digestive system, although it is also in blood platelets and throughout the central nervous system. Serotonin is made from the essential amino acid tryptophan.

3.2 What does this Mean in Theory?

Theories suggest that newborn hippocampal neurons are likely to be particularly important for storing new memories and keeping old and new memories separate and distinct – Meaning neurogenesis allows a healthy level of flexibility in the use of existing memories, and in the flexible processing of new information.

Frequently, mental ill health is characterised by a cognitive inflexibility that:

  • Keeps the individual repeating unhelpful behaviours;
  • Restricts their ability to process or even acknowledge new information; and
  • Reduces their ability to use what they already know to see new solutions or to change.

Consequently, this suggests that it is plausible that exercise leads to better mental health, in general, through its effects on systems that increase the capacity for mental flexibility.

4.0 Substances that Play an Important Role in Brain Function

  • BDNF (brain derived neurotrophic factor) is a protein that creates and protects neurons (nerve cells) in the brain helps these cells to transmit messages more efficiently, and regulates depression-like behaviours (Vithlani et al., 2013; Sleiman et al., 2016).
  • Endorphins are a type of chemical messenger (neurotransmitter) that is released when we experience stress or pain to reduce their negative effects and increase pleasure throughout the body (Bortz, Angwin & Mefford, 1981).
    • Endorphins are also responsible for the euphoric feeling known as a “runner’s high” that happens after long periods of intense exercise.
  • Serotonin is another neurotransmitter that increases during exercise. It plays a role in sending messages about appetite, sleep, and mood (Young, 2007).
    • It is the target of medications known as SSRIs or SNRIs, which are used to treat anxiety and depression.
  • Dopamine is involved in controlling movement and the body’s reward response system. Due to its role in how the body perceives rewards, it is heavily involved with addictions.
    • When amounts of this chemical messenger are low, it is linked to mental health conditions including depression, schizophrenia, and psychosis (Grace, 2016).
  • Glutamate and GABA (gamma-amino butyric acid) both act to regulate the activity of nerve cells in the parts of the brain that process visual information, determine heart rate, and affect emotions and the ability to think clearly (Maddock et al., 2016).
    • Low levels of GABA have been linked to depression, anxiety, PTSD, and mood disorders (Streeter et al., 2012).

5.0 Exercise as Treatment in Mental Health

  • Just one hour of exercise a week is related to lower levels of mood, anxiety, and substance use disorders (de Graaf & Monshouwer, 2011).
  • Among people in the US, those who make regular physical activity a part of their routines are less likely to have depression, panic disorder, and phobias (extreme fears) (Goodwin, 2003).
  • One study found that for people with anxiety, exercise had similar effects to cognitive behavioural therapy in reducing symptoms (Wipfli, Rethorst & Landers, 2008).
  • For people with schizophrenia, yoga is the most effective form of exercise for reducing positive and negative symptoms associated with the disorder (Vancampfort et al., 2012).
  • While structured group programmes can be effective for individuals with serious mental illness, lifestyle changes that focus on the accumulation and increase of moderate-intensity activity throughout the day may be the most appropriate for most patients (Richardson et al., 2005).
  • Interestingly, adherence to physical activity interventions in psychiatric patients appears to be comparable to that in the general population (Sharma et al., 2006).
  • Exercise is especially important in patients with schizophrenia since these patients are already vulnerable to obesity and also because of the additional risk of weight gain associated with antipsychotic treatment, especially with the atypical antipsychotics.
  • GP surgeries, across the UK, are starting to routinely prescribe exercise as a treatment for a variety of conditions, including depression.
  • The National Institute for Health and Care Excellence (NICE) recommends that if an individual has mild to moderate depression, taking part in three exercises sessions a week can help.

6.0 Examples of How Exercise can Support Mood, Well-being, and Mental Health

  • General:
    • Exercise improves mental health by reducing anxiety, depression, and negative mood and by improving self-esteem and cognitive function (Callaghan, 2004).
    • Exercise has also been found to alleviate symptoms such as low self-esteem and social withdrawal (Peluso & Andrade, 2005).
  • Depression:
    • According to findings from the Royal College of Psychiatrists (2019), if an individual keeps active they are less likely to experience symptoms of depression.
    • The reason for this is because exercise has a certain effect on chemicals in our brains, such as dopamine and serotonin, which affect both your mood and thinking.
    • Just by adding a bit more physical activity into their daily life, an individual can create new activity patterns in the brain which can boost their mood.
    • However, the individual should take it at their own pace, and not attempt difficult new exercises straight away.
  • Anxiety:
    • Frequent exercise can help people with anxiety to be less likely to panic when they experience ‘fight-or-flight’ sensations.
    • This is because the human body produces many of the same physical reactions, including heavy perspiration (sweating) and increased heart rate, in response to exercise.
    • A study by the American Psychological Association in 2011 demonstrated that over a two-week exercise programme, a test group of 60 people who took part in exercises showed significant improvements in anxiety sensitivity compared to a control group (Weir, 2011).
  • Stress:
    • Stress does not just affect an individual’s brain, with its many nerve connections, it also has an impact on the way they feel physically.
    • This can manifest as muscle tension, especially in the face, neck and shoulders.
    • However, research by the Anxiety and Depression Association of America (2018) shows that physical activity is helpful when stress has depleted an individual’s energy – because exercise produces endorphins that act as a natural painkiller.
    • And, these endorphins help relieve tension in the body and relax muscles, which can alleviate stress.
  • Attention Deficit Hyperactivity Disorder (ADHD):
    • Although the exact cause of ADHD is unknown, research suggests that exercise can have a similar effect on the brain as medication for ADHD does.
    • This is because exercise releases chemicals in the brain such as norepinephrine, serotonin and dopamine, which help to improve focus and attention.
    • And, physical activity can help to improve mood, concentration and motivation – all of which help to reduce symptoms of ADHD.
  • Post-Traumatic Stress Disorder (PTSD) and Trauma:
    • Activities such as sailing, hiking, and mountain biking, and rock climbing have particularly been shown to alleviate the effects of PTSD and trauma.
    • By focusing on their body and how it feels when exercising, an individual can help their nervous system become ‘unstuck’, so that it moves out of the immobilisation stress response that can create PTSD or trauma.
  • Memory:
    • As well as improving our concentration, physical activity can also help age-related memory problems.
    • A study in 2012 (Sifferlin, 2012) found that people in their 70s who participated in more physical exercise, such as walking several times a week, experienced fewer signs of ageing in the brain than those who were less physically active.

7.0 How much Exercise should an Individual Be Doing?

In the UK, the NHS (2019) suggests that adults (19 to 64) should:

  • Do some form of physical activity every day – with any activity being better than none.
  • Do strengthening activities that work all the major muscles (legs, hips, back, abdomen, chest, shoulders and arms) on at least 2 days a week.
  • Do at least 150 minutes of moderate intensity activity a week or 75 minutes of vigorous intensity activity a week.
    • Moderate activity includes: brisk walking, water aerobics, riding a bike, dancing, tennis, pushing a lawn mower, hiking, and roller blading.
    • Vigorous activity includes: Jogging or running, swimming fast, riding a bike fast or on hills, walking up the stairs, sports (e.g. football, rugby, netball, and hockey), skipping rope, aerobics, gymnastics, and martial arts.
  • Reduce time spent sitting or lying down, and break up long periods of not moving with some activity.

Do not be disheartened, as exercise does not have to be done for hours on end. For example, ten minutes of moderate or vigorous activity at a time, fifteen times a week will see the individual achieve the recommended amount.

Muscle strengthening activities should be incorporated into an individual’s exercise routine twice a week. This includes yoga, lifting weights, resistance band exercises, and things like press/push-ups, and sit-ups. An individual’s muscles should be tired by the time they are finished with their exercises, but the individual should make sure they are not trying to lift too much too soon, or they could injure themselves.

In 2013, Rethorst and Trivedi, psychiatrists, demonstrated that three or more sessions per week of aerobic exercise or resistance training, for 45 to 60 minutes per session, can help treat even chronic depression. In terms of intensity, for aerobic exercise, Rethorst and Trivedi (2013) recommend achieving a heart rate that is 50-85% of the individual’s maximum heart rate (HRmax).  For resistance training, they recommend a variety of upper and lower body exercises – three sets of eight repetitions at 80% of 1-repetition maximum (RM, that is, 80% of the maximum weight that the individual can lift one time). They suggest that effects tend to be noticed after about four weeks (which incidentally is how long neurogenesis takes, refer to Section 3.1), and training should be continued for 10-12 weeks for the greatest anti-depressant effect.

With contemporary trends for exercise ‘quick fixes’, this may seem like a lot of exercise, but no worthwhile mental health fix comes for free. Remember, even exercise levels below these recommended amounts are still beneficial and, of course, the side effects (e.g. weight loss, increased energy, better skin, improved physical health, etc.) are very acceptable.

8.0 Mental Health and the Fitness Industry

“Physical health is one thing, but mental health, despite being something which can dramatically impact and affect someone’s life, is an often overlooked component of a person’s wellbeing.” (Waterman, 2018).

Traditionally, determining whether an individual was ‘healthy’ or ‘unhealthy’ ultimately come down to how the individual looked, their fitness levels, their diet, and whether they suffered from any specific physical health conditions.

The fitness industry is geared towards physical health improvements, and health questionnaires (also known as Physical Activity Readiness – Questionnaires, PAR-Q, or Exercise Readiness Questionnaire, ERQ) are largely focussed on physical health conditions.

Catch all questions that are typically asked include:

  • Do you have any other medical conditions?
  • Do you have, or have you had any illnesses recently?
  • Do you know of any other reason why you should not do physical activity?
  • Is stress from daily living an issue in your life?
  • Are you on medication?
  • Do you take any medications, either prescription or non-prescription, on a regular basis?
    • What is the medication for?
    • How does this medication affect your ability to exercise or achieve your fitness goals?

Questionnaires can vary from basic information collection (1 page) to fairly data intensive (6-8 pages), but questions asked and information collected vary vastly between fitness providers.

“In fitness, we get so caught up talking about bodyfat levels, bodyweight, aerobic fitness abilities, and food choices, that we neglect to address hugely important factors which affect our mental health.” (Waterman, 2018).

9.0 Summary

An individual does not have to have a gym membership to make exercise a part of their life! Picking physical activities that are easy to incorporate into the things/activities they already do and having a strong social support system are important in incorporating exercise into an individual’s routine.

Exercise also may help to meet the need for cost-effective and accessible alternative therapies for depressive disorders – particularly for the substantial number of individuals who do not recover with currently available treatments.

It is important to note that even small improvements in exercise levels or diet create a positive upward spiral that increases the sensitivity of the dopamine receptors that signal reward, so that exercise will eventually become rewarding, even if that seems unimaginable at the outset!

10.0 Useful Publications

11.0 References

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Anxiety and Depression Association of America. (2018) Exercise for Stress and Anxiety. Available from World Wide Web: https://adaa.org/living-with-anxiety/managing-anxiety/exercise-stress-and-anxiety. [Accessed: 27 November, 2019].

Bortz, W.M., Angwin, P., Mefford, I.N. (1981) Catecholamines, Dopamine, and Endorphin Levels during Extreme Exercise. New England Journal of Medicine. 305, pp.466-467.

Callaghan, P. (2004) Exercise: A Neglected Intervention in Mental Health Care? Journal of Psychiatric Mental Health Nursing. 11, pp.476-483.

CDC (Centres for Disease Control and Prevention). (2019) Physical Activity Basics. Available from World Wide Web: https://www.cdc.gov/physicalactivity/basics/index.htm?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fphysicalactivity%2Fbasics%2Fpa-health%2Findex.htm. [Accessed: 26 November, 2019].

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Goodwin, R.D. (2003) Association between physical activity and mental disorders among adults in the United States. Preventative Medicine. 36(6), pp.698–703. https://doi.org/10.1016/S0091-7435(03)00042-2.

Grace, AA. (2016). Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nature Reviews. Neuroscience. 17(8), 524-532. http://doi.org/10.1038/nrn.2016.57.

Guszkowska, M. (2004) Effects of Exercise on Anxiety, Depression and Mood [in Polish]. Psychiatria Polska. 38(4), pp.611-620.

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Maddock, R.J., Casazza, G.A., Fernandez, D.H. & Maddock, M.I. (2016) Acute Modulation of Cortical Glutamate and GABA Content by Physical Activity. Journal of Neuroscience. 36(8), pp.2449. DOI:10.1523/JNEUROSCI.3455-15.2016.

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Phelan, M., Stradins, L. & Morrison, S. (2001) Physical Health of People with Severe Mental Illness. BMJ. 322(7284), pp.443-444.

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Richardson, C.R., Faulkner, G., McDevitt, J., Skrinar, G.S., Hutchinson, D.S. & Piette, J.D. (2005) Integrating Physical Activity into Mental Health Services for Persons with Serious Mental Illness. Psychiatric Services. 56(3), pp.324-331.

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Sleiman, S.F., Henry, J., Al-Haddad, R., El Hayek, L., Haider, E.A., Stringer, T., Ulja, D., Karuppagounder, S.S., Holson, E.B., Ratan, R.R., Ninan, I. & Chao, M.V. (2016) Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife. 2016;5:e15092 doi:10.7554/eLife.15092.

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