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Is there a known or quantifiable correlation between capsaicin and its effect on the body's metabolism?

Is there a known or quantifiable correlation between capsaicin and its effect on the body's metabolism?


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I've often heard that spicy foods can speed up your metabolism, I presume, due to the capsaicin. Though I'm sure this is a minor effect - I doubt eating a pound of jalapenos a day will help me lose weight - has the medical/nutrition community quantified how various levels of capcaicin affect the body's metabolism?


Capsaicin do affect your metabolism. It affects your Capsacin receptors ( scientifically TRPV1 receptors). These receptor starts calcium influx into various types of tissues. In endothelial cells because of this it mimics stress response (McCarty et al 2015). Quoting from McCarty et al,

Clinically, ingestion of capsaicin-or its less stable non-pungent analogue capsiate-has been shown to boost metabolic rate modestly. opical application of capsaicin via patch was found to increase exercise time to ischaemic threshold in patients with angina

Coming to your question, there are scientific studies which suggest that capsaicin helps in maintaining weight by limiting weight regain after weight loss. Not just this, capsaicin has also shown potential in treatment of obesity. However you should remember that it will required specific amount of dose (you can check details in papers I cited ) to help maintaining your weight. Do not eat pound of jalapenos a day :P


Scoville scale is used by legislators to specify the allowed concentrations on pepper spray used by the police.

Although that is most important for excessive concentrations, you'll find more studies using this scale in relation to the effects you look for (for instance: https://scholar.google.com.br/scholar?q=Scoville+scale+metabolism).

The Wikipedia article cited talks about "sensation of heat", and indeed we sweat a lot when we eat strong peppers. But I think that eat the maximum diversity of food is healthier than seek the "best foods" according to the "public opinion" of the season. You should be worried about living healthier, not just losing weight. Seek the former and you'll reach the latter.


This Is Your Brain on Capsaicin

When it comes to food, there are two types of people in this world: those who EAT TO LIVE and those who LIVE TO EAT. I, unapologetically, belong to the second group. I am a foodie through and through! If I hadn’t become a scientist, I would have become a chef or a baker. Whenever I’m having a bad day, food has the ability to cheer me up. When I’m having a great day, food is how I celebrate. My favorite foods have generally included anything that is fried, but recently I’ve acquired a craving for all things spicy, especially peppers.

A few years ago, I swore up and down that spicy food was not for me! “I would have to be insane to want to eat something so spicy it brings me to tears,” I would tell my now hubby, who has always had an affinity for spicy foods. Inevitably, he got me to try a spicy dish that he ordered and my life changed. I’m not going to lie, that first taste was rough. My mouth and lips were on FIRE!! I probably downed a whole glass of cold water to get any kind of relief from the burn. However, with each new bite of spicy food I started to get used to the sensation and almost even craved it. Soon I was eating entire dishes of spicy food on my own and slowly but surely I started seeking out things that were hotter and hotter. You could almost say I’ve developed an “addiction” to spicy food, but that wouldn’t be entirely accurate. Although you can come to crave spicy foods, your body will not develop a dependence on them like you would to truly addicting molecules like caffeine or nicotine. However, there is some very real chemistry and neuroscience involved in that craving for spicy food.

So let’s talk some food science! That painful burning associated with the consumption of a chili pepper comes from compounds known as capsaicinoids, the most well-known of which is capsaicin. (FUN FACT: Capsaicinoids are derived from the compound vanillin, which gives vanilla its delicious taste and smell.) Surprisingly, their “hotness” or “spiciness” is not a taste but rather a sensation. There are no taste buds associated with capsaicinoids.

When they reach the tongue, capsaicinoids interact with a special type of protein located on the surface of nerve cells. This protein, called TRPV1, acts a sensor for the cell giving it information about the outside world. Normally, TRPV1 gets turned on by physical heat, like a fire, above 109˚F (43˚C). This signal will turn the nerve cell on to allow it to trigger other nerve cells that will carry the message to the brain that it has to respond to this dangerous temperature (think of it as your neurons playing telephone). When capsaicinoids interact with TRPV1 they also turn the protein on and cause the same signal to be transmitted to the brain into thinking it is being burned even though there is no real heat present. Note: TRPV1 is actually present on nerve cells in many locations on the body so this burning sensation can be experienced elsewhere, which is why you should always wash your hands after dealing with chili peppers, especially before touching your eyes!

Now that we know why peppers are hot, you might be asking yourself, “Why exactly would anyone seek out this burning sensation?” The answer to this question can be found in the way our brains are wired. Capsaicinoids trick the brain into thinking it is being burned, which is a painful experience, through the transmission of neurotransmitters. Remember, earlier when I said your neurons play telephone. Well, when your body senses pain somewhere like the tongue that message has to make it to the brain. The message is sent from the location it is initially generated to the brain through a network of neurons by talking to each other via neurotransmitters, which are essentially chemical messages. One such message produced by capsaicinoids is substance P, which transmits pain signals. The brain responds by releasing another type of neurotransmitter known as endorphins. Endorphins are the body’s natural way of relieving pain by blocking the nerve’s ability to transmit pain signals. Additionally, the neurotransmitter dopamine, responsible for a sense of reward and pleasure, is also released. In essence, for some people eating large amounts of spicy food triggers a sense of euphoria similar to a “runner’s high”.

So next time you need a little pick-me-up consider giving into the power of the chili pepper and discover why chiliphiles have come to love the burn!


Introduction

Hydrotherapy is the external or internal use of water in any of its forms (water, ice, steam) for health promotion or treatment of various diseases with various temperatures, pressure, duration, and site. It is one of the naturopathic treatment modality used widely in ancient cultures including India, Egypt, China, etc.[1] Though many countries used water to produce different physiological/therapeutic effects on different part of the system for maintaining health, preventing, and treating the diseases, the scientific evidence-based effects are not well documented. There are many studies/reviews that reported either physiological or therapeutic or combination of both the effects of hydrotherapy on particular system but did not report in all the major systems of the body, which made us to do this review with the aim and objective to report scientific evidenced-based effects of hydrotherapy on various systems of the body. In order to provide a general overview, we performed PubMed and PubMed central search to review relevant articles in English literature based on �ts of hydrotherapy/balneotherapy” on various systems of the body. Articles published from 1986 to 2012 were included in this review.

Hydrotheraphy in general

Superficial cold application may cause physiologic reactions such as decrease in local metabolic function, local edema, nerve conduction velocity (NCV), muscle spasm, and increase in local anesthetic effects.[2]

One hour head-out water immersions (WI) in various temperatures (32ଌ, 20ଌ, and 14ଌ) produced various effects. Immersion at 32ଌ did not change metabolic rate (MR) and rectal temperature (Tre), but it lowered the heart rate (HR) by 15%, systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 11% and 12%, respectively, compared, with controls at ambient air temperature. Along with HR and blood pressure (BP), the plasma renin activity, plasma cortisol, and aldosterone concentrations were also lowered by 46%, 34%, and 17%, respectively, while diuresis was increased by 107%.[3]

Immersion at 20ଌ produced similar decrease in plasma renin activity, HR, SBP, and DBP, in spite of lowered Tre and increased MR by 93%. Plasma cortisol concentrations tended to decrease, while plasma aldosterone concentration was unchanged. Diuresis was increased by 89%. No significant differences in changes in plasma renin activity, aldosterone concentration, and diuresis compared with subjects immersed in 32ଌ.[3]

Immersion at 14ଌ lowered Tre and increased MR by 350%, HR, SBP, and DBP by 5%, 7%, and 8%, respectively. Plasma noradrenaline and dopamine concentrations were increased by 530% and by 250%, respectively, while diuresis increased by 163%, which was more than at 32ଌ. Plasma aldosterone concentrations increased by 23%. Plasma renin activity was reduced. Cortisol concentrations tended to decrease. Plasma adrenaline concentrations remained unchanged. Changes in plasma renin activity were not related to changes in aldosterone concentrations.[3]

WI in different temperatures did not increase blood concentrations of cortisol. There was no correlation between changes in Tre and changes in hormone production. The physiological changes induced by WI are mediated by humoral control mechanisms, while responses induced by cold are mainly due to increased activity of the sympathetic nervous system (SNS).[3]

Regular winter swimming significantly decreased tension, fatigue, memory, and mood negative state points with the duration of swimming period significantly increased vigor-activity scores relieved pain who suffered from rheumatism, fibromyalgia, or asthma and improved general well-being in swimmers.[4]

Cardiovascular system

Cold exposure (CE) to small surface area produced compensatory vasodilatation in deeper vascular system resulting increased blood flow to the tissues underlying the site of exposure. This vascular reaction occurs mainly to maintain constant deep tissue temperature.[2]

In patient with chronic heart failure (CHF), thermal vasodilatation following warm-water bathing and low-temperature sauna bathing (LTSB) at 60ଌ for 15 min improves cardiac function[5] repeated sauna-therapy (ST) increased left ventricular ejection fraction increased 6-min walk distance in association with improvement in flow-mediated dilation and increase in number of circulating CD34 (+) cells reduced plasma levels of norepinephrine and brain natriuretic peptide. These indicates that ST improves exercise tolerance in association with improvement in endothelial function.[6] LTSB improves peripheral circulation in cerebral palsy (CP).[5]

After ST reduced level of total and low density lipoprotein (LDL)-cholesterol concentration, while increased level of high density lipoprotein (HDL)-cholesterol was observed. These changes are good prognoses for the prevention of ischemic heart disease.[7] ST increases endothelial nitric oxide synthase (eNOS) activity and improves cardiac function in heart failure and improve peripheral blood flow in ischemic limbs. In myocardial infarction (MI)-induced Wistar rats ST increases myocardial eNOS, vascular endothelial growth factor mRNA levels. It attenuates cardiac remodeling after MI through improving coronary vascularity in the noninfarcted myocardium and thus ST might serve as a novel noninvasive therapy for patients with MI.[8] Acute MI was thought to result from thrombosis or plaque rupture because of coronary artery spasm. The vasospasm might be induced by stimulation of the alpha-adrenergic receptors during alternating heat exposure during sauna bath followed by rapid cooling during cold water bath. This effect showed the dangers of rapid cooling after sauna bathing in patients with coronary risk factors.[9] Regular ST (either radiant heat or far-infrared units) appears to be safe and produce multiple health benefits but use of ST in early pregnancy is a potential concern because evidence suggesting that hyperthermia might be teratogenic.[10]

Cold water immersion (CWI) induces significant physiological and biochemical changes in the body such as increase in HR, BP, metabolism, and peripheral catecholamine concentration and decrease in cerebral blood flow.[11]

Reduction in HR, and increases in systolic and diastolic biventricular functions, were observed during acute warm-WI.[12] In contrast, increase in HR and a decrease in SBP and DBP were observed in 30 min of head-out WI (38.41 ± 0.04ଌ).[13]

Hyperthermic immersion (HI) produced shortening of activated partial thromboplastin time. During HI plasminogen activator inhibitor (PAI) activity was decreased thrombocyte count was increased increases in tissue-type plasminogen activator concentration and leukocytes count were attributed to hemoconcentration. Immediately after HI, fibrinogen concentration decreased but increased during recovery. During thermo-neutral immersion prothrombin time, PAI activity and granulocyte count ecreased. Warm water bathing leads to hemoconcentration and minimal activation of coagulation decrease in PAI-1 activity. During warm water bathing, marked risk for thrombotic or bleeding complications in healthy males could not be ascertained.[14] During contrast baths, longer duration in the second heating phase was required to produce sufficient fluctuation in blood flow.[15]

WI up-to shoulder levels at different temperatures (25ଌ, 34ଌ, and 40ଌ) showed no significant effect on cardiac output in 25ଌ compared with 34ଌ, but in 40ଌ a considerable increase in cardiac output was observed.[16]

Carbon dioxide (CO2) enriched WI reduced free radical plasma levels, raised antioxidants levels, and induce peripheral vasodilatation suggests improvement in microcirculation.[17,18] Decrease in tympanic temperature increase in cutaneous blood flow at immersed site was significantly greater in CO2-WI compared with fresh WI.[18] The three main effects of CO2 enriched WI are decline in core temperature, increase in cutaneous blood flow, and elevation of score on thermal sensation, which were analyzed.[19]

Respiratory system

WI up-to shoulder levels at different temperatures (25ଌ, 34ଌ, and 40ଌ) showed increased MR, oxygen (O2) consumption (VO2) only at 25ଌ. Two main factors affecting O2 transport during immersion are temperature and hydrostatic pressure. O2 transport was improved above neutral temperature, because of increase in cardiac output resulting from the combined actions of hydrostatic counter pressure and body heating. Below neutral temperature, O2 transport is altered. At any of the temperatures tested, the pulmonary tissue volume and arterial blood gases were not significantly affected.[16]

Significant decrease in vital capacity (VC) with bath temperature was observed (i.e., VC at 40ଌ 㸴ଌ 㸥ଌ). Significant increase in tidal volume (VT) in cold or hot water compared with thermo neutral water (i.e., VT 40ଌ 㸴ଌ< 25ଌ). Alterations in respiratory muscles functioning might produce variations of the pulmonary volumes as a function of water temperature.[20]

CWI was associated with increase in respiratory minute volume and decrease in end tidal CO2 partial pressure.[11] Repeated cold water stimulations reduced frequency of infections increased peak expiratory flow, lymphocyte counts, and expression of gamma-interferon modulated interleukin expression and improved quality of life (QOL) in patients with chronic obstructive pulmonary disease.[21]

In children suffering from recurrent and asthmatic bronchitis in remission, a single total air bath, or douche and local (cooling of the feet with water) exposure to mild cold did not raise noticeable disorders of the respiratory function. Local cold procedures improve bronchial patency but heat exposure resulted in its worsening.[22]

Inhaling hot air while in a sauna produced no significant impact on overall symptom severity of common cold.[23] A male track and field athlete, a case of breathing difficulties at rest and during exercise, was exacerbated in the supine position and during WI.[24]

Nervous system

Three cold modalities such as ice massage, ice pack, and CWI applied to right calf region for 15min reduced skin temperature (Tsk) (mean 18.2ଌ) reduced amplitude and increased latency and duration of compound action potential. It also reduced sensory NCV by 20.4, 16.7, and 22.6 m/s and motor NCV by 2.5, 2.1, and 8.3 m/s, respectively. Even though all three modalities effectively reduced Tsk and sensory conduction at a physiological level, CWI is the most indicated, effective modality for inducing therapeutic effects associated with the reduction of motor nerve conduction.[25]

Temperature and pressure of water in aquatic or hydrotherapy can block nociceptors by acting on thermal receptors and mechanoreceptors and exert positive effect on spinal segmental mechanisms, which is useful for painful condition.[26] Forty sessions of Ai Chi aquatic exercise (AE) program improves pain, spasms, disability, fatigue, depression, and autonomy in patient with multiple sclerosis.[27]

In a study on physiotherapy on land or water in patient with Parkinson's disease (PD), functional reach test was improved in both therapies, but Berg Balance Scale (BBS) and Unified Parkinson's Disease Rating Scale (UPDRS) were improved only in aquatic therapy group. It indicates improvement in postural stability in PD was significantly larger after aquatic therapy.[28]

Sauna bath on paraplegic (P) group and tetraplegic (T) group, HR increased significantly during sauna but decreased significantly during postsauna phase in P group. DBP significantly reduced in T group during postsauna phase but no significant changes in SBP in both the groups.[29]

In a study on CP, LTSB produced increase in HR and cardiac output decrease in BP and total peripheral resistance significant improvement in skin blood flow, blood flow velocity, pulsatile index, and resistive index decrease in numbness and chronic myalgia of the extremities with no adverse effects.[5]

Ten minutes of immersions in whirlpools produced increases in pulse and finger temperature with increased feelings of well-being and decreased state anxiety.[30] CO2-WI activates parasympathetic nerve activity in humans.[18]

Adapted cold shower might have antipsychotic effect similar to that of electroconvulsive therapy because it could work as mild electroshock applied to sensory cortex. Additionally, cold shower is example of stress-induced analgesia and would also be expected to 𠇌rowd out” or suppress psychosis-related neurotransmission within mesolimbic system.[31]

CE can activate components of reticular activating system such as locus ceruleus and raphe nuclei, which can result in activation of behavior and increased capacity of central nervous system (CNS) to recruit motoneurons.[32] CE activates SNS increase blood level of beta-endorphin and noradrenaline and increase synaptic release of noradrenaline in brain. Antidepressive effect of cold shower attributed to presence of high density of cold receptors in skin expected to send an overwhelming amount of electrical impulses from peripheral nerve endings to the brain. It has significant analgesic effect and it does not cause dependence or noticeable side effects.[33] Most narcotics administered rectally can cause intoxication. There is a significant co-morbidity of schizophrenia with intestinal illnesses and thus colon cleansing can significantly improve mental state.[31]

Musculo skeletal system

Walking in water at umbilical level increases the activity of erector spinae and activates rectus femoris to levels near to or higher than walking on dry ground.[34] CWI 㰕ଌ is one of the most popular intervention used after exercise,[11,35] which significantly lowered ratings of fatigue and potentially improved ratings of physical recovery immediately after immersion with reduction in delayed onset muscle soreness at 24, 48, 72, and 96 h follow-ups after exercise compared with passive interventions involving rest or no intervention.[35]

Rate of decrease in plasma lactate concentration over 30 min recovery period after intense anaerobic exercise was significantly higher in contrast-WI [hot (36ଌ) and cold (12ଌ)] compared with passive recovery on bed for both genders.[36]

Leg immersion in warm water (44 ± 1ଌ) for 45 min before stretch-shortening exercise reduced most of the indirect markers of exercise-induced muscle damage, including muscle soreness, creatine kinase activity in the blood, maximal voluntary contraction force, and jump height. Decreasing muscle damage did not improve voluntary performance, therefore clinical application of muscle prewarming may be limited.[37]

Contrast water therapy (CWT) [alternating 1-min hot (38ଌ) and 1-min cold (15ଌ)] for 6/12/18 min lowered subjective measures of thermal sensation and muscle soreness compared with control (seated rest) but no consistent differences were observed in whole body fatigue. It indicates CWT for 6 min assisted acute recovery from high-intensity running and CWT duration did not have dose-response effect on running performance recovery.[38] Contrast baths have been suggested for reducing pain hand volume and stiffness in affected extremities but it had no significant effect on pre- and/or postoperative hand volume in carpal tunnel syndrome.[39]

Cold water or cold/thermoneutral water did not induce modifications of inflammatory and hematological markers. The performances of athletes were not negatively influenced by CWI or CWT. Reduced perception of fatigue after training session was the principal effect of CWI[45] because CE increases opioid tone and high MR, which could diminish fatigue by reducing muscle pain and accelerating recovery of fatigued muscle, respectively,[32] which can improve training and competitions in young soccer players.[40]

A systematic review on management of fibromyalgia syndrome (FMS) through hydrotherapy described as “there is strong evidence for the use of hydrotherapy in the management of FMS” and it showed positive outcomes for pain tender point count and health-status.[41] Combination of ST (once daily for 3 days/week) and underwater exercise (once daily for 2 days/week) for 12 weeks significantly reduced pain and symptoms (both short- and long-term) and improved QOL in patients with FMS.[42] Pool-based exercise using deep water running three times/week for 8 weeks is safe and effective intervention for FMS because it showed significant improvement in general health and QOL compared with control and significant improvement in fibromyalgia impact questionnaire score, incorporating pain fatigue physical function stiffness and psychological variables.[43]

Hydrotherapy may have some short-term benefit to passive range of movement in rehabilitation after rotator cuff repair.[44] Spa water (37ଌ) and tap water heated to 37ଌ for the duration of 20 min/day for 5 days/week for the period of 2 weeks with home-based exercise program improved the clinical symptoms and QOL in patient with osteoarthritis of knee (OAK). However, pain and tenderness statistically improved in spa water.[45] It may be due to that spa waters are not only naturally warm, but their mineral content is also significant. Spa water has mechanical, thermal, and chemical effects.

In ankylosing spondilitis (AS) patients, balneotherapy statistically improved pain physical activity tiredness and sleep score Bath Ankylosing Spondilitis Disease Activity Index (BASDAI) Nottingham Health Profile (NHP) patient's global evaluation and physician's global evaluation at 3 weeks, but only on modified Shober test and patient's global evaluation parameters at 24 weeks. It indicates the effect of balneotherapy in improving disease activity and functional parameters in AS patients.[46] Infrared sauna, a form of total-body hyperthermia was well tolerated no adverse effects and no exacerbation of disease were reported in patients with rheumatoid arthritis (RA) and AS in whom pain, stiffness, and fatigue showed clinical improvements during the 4 weeks treatment period but these did not reach statistical significance.[47]

Aqua-jogging without caloric restrictions in obese persons for 6 weeks was associated with reductions in waist circumference and body fat improvement of aerobic fitness and QOL.[48]

AE may be an excellent alternative to land exercise for individuals who lack confidence, have high risk of falling, or have joint pain.[49] Water buoyancy reduces the weight that joints, bones, and muscles have to bear.[50] Warmth and pressure of water also reduce swelling and reduces load on painful joints, remotes muscle relaxation.[51] AE has significant effects on pain relief and related outcome measurements for locomotor diseases. Patients may become more active and improve their QOL as a result of AE.[52] Water-based and land-based exercises reduced pain and improved function in patients with OAK and that water-based exercise was superior to land-based exercise for relieving pain before and after walking.[53] Hydrotherapy is highly valued by RA patients who were treated with hydrotherapy (30-min session/week) reported feeling much better/very much better than those treated with land exercises (similar exercises on land) immediately on completion of the treatment program (6 weeks). But this benefit was not reflected on 10 m walk times, functional scores, QOL measures, and pain scores by differences between groups.[51] Hot compress (HC) with surrounding electro-acupuncture needling was significantly effective on rear thigh muscles strain and it was superior to conventional needling method and cupping in improving symptoms and physical signs as well as recovery of walking function of athletes.[54]

Gastrointestinal system

Drinking water significantly elevates the resting energy expenditure (REE) in adults but in overweight children transient decrease in REE was observed immediately after drinking 10 ml/kg cold water (4ଌ). Then a subsequent rise in REE was observed, which was significant after 24 min and the maximal mean REE values were seen after 57 min, which was 25% higher than baseline. The recommended daily amount of water consumption in children could result in energy expenditure equivalent to additional weight loss of about 1.2 kg/year suggesting that water drinking could assist overweight children in weight loss or maintenance.[55] Exposure to cold increases MR, for example, head-out immersion in cold water of 20ଌ almost doubles MR, while at 14ଌ it is more than quadrupled.[3]

When very-HC applied to lumbar region of healthy female for 10-min blood flow to the back increased to 156% with increased blood flow to upper arm. Immediately after HC, bowel sounds increased 1.7 times compared with before application, which suggest that a very HC can be useful to promote flatus or defecation.[56] Low mineral water intake normalizes the intestinal permeability of patients with atopic dermatitis.[57]

Warm water is effective for colonic spasm in which significantly less discomfort was reported compared with control group and this may be useful as an alternative for glucagon (expensive) and hyoscyamine (has side effects) because it has no side effects and costs practically nothing.[58]

In patients with acute anal pain due to hemorrhoids or anal fissures, neither cold water (㰕ଌ) nor hot water (㸰ଌ) sitz bath (SB) did control pain statistically.[59] Similarly, after sphincterotomy for anal fissure, SB produced no significant difference in pain but significant relief in anal burning and better satisfaction score with no adverse effects were observed compared with control group.[60] Healing and pain relief was not significant in SB but it improved patient satisfaction in acute anal fissures.[61]

Though there was no strong evidence to support the use of SB for pain relief and to accelerate fissure or wound healing among adult patients with anorectal disorders (ARDs), patients were satisfied with using SB and no severe complications were reported.[62] In contrast, warm-water SB (40ଌ, 45ଌ, and 50ଌ for 10 min each time) in ARD, pain relief was more evident and lasted longer at higher bath temperatures. Pain relief after SB might attribute to internal anal-sphincter relaxation, which might be due to thermosphincteric reflex, resulting in diminution of the rectal neck pressure. The higher the bath temperature, the greater the drop in rectal neck pressure and internal sphincter electromyographic activity, and longer the time needed to return to pretest levels.[63]

In posthemorrhoidectomy care, water spray method could provide a safe and reliable alternative to SB as a more convenient and satisfactory form of treatment.[64]

Spa treatment with mineral water Nizhneivkinskaya (sulfate calcium) induced clinical remission of the disease, normalization of the echoscopic picture of stomach and gallbladder, their motor function, tesiocrystalloscopic characteristics of saliva suggest its effectiveness in rehabilitation of patients with gastric and gallbladder motor-evacuatory dysfunction.[65] Intake of sulfate-chloride-sodium mineral water activates regulation of carbohydrate metabolism by insulin and cortisol due to the formation of adaptive reactions. It promoted trophic effects of insulin and gastrin in animals with significant reduction in peptic ulcer size and enhanced resistance to stressful factors.[66]

Immersion in Dead Sea water produced significant reduction in blood glucose in type-2 diabetes mellitus (DM) and no significant differences in insulin, cortisol, and c-peptide levels were observed between DM patients and healthy volunteers following immersion.[67]

Genito urinary system

Mean labor pain scores were significantly higher in control group than immersion bath (IB) group suggest that use of IB as an alternative form of pain relief during labor.[68] WI in primipara at any stage of labor, from 2 cm external opening of the uterine cervix, significantly decreased parturition duration compared with traditional delivery. It raised both the amplitude and frequency of uterine contractions proportional to uterine cervix gaping with no disturbances in contraction activity of the uterus. A 3-cm gaping of uterine cervix is the optimal timing for WI in the primipara because earlier WI at 2-cm uterine cervix gaping also accelerated the labor but required repetitions of WI or use of oxytocin for correcting weakened uterine contraction.[69]

In contrast, IB did not influence the length of labor and uterine contractions frequency. However, contractions length was statistically shorter in IB and it can be an alternative for woman's comfort during labor, since it provides relief to her without interfering on labor progression or jeopardizing the baby.[70]

WI during first stage of labor reduces the use of epidural/spinal/paracervical analgesia/anesthesia compared with controls and there is no evidence of increased adverse effects to fetus/neonate or woman from laboring in water or water birth.[71] Neonatal swimming can accelerate babies growth in early stage.[72] In a microbiological study, comparing neonatal bacterial colonization after water birth to conventional bed deliveries with or without relaxation bath showed no significant difference between three groups in neonatal outcome, infant's and maternal infection rate.[73]

Cold-SB but not warm-SB, significantly reduced edema during postepisiotomy period[74] and perineal pain, which was greatest immediately after the bath.[75] Bakera, a steam bath prepared with various plants (commonly the essential oil plants) is traditionally used in Minahasa (Indonesia) mainly for recuperation after childbirth. It is based onthermotherapy with aromatherapy which attribute for its therapeutic effects. Thermotherapy soothes symptoms such as heaviness in limbs, edema, muscular strain, loss of appetite, and constipation. Essential oils of the plants used have antiseptic, antiphlogistic, and immunostimulant effect. Hence it can be an effective and safe method for recuperation after child birth.[76] In postnatal mothers, alternate (hot and cold) compress and cold cabbage leaves were equally effective in reducing breast engorgement, but in relieving breast engorgement pain, alternate compresses were more effective than cold cabbage leaves.[77]

Warm-SB (40-45ଌ) for 10 min, for at least 5 days immediately after the removal of Foley urethral catheter in patient undergone transurethral resection of prostate, significantly reduced urethral stricture compared with no SB group who had 1.13-fold increased risk of re-hospitalization within 1 month after surgery due to postoperative complications compared with warm-SB group.[78] Thirty healthy volunteers and 21 patients with urinary retention after hemorrhoidectomy underwent SB at 40ଌ, 45ଌ, and 50ଌ where the number of spontaneous micturitions increased with higher-temperature baths and it seems to be initiated by reflex (thermo-sphincter reflex) internal urethral sphincter relaxation. The urethral pressure both in normal and retention subjects showed significant reduction, which increased with higher temperature and vesical pressure or EMG activity of the external urethral sphincter did not show significant differences.[79]

Hematology/immunology

Subsequent CE induced increase of leukocytes, granulocytes, circulating levels of interleukin (IL)-6, and natural killer (NK) cells and its activity. Leukocytes, granulocyte, and monocyte responses were augmented by pretreatment with exercise in water (18ଌ) and thus acute-CE has immune-stimulating effects.[80]

Daily brief cold stress can increase both numbers and activity of peripheral cytotoxic T-lymphocytes and NK cells, the major effectors of adaptive and innate tumor immunity, respectively. It (for 8 days) improved survival of intracellular parasite Toxoplasma gondii infected mice, with consistent enhancement in cell-mediated immunity. The sustained/longer-term effects of cold stress repeated daily over the period of 5 days to 6 weeks increased plasma levels of tumor necrosis factor-α, IL-2, IL-6. A hypothesis describes, daily brief cold-water stress over many months could enhance antitumor immunity and improve nonlymphoid cancer survival rate. The possible mechanism of nonspecific stimulation of cellular immunity might attribute to transient activation of SNS, hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid axes. Though daily moderate cold hydrotherapy does not appear to have noticeable adverse effects on normal subjects, some studies showed that it can cause transient arrhythmias in patients with heart problems and can also inhibit humoral immunity. Sudden ice-cold WI can produce transient pulmonary edema and increase blood-brain barrier permeability, thereby increasing mortality of neurovirulent infections. Studies are required to warrant this hypothesis for immunotherapy development for some (nonlymphoid) cancers, including those caused by viral infections.[81]

Warm water (28ଌ) treatment could not only cure bacterial cold-water disease but also immunize against causative agent Flavobacterium psychrophilum.[82]

Head-out WI (38.41 ± 0.04ଌ) for 30 min decreased blood viscosity red blood cells count and mean hematocrit without significant changes in leukocytes and platelets count mean corpuscular volume plasma viscosity erythrocyte filtration time and red cell deformability index.[13] Application of hyper-thermic water bath produced significant reduction of relative B-lymphocyte. Whole-body hyperthermic water bath reduced relative total T-lymphocyte counts increased relative CD8+ lymphocyte NK cell counts and its activity, which were probably dependent on increased somatotropic hormone production.[83]

Endocraine/hormonal system

During CE increase levels of circulating norepinephrine was observed[80] and exercising HPA system by repeated CE could potentially restore its normal function in chronic fatigue syndrome, or at least increase net HPA activity (without changing baseline activity).[84] It produces temporary increase in plasma levels of adrenocorticotropic hormone (ACTH), beta-endorphin, and cortisol.[32] The sustained/longer-term effects of cold stress repeated daily produced increase in ACTH, corticosterone, and decrease in α-1-antitrypsin and testosterone.[81] Cold stress reduces level of serotonin in most regions of brain (except brainstem).[32] Cold stress-induced analgesia might be mediated by increased production of opioid peptide beta-endorphin (an endogenous pain-killer).[85,86]

Exposure to sauna and ice-WI significantly elevated epinephrine levels in winter swimmer.[87] Steam bath produced increase in blood serum concentrations of gastric and aldosterone, with decrease in concentrations of cortisol in athlete-fighters.[88] Whole-body hyperthermic bath increased STH activity in 8 out of 10 volunteers.[83]

Eye, skin, and hair

Warm moist air device seems to be safe and produced improvement in tear stability and symptomatic relief in ocular fatigue in patients with meibomian gland dysfunction.[89] Sauna (80ଌ) produced stable epidermal barrier function increase in stratum corneum hydration faster recovery of both elevated water loss and skin pH decrease in casual skin sebum content on skin surface of forehead increase in ionic concentration in sweat and epidermal blood perfusion in volunteers. It suggests protective effect of ST on skin physiology.[90] Clinical remission of atopic dermatitis has been reported after intake of low-salt water.[57] Application of heated mustard compress produced second-degree, partial-thickness burn followed by hyperpigmentation and hypertrophic scarring.[91] Persistent use of cold pillow compress could reduce hair follicles inhibition or damage caused by chemotherapeutic agents. So alopecia can be decreased or prevented.[92]

Temperature regulation

Very-HC applied to lumbar region of healthy female for 10 min increased back Tsk to 41.1-43.1ଌ under HC, followed by decreased rapidly but no changes observed in BT.[56] A case of 20% of 2 nd degree burns and severe heat stroke followed by temperature rose up to 40.5ଌ and patient developed severe multiorgan failure and critical polyneuropathy was reported after exposure to extreme heat in sauna for unknown period of time.[93] The most effective method of reducing body core temperature appears to be immersion in iced water, main predictor of outcome in exertional heatstroke is the duration and degree of hyperthermia where possible patients should be cooled using iced-WI, but if it is not possible, combination of other techniques may be used to facilitate rapid cooling[94] such as fan-therapy, CWI, iced-baths, and evaporative cooling.[95]

Wet-ice, dry-ice, and cryogen packs applied to skin overlying right triceps surae muscle for 15 min on 10 females decreased mean Tsk 12ଌ, 9.9ଌ, and 7.3ଌ, respectively. None of the modalities produced Tsk cooling below 17ଌ and no cooling was demonstrated 1 cm proximal or distal to any modalities after 15 min of application. Significant mean Tsk reduction in between pretreatment rest interval (time 0) and 15 min after removal of modality (time 30) was observed only in wet-ice. It suggests wet-ice was significantly more efficient in reducing Tsk than dry-ice and cryogen packs.[96]

After exercise at 65% maximal oxygen consumption at ambient temperature of 39ଌ until Tre increased to 40ଌ produced no difference in cooling rate between WI at 8ଌ, 14ଌ, and 20ଌ but cooling rate was significantly greater during 2ଌ, which was almost twice as much as other conditions. It suggests that 2ଌ WI is the most effective treatment for exercise-induced hyperthermia.[97] When hyperthermic individuals are immersed in 2ଌ water for approximately 9 min to Tre cooling limit of 38.6ଌ negated any risk associated with overcooling.[98]

Whole body immersion in moderately cold water is effective cooling maneuver for lowering BT and body heat content of approximately 545 kJ at the end of immersion in absence of severe physiological responses generally associated with sudden cold stress.[99] Significant less BT variability and an overall higher BT were observed in late preterm infants following tub bathing procedure.[100]


How Your Chilli Addiction Could Be Helping You Live Longer

From the flicker of heat in pepperoncini to the incendiary burn of the Carolina Reaper, the chilli has conquered the world. These pungent pods are now the most widely grown spice crop of all. But, in recent years, the medical profession has become increasingly interested in the chemical ingredient of its trademark heat, with one recent study even suggesting the spice may also offer a way to help conquer the ravages of old age.

The chilli pepper is the fruit of plants from the genus Capsicum, a member of the nightshade family that includes tomatoes, potatoes and eggplants. The compound that makes them so spicy is known as capsaicin, a nitrogen-containing lipid related to the active principle in vanilla (vanillin) and has the same effect on our pain receptors as heat.

The blowtorch effect of a Scotch Bonnet arises because pain-sensitive nerves in the mouth, notably the tongue, harbour a receptor protein known as TRPV1. When this receptor is activated by capsaicin, it produces the sensation of scalding heat. Strictly speaking, however, chilli does not really taste hot. Our taste buds respond to salt, sweet, sour, bitter and umami, while chilli offers the sensation of heat. That's why, when exiting the body, capsaicin has a second opportunity to burn, even though there are no taste buds at its point of departure.

While capsaicin might set our mouth on fire, it also leads blood vessels to relax, so it could help people with high blood pressure. Prolonged activation of TRPV1 on the membranes of pain and heat-sensing nerve cells also depletes substance P, one of the body's messenger chemicals. That is why the compound that puts the fire in jalapeños is used as an analgesic in ointments, nasal sprays and patches to relieve minor aches and pains, and the itching of psoriasis.

Now a study by Andrew Dillin of the University of California, Berkeley, suggested this analgesic effect could have a yet more profound impact on humanity. He explained how as humans age they report a higher incidence of pain, suggesting that pain might drive the ageing process and, indeed, his team found that mice genetically manipulated to lack TRPV1 lived on average about 14% longer than normal mice and, importantly, without apparent complications.

Blocking the pain receptor not only extends life­span, it also gave the mice a more youthful metabolism, including an improved insulin response that allows them to deal better with high blood sugar. "Pharmacological manipulation of TRPV1 may improve metabolic health and ­longevity," Dillin says.

But, of course, chilli offers another way to achieve the same end because constant activation of the TRPV1 receptor results in death of its host nerve cell, mimicking the loss of TRPV1 that extended lifespan. Eating a diet rich in capsaicin might, he says, "help prevent metabolic decline with age and lead to increased longevity in humans".

There are caveats, of course. Mice have enjoyed many advanced therapies that have not translated to people. And to enjoy the health benefits might require the kind of heroic chilli consumption that would daunt even the most hard core "heat geek". Still, Dillin points out that diets which are rich in capsaicin correlate with a lower incidence of diabetes and metabolic problems in people.

All the while, other research has shed light on this spicy story of global warming, one that speaks volumes, not just about our taste and health but psychology too.

Normally a plant creates fruit in order to entice animals to eat and disperse its seeds, so it was puzzling that a fruit evolved to be painfully hot. To investigate, Joshua Tewksbury of the University of Washington, with Douglas Levey of the University of Florida, and colleagues studied chillies that grow in the Bolivian wild and found a correlation between high capsaicin levels and low seed mortality, particularly in moist conditions.

It seems that evolution smiled on capsaicin because it slows microbial growth and protects against damaging fungi that invade the fruits through wounds left by insects. Plants that produced hot chillies had seeds with thin coats, a presumed consequence of sacrificing the production of lignin, a complex molecule that forms the protective seed coat, in favour of more capsaicin.

Capsaicin deters mammals, such as raccoons, foxes and mice which, having molars, kill seeds when they chew the fruit. However, birds lack the right receptors. They will happily eat the hottest of hot chilli peppers (which is why some varieties are popularly known as "bird peppers") and gobble seeds whole only to deposit them further afield, where young chillies can grow with less competition.

In coming months, festivals in Espelette in the Basque country, Tampere in Finland, Santa Fe in the United States and beyond will celebrate chilli. So why do we like them so much?

One clue emerged in 1998, when Jennifer Billing and Paul W Sherman published a study in The Quarterly Review of Biology in which they surveyed 4,578 recipes from 93 cookbooks on meat-based ­cuisines from 36 countries. Countries with hotter climates used chilli and spices more frequently than countries with cooler climates. This makes sense since bacteria grow faster in warmer areas and, as Sherman points out, chilli is one of many spices that are antibacterial. A follow-up study by Sherman, this time with Geoffrey A Hash, studied 2,129 vegetable-only recipes from 107 cookbooks from 36 countries and found that they relied on fewer spices than meat recipes. The reason? Bacteria do not proliferate as well in vegetables, so adding spices was not as necessary.

Chilli and other spices probably helped to protect our food from microbial attack long before freezers or artificial preservatives. "Before there was refrigeration, it was probably adaptive to eat chillies, particularly in the tropics," Tewksbury commented. "Back then, if you lived in a warm and humid climate, eating could be downright dangerous because everything was packed with microbes, many harmful. People probably added chillies to their stews because spicier stews were less likely to kill them."

But some argue the antimicrobial hypothesis may not be enough to account for the advance of spicy foods in the modern age of refrigeration and preservatives. "I don't think there is actually much evidence for the antimicrobial action of chilli," explains Paul Rozin at the University of Pennsylvania. "People get to like the burn. In fact, the one effect it definitely has is to cause salivation, which lubricates the mouth and facilitates chewing."

Capsaicin causes the body to release painkilling endorphins, which are themselves pleasurable, so he argues that our love of chilli heat may also be a kind of benign masochism. By this he means something seemingly dangerous, such as riding a fairground thrill ride, in the knowledge that it won't do any real harm. Perhaps the adrenalin kick from tackling the scorching heat of a Dorset naga, plus the natural opiates, are an unbeatable combination.

The hotspot where ancient farmers first warmed to the charms of the chilli pepper was revealed by research published this year by an international team led by Paul Gepts at the University of California, Davis. Scientists traditionally pinpoint the origin of domestication by seeking the location with the most diversity of wild relatives, reasoning that the greater the diversity, the longer lineages have been evolving. Genetic evidence, based on 139 wild peppers collected by colleagues Kraig Kraft and José Luna, suggested the hot big bang took place in northeastern Mexico.

Gepts and his colleagues went further, taking into account linguistic evidence uncovered by Cecil Brown of Northern Illinois University and Geo Coppens of CNRS in Montpellier, France. They found that east of the Valley of Tehuacán, where the most ancient remains of the spice have been uncovered, the oldest word for chilli was spoken in Proto-Otomanguean some 6,500 years ago. To bolster this evidence, team members Kraig Kraft, Eike Luedeling, and Robert Hijmans used a mathematical model to predict the most suitable locations for the domesticated pepper.

The origins of domesticated chilli seem to lie in a region of central-east Mexico, in a swathe ranging from southern Puebla and northern Oaxaca to southeastern Veracruz. When it comes to studies of domestication, "this is the first research to integrate multiple lines of evidence," says Gary Nabhan at the University of Arizona, another team member.

We know little about how the Mayans and others in the region used chilli peppers. But research by Terry Powis at Kennesaw State University and colleagues revealed clues in 2,000-year-old pottery samples from a site in southern Mexico, home of the Mixe-Zoquean. They discovered Capsicum residues in a spouted jar, a vessel used for pouring liquid for culinary, pharmaceutical, or ritual uses.

Upon reaching the New World in 1492, ­Columbus was one of the first Europeans to encounter the fruits of Capsicum, calling them peppers because they had a hot taste dissimilar to anything else he had encountered. Not long after, they were being added to dishes prepared in Spain and Portugal and their use soon spread to Asia and beyond. From familiar curved varieties to those that are pea-shaped, heart-shaped, bumpy and flat &ndash with colours ranging from green to red, orange, purple and black &ndash they're now found in endless cuisines and everything from ready meals to cocktails.


Oxidative Stress and Excitatory Neurotoxins in Neuropathy

Evidence of Oxidative Stress in Non-neural Tissue

Human Diabetes

Plasma levels of lipid peroxide are increased in human diabetes. 1, 72, 111, 159 The highest levels were found in patients with microvascular angiopathy, manifested as retinopathy or microalbuminuria, and the lowest in those diabetic patients without angiopathy 27, 159 levels were normal in patients with well-controlled diabetes. 159 The relationship may relate to the observation that low-density lipoproteins of diabetic patients are significantly more oxidizable than those of controls, an abnormality that is correctable by 6 weeks' treatment with the antioxidant probucol. 3 Presumably diabetics with angiopathy, who have higher levels of low-density lipoproteins, will have the greatest lipid peroxidation.

GSH is reduced in erythrocytes from patients with type 2 diabetes mellitus, and there is a corresponding increase in oxidized glutathione (GSSG). 122 In subsequent studies, these workers additionally demonstrated reductions in the glutathione-synthesizing enzyme γ- glutamylcysteine synthetase, and in transport of the thiol [S-(s,4-dintrophenyl)glutathione] in erythrocytes of these patients. These abnormalities were reversible with improved glycemic control. They also demonstrated that a high-glucose medium augments the toxicity of xenobiotics on K562 cells, associated with reduction in both the enzyme and its messenger RNA (mRNA). 197

Erythrocyte cuprozinc SOD is reduced in patients with type 2 diabetes. 111 This reduction is suggested to be mediated by the accumulation of intracellular H2O2. 99

α-Tocopherol levels are reported to be reduced in the platelets 78, 99 and erythrocytes but not plasma of insulin-dependent diabetes mellitus patients.

Wolff 190 has emphasized the role of decompartmentalized transitional metals in diabetic patients in addition to the effects of hyperglycemia in producing auto-oxidative lipid peroxidation. Particular emphasis has been placed on copper and iron. Copper levels have been reported to be higher in diabetics than in normal subjects and are highest in those with angiopathy. 110, 134

Experimental Diabetes

Oxidative stress occurs in experimental diabetes induced by streptozotocin and alloxan, and in the diabetic BB Wistar rat. Lipid peroxidation in chemical diabetes appears to be due to hyperglycemia and not the agent, because the pattern of changes is not agent specific. Streptozotocin and alloxan cause similar changes, and additionally the spontaneously diabetic BB Wistar rat shows virtually identical patterns of tissue antioxidant enzyme changes. 50 Furthermore, these alterations are preventable by insulin treatment. 10, 50, 188, 189 The common mechanism of increased oxidative stress is, therefore, diabetes (hyperglycemia) and not its mode of induction.

Plasma and liver lipid peroxides are increased in streptozotocin- or alloxan-induced diabetes 111, 150 and improved by α-tocopherol supplementation. 150 Tissue levels of lipid peroxide, estimated by the thiobarbituric acid method, were increased in kidney and retina and accompanied by a reduction in fat-soluble antioxidants as determined by the ferric chloride–bipyridyl reaction. These changes were eliminated by insulin treatment. 132

Complex patterns of changes in antioxidant enzymes have been described in different tissues in streptozocin diabetes. 188, 189 Liver and kidney have reduced catalase and SOD. Glutathione peroxidase and GSH are reduced in liver glutathione peroxidase is increased in kidney. Catalase and glutathione reductase are increased in heart and pancreas and SOD is additionally increased in pancreas.

One of the most common alterations is a reduction in cuprozinc SOD. This reduction has been reported in numerous tissues, including erythrocyte 32, 43, 100, 111, 201 liver 8, 111 retina and kidney 43, 100 and spleen, heart, testis, pancreas, and skeletal muscle in rats with streptozotocin and/or alloxan diabetes. 8, 43, 100, 111 The loss of SOD appears to be a function of duration and severity of diabetes. 85, 99

α-Tocopherol is reported to be reduced in streptozotocin diabetes. 85, 99 Our observations are that plasma α-tocopherol is very variable and is greatly dependent on dietary intake it can be increased in experimental diabetes because of polyphagia. 130


TRP Gene Polymorphism and Disease Risk

Ina Kraus-Stojanowic , . Ingolf Cascorbi , in TRP Channels As Therapeutic Targets , 2015

The TRPV Subfamily

TRPV1 has various physiological functions. TRPV1 is predominantly expressed on small-diameter nociceptive neurons, likely to be C-fibers [ 105 ], and is involved in the transduction of noxious heat. Interestingly, it can be stimulated by the hot chili pepper constituent capsaicin [ 106 ]. Accordingly, the role of TRPV1 in human pain sensitivity was addressed in different studies. To examine the contribution of TRPV1 to individual cold and heat pain sensitivity, genetic variations in TRPV1 were investigated in certain association studies. Caucasian-American women with the TRPV1 585Val allele (p.Ile585Val, c.1753A>G, rs8065080) showed longer cold withdrawal times [ 73 ]. In a larger cohort, SNPs rs222747 (p.Met315Ile, c.945G>C) and rs8065080 (p.Ile585Val) showed no significant association with cold/heat pain sensitivity in Americans of European extraction [ 3 ]. To investigate genetic variations of TRPV1 in patients with chronic pancreatitis suffering from pancreatic pain, four SNPs (rs222749, rs222747, rs224534, rs8065050) were genotyped in patients and healthy controls. There was no significant difference in allele frequency between chronic pancreatitis patients and healthy controls. Furthermore, based on the SNP distribution, 17 diplotypes were generated. There was no significant difference in distribution of diplotypes between patients and controls [ 69 ]. In neuropathic pain patients with mainly preserved sensory function (a subgroup of the entire patient population), TRPV1 SNPs 1911A>G (rs8065080, c.1753A>G) and 1103C>G (rs222747, c.945G>C) had a significant relationship with the somatosensory function. The TRPV1 1911A>G (c.1753A>G) polymorphism was significantly associated with altered heat pain thresholds (HPT). Neuropathic pain patients with AA or AG genotype tended to show heat hyperalgesia, whereas GG homozygotes exhibited significantly higher, i.e., normal, HPT. TRPV1 1911A>G was also identified to be associated significantly to mechanical pain sensitivity (MPS). The presence of at least one G-variant allele was associated with lower, i.e., normalized, MPS to pinprick stimuli. Moreover, TRPV1 1911A>G wild-type carriers (AA) showed higher mechanical detection thresholds, i.e., mechanical hypoaesthesia, than variant subjects. The 1103C>G SNP (c.945G>C) was significantly associated with cold detection threshold. Homozygous variant carriers (GG) exhibited cold hypoaesthesia compared with heterozygous or wild-type carriers [ 1 ].

TRPV1 variants were also investigated for their association with a variety of other diseases. In a Japanese population, a significant inverse association between CC genotype of the TRPV1 SNP c.945G>C and functional dyspepsia was found. This genotype also had a lower risk of epigastric pain syndrome, postprandial syndrome, and Helicobacter pylori positive functional dyspepsia [ 71 ]. Because TRPV1 expression is known to be up-regulated in patients with irritable bowel syndrome (IBS), a Korean population was screened for their genotype frequencies of nonsynonymous TRPV1 SNPs rs9894618, rs222749, and rs222747. There was no significant difference in allele frequency of these three SNPs between controls and IBS group [ 68 ]. There was a significant increase in the rs222747 (p.Met315Ile) variant of the TRPV1 gene in the type 1 diabetes cohort compared to the control. Logistic regression analysis revealed that type 1 diabetes was significantly associated with p.Met315Ile. No difference was found in the rs224534 (p.Thr469Ile) and rs8065080 (p.Ile585Val) allelic variants [ 72 ]. In a study where capsinoids were taken for weight loss, the TRPV1 SNP p.Ile585Val correlated significantly with change in abdominal adiposity. Subjects with the Val/Val and Val/Ile variants lost about twice as much abdominal fat as the study average, whereas Ile/Ile subjects lost almost none [ 74 ]. The TRPV1 rs8065080 polymorphism was found to be associated with an individual’s perception of salt at suprathreshold levels [ 76 ]. TRPV1 expression and activity in the respiratory system appear to be altered under pathophysiological conditions such as chronic cough and airway hypersensitivity. In childhood asthma, carriers of the TRPV1 p.585Val variant showed a lower risk of current wheezing or cough [ 75 ]. No association with nonspecific chronic cough in children was found for TRPV1 SNPs rs222748 and rs8065080 [ 70 ]. Also the 3′-UTR region of TRPV1 was associated with childhood asthma. Allele frequency of SNP rs4790521 T>C was significantly increased in asthmatic children, but no significant difference was found in MAF of rs4790522 A>C. Genotype analysis showed that rs4790521 C/C and rs4790522 A/C were significantly associated with childhood asthma in Chinese of Han Nationality [ 79 ]. Statistically significant associations of six TRPV1 SNPs (rs11655540, rs161365, rs17706630, rs2277675, rs150854, rs224498) with cough symptoms were found in nonasthmatics after correction for multiple comparisons. Haplotype-based association analysis confirmed the SNP analyses for nocturnal cough and usual cough in subjects without asthma [ 4 ].

In multiple sclerosis (MS) patients, a selective risk-association of TRPV1 SNP rs877610 was found in primary progressive disease. Specific SNPs in the TRPV1 locus were either significantly overrepresented in DNA of patients with malignant MS or underrepresented in the genomes of patients with benign MS [ 77 ]. A genome-wide and candidate gene association study of cigarette smoking behaviors revealed an association of TRPV1 polymorphism rs4790520 with cigarettes smoked per day [ 11 ]. To identify SNPs in TRP genes that may confer increased genetic susceptibility to migraine, a case-control genetic association study with replication was performed. After replication, nominal association was confirmed for two intronic SNPs, the T allele from TRPV1 rs222741 in the all-migraine group and the A allele from TRPV3 rs7217270 in the migraine with aura group. However, after applying Bonferroni correction for multiple comparisons, none of them remained significant [ 78 ].

Mutations in the TRPV3 gene are described to be associated with Olmsted syndrome, a rare congenital disorder characterized by palmoplantar and periorificial keratoderma. In six cases from China missense variants in TRPV3, which produced p.Gly573Ser, p.Gly573Cys, and p.Trp692Gly, were reported [ 80 ].

Numerous missense variations in TRPV4 lead to several skeletal diseases and neuropathies, e.g., metatropic dysplasia (MD) [ 85 , 92 ], brachyolmia type 3 [ 94 ], Charcot-Marie-Tooth disease [ 86–88 , 91 ], familial digital arthropathy brachydactyly [ 90 ], spondylometaphyseal dysplasia Kozlowski type [ 85 , 93 ], spondyloepiphyseal dysplasia Maroteaux type [ 84 ], scapuloperoneal spinal muscular atrophy [ 88 , 89 ], and congenital distal spinal muscle atrophy [ 83 , 89 ]. (For details, see Chapter 2 .)

To assess the impact of TRPV4 polymorphisms on chronic obstructive pulmonary disease (COPD)-related phenotypes, an association of 20 SNPs with COPD was performed in a family-based analysis. Seven SNPs (rs12578401 in intron 7, rs3825396 in intron 6, rs12579553 in intron 6, rs16940583 in intron 5, rs3742030 in exon 2 p.Pro19Ser, rs7971845 in intron 1, and rs6606743) showed significant association with COPD. Four of these SNPs (rs12578401, rs3825396, rs12579553, and rs16940583) were significantly associated with COPD even after a Bonferroni correction. The significant associations between the four SNPs and COPD in the case-control population replicated the results with the same effect directions (same risk allele in both populations) in the family data [ 82 ]. Hyponatremia (i.e., relative water excess, serum sodium concentration ≤ 138 mEq/L) was significantly associated with the TRPV4 p.Pro19Ser allele in two non-Hispanic Caucasian male populations. Mean serum sodium concentration was significantly lower in the TRPV4-p.Pro19Ser-positive subjects. Subjects with the minor allele were 2.43-6.45 times as likely to exhibit hyponatremia as subjects without the allele. Mean serum sodium concentration among subjects with one copy of the minor allele was significantly lower [ 81 ]. In childhood asthma, TRPV4 p.Pro19Ser showed no significant association with asthma or the presence of wheezing [ 75 ]. Associations between SNPs in TRPV4 and cough symptoms in subjects with or without asthma were also not significant after adjusting for multiple testing [ 4 ].

In patients with hypercalciuria and concomitant polyuria or decreased urinary pH synonymous polymorphisms of TRPV5 (p.Leu205 =, p.Tyr222 =, p.Tyr278 =, p.Thr281 =, p.Thr344 =) and nonsynonymous SNPs (p.Ala8Val, p.Arg154His, p.Ala561Thr) were identified. In this specific research population, data do not support a primary role for TRPV5 in the pathogenesis of renal hypercalciuria [ 95 ]. Also, the relatively high frequency of TRPV5 p.Ala563Thr variant in African Americans, which exhibited an increased Ca 2 + influx in in vitro assays [ 107 ], was not investigated for their function in Ca 2 + hyperuria in African Americans.

In renal calcium stone patients, three major nonsynonymous TRPV6 polymorphisms were identified (p.Cys157Arg, p.Met378Val, and p.Met681Thr). The frequency of the ancestral haplotype (157Arg+378Val+681Thr) was higher in Ca 2 + stone formers when compared to a cohort of nonstone formers [ 96 ]. TRPV6 is overexpressed in prostatic adenocarcinoma tissue but is not detectable in healthy and benign prostate tissue [ 108 ]. The prostatic adenocarcinoma incidence within African Americans is two to three times increased compared to Caucasians. The ancestral haplotype of TRPV6 (157R+378V+681T), here named TRPV6a, is common among African populations. Within Caucasians

87% exhibit the homozygous TRPV6b (157C, 378M, and 681M) genotype [ 109 ]. In the samples of prostatic adenocarcinoma tested, the TRPV6b allele was found in 87% without correlation with Gleason score and tumor stage. The occurrence of the TRPV6a allele did not correlated with a higher incidence of prostatic adenocarcinoma [ 97 ].


Clinical and Preclinical Experience with TRPV1 Antagonists as Potential Analgesic Agents

Identification of novel antagonists targeting the transient receptor potential vanilloid type 1 (TRPV1) protein has been at the forefront of pain research in the pharmaceutical industry for nearly 15 years. Activation of TRPV1 by algesic stimuli results in enhanced signaling in sensory neurons and contributes to sensitization of nociceptive pathways. First-generation TRPV1 antagonists were designed to block heat, capsaicin, lipid, and acid activation of the channel. Clinical development of first-generation TRPV1 antagonists were challenged by deficits in thermosensation and thermoregulation. Thereafter, it was realized that chemical matter could be selectively designed such that acid activation of the channel was maintained or only partially blocked. Distinguishing between modes of channel activation resulted in pharmacological separation of analgesic and thermoregulatory effects, and led to the discovery of ­modality-specific TRPV1 antagonists. Despite these advances, a novel analgesic acting exclusively through antagonism of TRPV1 still lacks clinical proof of concept.

It has been well established that capsaicin, the algesic component of chili peppers, produces tissue injury leading to neuronal activation and sensitization [1–4]. Psychophysical studies have demonstrated that mechanical and heat hyperalgesia and a cutaneous flare response follow intradermal injection of capsaicin into human skin and are correlated with pain magnitude and duration [1,4]. Neurophysiological studies in monkeys identified heat-induced sensitization of A and C fiber mechano-heat-sensitive (AMH, CMH) fibers and capsaicin-induced sensitization of spinal dorsal horn neurons conducting along the spinothalamic tract [3,5,6]. Interestingly, heat-evoked pain in human subjects and heat-evoked neural activity in monkey CMH fibers overlapped, with an activation threshold of approximately 45 °C and a stimulus-response function that increased monotonically with increasing stimulus intensity [6]. Later, heat activation of the heterologously expressed cloned capsaicin receptor was defined to be in the noxious range with an activation threshold of 42 °C, thereby providing a molecular mechanism by which heat and capsaicin exert physiological effects [7,8]. Following this seminal discovery, pharmaceutical and academic laboratories have spent more than 15 years researching this protein as a therapeutic target for analgesia.

The cloned capsaicin receptor, initially called the vanilloid receptor subtype 1 because of the unique gating by vanilloids such as capsaicin, was recognized as the first member of the transient receptor potential vanilloid family and was designated TRPV1. Structurally, TRPV1 is a tetrameric six-transmembrane ion channel protein with nonselective permeability to cations. Consistent with early neurophysiological studies demonstrating that capsaicin activated AMH and CMH fibers that travel along the spinothalamic tract, TRPV1 resides primarily on peptidergic small- and medium-diameter neurons in the peripheral nervous system [9–11]. Initially classified as the capsaicin receptor, TRPV1 functions as a molecular integrator of a variety of stimuli, including endogenous lipids, noxious heat, and acid. In addition to capsaicin, TRPV1 can be activated by plant products, including resiniferatoxin (RTX), piperine, gingerol, zingerone, as well as camphor and eugenol, ethanol, and spider and jellyfish venom ([12,13], and reviewed in Refs. [14,15]). Channel activation results in electrical and chemical activity in neurons. Channel opening results in signal transduction of nociceptive stimuli in neurons. Pronociceptive mediators including substance P, glutamate, and calcitonin gene-related peptide (CGRP) are released in response to TRPV1 activation, which in turn contributes to the development of neurogenic inflammation. The resulting proinflammatory milieu can sensitize TRPV1, leading to enhanced channel opening and thereby contributing to neuronal sensitization. Initially thought to exert effects primarily in the peripheral nervous system, TRPV1 expression and function in the central nervous system (CNS) is now widely reported, although the full extent of its physiological function in the CNS has not been elucidated [16–19].

TRPV1 functions as a molecular integrator of multiple physical and chemical stimuli, consistent with its localization on polymodal nociceptors in the peripheral nervous system. First-generation TRPV1 antagonists were designed to block all modes of TRPV1 activation. Clinical investigations of these compounds unveiled thermosensory deficits as a key limitation to further development. A breakthrough in the field was realized when TRPV1 antagonists could be designed to selectively block different modes of activation. The field quickly shifted toward the discovery of selective TRPV1 antagonists that could differentially block heat and capsaicin, but not acid activation of the channel to pharmacologically separate analgesic and thermoregulatory effects. Such modality-specific pharmacology has since been the focus for development of a novel analgesic-targeting TRPV1.

In an effort to achieve analgesia through modulation of TRPV1 without the burning sensation associated with agonists such as capsaicin and RTX, the Sandoz group (now Novartis) reported on discovery of antagonists of TRPV1 and their assessment as pain relievers [20,21]. Synthesis of small molecules with structural resemblance to capsaicin led to the development of capsazepine, the first TRPV1 antagonist pharmacological tool compound widely utilized in early TRPV1 research (Figure 8.1).


The beginning of the 21st century witnessed a burst of TRPV1 drug discovery activities in major pharmaceutical and smaller biotechnology companies. The potential role of TRPV1 antagonists as analgesic agents was suggested based in part on attenuation of pain-like behaviors in TRPV1 knockout (KO) mice [22]. However, the first generation of TRPV1 antagonists was limited by chemotype-independent hyperthermia in preclinical species and humans ([23], and reviewed in Refs. [24,25]). These findings, along with hypothermia-inducing properties of TRPV1 agonists and absence of hyperthermia in KO mice treated with TRPV1 antagonists, unambiguously established a thermoregulatory role for the TRPV1 channel [26–28]. Therefore, pharmacological separation of analgesic and hyperthermic effects became the key challenge in developing TRPV1 antagonists as viable agents for pain management.

One of the approaches to decouple undesired thermoregulatory effects from desired analgesic effects consisted of preventing TRPV1 antagonists from penetrating the brain where the hypothalamus is known to be involved in thermoregulation [29]. However, potent peripherally restricted TRPV1 antagonists still caused hyperthermia in rats, suggesting that peripheral restriction was not sufficient to attenuate the thermoregulatory effects and that the site of action for the hyperthermic effect was predominantly outside the CNS [30]. Direct administration of a selective but undifferentiated TRPV1 antagonist into the medial preoptic area of the hypothalamus did not affect core body temperature [18]. However, TRPV1-antagonist-induced increase in core body temperature was blocked by systemic RTX-mediated desensitization of TRPV1 [27]. Together, these studies suggest that visceral TRPV1 receptors are responsible for regulation of core body temperature.

Selective pharmacological blockade of some but not all modes of TRPV1 activation emerged as a more promising direction toward discovery of TRPV1 antagonists that could provide pain relief without affecting body temperature. AMG-8562 (Figure 8.2) from Amgen was one of the early and most characterized modality-specific TRPV1 antagonists [31].


AMG-8562 blocked capsaicin activation of rat TRPV1 with an IC 50 of 1.75 nM, did not affect heat activation, and potentiated pH 5 activation in a 45 Ca 2 + uptake assay using cells expressing recombinant rat TRPV1 [31]. Oral administration of AMG-8562 in rats either did not induce hyperthermia or had small hypothermic effect, but still showed efficacy in several preclinical pain models, albeit at rather high plasma concentrations. It should be noted that the pharmacological profile of AMG-8562 at human TRPV1 differs from the rat profile in that it partially blocked pH 5 activation in humans, whereas it potentiated acid activation at rat TRPV1. Significance of the blockade of proton activation for the thermoregulatory effects was confirmed in a systematic study of hyperthermic responses of rats, mice, and guinea pigs to TRPV1 antagonists displaying different pharmacological profiles [32]. It was concluded that TRPV1 antagonists that do not block low pH activation would exhibit a hyperthermia-free profile, even if they are potent blockers of heat activation.

AS-1928370 (Figure 8.2) from Astellas Pharma displays differential pharmacology in blocking the activation of TRPV1 [33]. This compound inhibited capsaicin-induced Ca 2 + flux in rat TRPV1 with an IC 50 value of 880 nM and capsaicin-induced currents in electrophysiological assay with an IC 50 value of 32 nM, but showed very small inhibitory activity against pH 6 activation (< 20% block at 10 μM). This profile was responsible for lack of effect on rectal body temperature in rats up to 10 mg/kg oral dose, although 30 mg/kg dose induced significant hypothermia. At an oral dose of 1 mg/kg, AS-1928370 fully attenuated pain-like behaviors evoked by intradermal capsaicin in a model of secondary hyperalgesia and exerted full efficacy in the rat spinal nerve ligation (SNL) model of mechanical allodynia (1-3 mg/kg dose range). These data provided evidence that analgesic effects in the SNL model of neuropathic pain were mediated by TRPV1. Such a conclusion was supported by high brain drug concentration, which sufficiently covered the IC 50 value obtained from electrophysiological recordings (355 versus 32 nM). This was the first demonstration that a TRPV1 antagonist displaying no inhibitory effect on proton-induced activation can exhibit high efficacy in neuropathic pain model. Potent effects in rats were recapitulated in mice, where AS-1928370 significantly suppressed both capsaicin-induced acute nocifensive and withdrawal responses in the hot plate test at oral doses of 10-30 mg/kg [34]. Significant efficacy was obtained in the SNL model at lower oral doses of 0.3-1.0 mg/kg. Despite favorable preclinical pharmacological and safety profiles, there was no information reported on whether AS-1928370 or any of its analogs entered clinical trials. It should be noted that AS-1928370 did inhibit proton activation of human TRPV1 with an IC 50 value of 1.5 μM, while having no effect at rat TRPV1 (IC 50 > 20 μM) [33]. Given the correlation established between inhibitory effects on proton-evoked activation of TRPV1 in vitro and changes in body temperature in vivo , there should be considerable caution in predicting a hyperthermia-free profile for AS-198370 in humans.

Grünenthal described several chemotypes of TRPV1 antagonists, some representatives of which displayed differential pharmacology against capsaicin, low pH, and heat activation of TRPV1. Compound 41 (Figure 8.2), a diaryl acetamide, is a very potent TRPV1 blocker against capsaicin activation ( K i = 0.1 nM), but much weaker against pH 6 activation (IC 50 = 87 nM) [35]. Several compounds from their propanamide series also exhibited large potency gaps inhibiting in vitro capsaicin and low pH. For example, compounds 12 (Figure 8.2) [36] and 15 (Figure 8.2) [37] were potent inhibitors of capsaicin activation with IC 50 values of 8 and 2 nM, but weak inhibitors of low pH activation with 0% and 15% effects correspondingly at 5 μM. Additional TRPV1 antagonists with differentiated pharmacology were discovered within carboxamide and urea containing series [38–40]. Grünenthal did not describe effects on core body temperature therefore, it is unknown if modality specific in vitro pharmacology for some TRPV1 antagonists was predictive of lack of hyperthermia in preclinical species.

In a series of patent applications AbbVie claimed TRPV1 antagonists of different chemical classes, several representatives of which did not produce thermosensation deficits in rats. Lack of thermosensory effects was demonstrated by increased average response latency for tail withdrawal from a 55 °C water bath. For example, Compound 10 (Figure 8.2) blocked capsaicin activation of TRPV1 with an IC 50 value of 54 nM, but blocked only 28% of pH 5 activation at 37.5 μM [41]. As a result of differentiated pharmacology, Compound 10 had no effect on latency to tail withdrawal in the rat tail immersion assay, suggesting no in vivo effect on thermosensation. Similarly, no thermosensation deficits were observed for Compound 6 (Figure 8.2) in the same tail immersion assay [42]. Compound 6, representing a different chemical class of TRPV1 antagonists than Compound 10, was characterized as a full blocker of capsaicin activation with an IC 50 = 4 nM and partial blocker of acid activation with only 38% inhibition at 37.5 μM. Compound 6 also attenuated pain-like behaviors with 88% effect in the capsaicin-induced flinching model at an oral dose of 100 μmol/kg and with 59% effect in capsaicin-induced secondary mechanical hypersensitivity model at an oral dose of 10 μmol/kg.

A more detailed account was reported from AbbVie on an additional series of differentiated TRPV1 antagonists [43]. A-1165442 (Figure 8.2) is a potent blocker of capsaicin activation of rat and human recombinant TRPV1 in FLIPR assays with IC 50 values of 35 and 17 nM, respectively, as well as in whole cell patch clamp electrophysiology studies in rat dissociated dorsal root ganglia neurons (IC 50 value 2.7 nM). In contrast, A-1165224 exhibited only a partial blockade of acid-evoked response at both rat and human TRPV1 measured in FLIPR (14% and 61% at 11 μM) and electrophysiology assays (66% block at 10 μM). Interestingly, biochemical analysis indicated that A-1165442 was less efficacious in blocking acid-evoked CGRP release compared with capsaicin-evoked CGRP release (22% vs. 100% block at 10 μM). A-1165442 and related analogues had a similar differentiated pharmacological profile highlighted by acid-sparring inhibition of TRPV1 and lack of or diminished body temperature elevations of < 0.5 °C in telemetrized rats. The relationship between acid blocking of TRPV1 in vitro and hyperthermic effects of TRPV1 antagonists in vivo is consistent with results of earlier studies with other classes of TRPV1 antagonists [31–33] and was demonstrated with a structural analogue, A-1106625 (Figure 8.2), which is a potent TRPV1 blocker at all modes of activation [43]. Although acid partial blocker A-1165442 did not change rat core body temperature at plasma concentrations

8.5-fold higher than its capsaicin blocking IC 50 , A-1106625 induced 1 °C temperature increase at lower multiples of plasma concentration. Both compounds exhibited comparable efficacy in a rat osteoarthritis (OA) pain model (ED 50

30-35 μmol/kg). However, unlike A-1106625, acid partial blocker A-1165442 was ineffective in attenuating allodynia in a mouse bone cancer pain model. The latter result can be explained by the importance of osteoclast-induced acidosis for bone cancer pain generation [44,45].

The first selective TRPV1 antagonist that was tested in humans was SB-705489 from GlaxoSmithKline. The compound effectively blocked TRPV1 activation in vitro by capsaicin, heat, and low pH and reduced inflammatory pain in rodents [46,47]. In target engagement studies during Phase 1 clinical trials, SB-705498 (Figure 8.3) at a single 400-mg oral dose significantly reduced the area of capsaicin-evoked flare versus placebo [48]. The same dose also reduced ultraviolet-B (UVB)-evoked flare area and heat hyperalgesia compared with placebo, albeit to a lesser degree. Reduction of flare area correlated with plasma exposure levels of SB-705495, suggesting effects were drug related and via a TRPV1-mediated mechanism. However, SB-705498 did not reduce the intensity of both capsaicin- and UVB-evoked flare as well as capsaicin-evoked thermal hyperalgesia. It is possible that the combination of capsaicin and heat resulted in more pronounced activation of TRPV1, blockade of which would require higher concentration of SB-705498. At the time point of pharmacodynamics assessments (

6 h postdose), total plasma concentration of SB-705498 was 0.5 ± 0.22 mg/mL, comparable to those predicted to be efficacious based on preclinical models. The maximum tolerated dose of 400 mg resulted in t max of 2 h (0.75-4 h) and half-life of 54 h (35-93 h) with SB-705498 remaining quantifiable for the 168 h postdose sampling period. Effects of SB-705498 on heat and taste thresholds were also investigated. Heat threshold was elevated into the noxious range, in line with the role of TRPV1 as thermosensor. Taste experiment results were not conclusive, but the threshold may have not changed after administering a series of diluted capsaicin solutions to volunteers [49]. Following Phase I, SB-705498 was investigated in clinical studies of acute migraine, dental pain, and rectal pain, but the results of these studies were not published.


Contents

The main indication for SSRIs is major depressive disorder however, they are frequently prescribed for anxiety disorders, such as social anxiety disorder, generalized anxiety disorder, panic disorder, obsessive–compulsive disorder (OCD), eating disorders, chronic pain, and, in some cases, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder, although with varying results. [8]

Depression Edit

Antidepressants are recommended by the UK National Institute for Health and Care Excellence (NICE) as a first-line treatment of severe depression and for the treatment of mild-to-moderate depression that persists after conservative measures such as cognitive therapy. [9] They recommend against their routine use in those who have chronic health problems and mild depression. [9]

There has been controversy regarding the efficacy of SSRIs in treating depression depending on its severity and duration.

  • Two meta-analyses published in 2008 (Kirsch) and 2010 (Fournier) found that in mild and moderate depression, the effect of SSRIs is small or none compared to placebo, while in very severe depression the effect of SSRIs is between "relatively small" and "substantial". [5][10] The 2008 meta-analysis combined 35 clinical trials submitted to the Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, the non-SSRI antidepressant nefazodone, and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine). The authors attributed the relationship between severity and efficacy to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication. [10] Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants. [11][12]
  • A 2012 meta-analysis of fluoxetine and venlafaxine concluded that statistically and clinically significant treatment effects were observed for each drug relative to placebo irrespective of baseline depression severity some of the authors however disclosed substantial relationships with pharmaceutical industries. [13]
  • A 2017 systematic review stated that "SSRIs versus placebo seem to have statistically significant effects on depressive symptoms, but the clinical significance of these effects seems questionable and all trials were at high risk of bias. Furthermore, SSRIs versus placebo significantly increase the risk of both serious and non-serious adverse events. Our results show that the harmful effects of SSRIs versus placebo for major depressive disorder seem to outweigh any potentially small beneficial effects". [7] Fredrik Hieronymus et al. criticized the review as inaccurate and misleading, but they also disclosed multiple ties to pharmaceutical industries. [14]

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective. [15]

In children, there are concerns around the quality of the evidence on the meaningfulness of benefits seen. [16] If a medication is used, fluoxetine appears to be first line. [16]

Social anxiety disorder Edit

Some SSRIs are effective for social anxiety disorder, although their effects on symptoms is not always robust and their use is sometimes rejected in favor of psychological therapies. Paroxetine was the first drug to be approved for social anxiety disorder and it is considered effective for this disorder, sertraline and fluvoxamine were later approved for it, too, escitalopram and citalopram are used off label with acceptable efficacy, while fluoxetine is not considered to be effective for this disorder. [17]

Post-traumatic stress disorder Edit

PTSD is relatively hard to treat and generally treatment is not highly effective SSRIs are no exception. They are not very effective for this disorder and only two SSRI are FDA approved for this condition, paroxetine and sertraline. Paroxetine has slightly higher response and remission rates for PTSD than sertraline, but both are not fully effective for many patients. [ citation needed ] Fluoxetine is used off label, but with mixed results, venlafaxine, an SNRI, is considered somewhat effective, although used off label, too. Fluvoxamine, escitalopram and citalopram are not well tested in this disorder. Paroxetine remains the most suitable drug for PTSD as of now, but with limited benefits. [18]

Generalized anxiety disorder Edit

SSRIs are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months.

Antidepressants provide a modest-to-moderate reduction in anxiety in GAD, [19] and are superior to placebo in treating GAD. The efficacy of different antidepressants is similar. [19]

Obsessive–compulsive disorder Edit

In Canada, SSRIs are a first-line treatment of adult obsessive–compulsive disorder (OCD). In the UK, they are first-line treatment only with moderate to severe functional impairment and as second line treatment for those with mild impairment, though, as of early 2019, this recommendation is being reviewed. [20] In children, SSRIs can be considered a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. [21] SSRIs, especially fluvoxamine, which is the first one to be FDA approved for OCD, are efficacious in its treatment patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo. [22] [23] Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration. [24] [25] [26]

Panic disorder Edit

Paroxetine CR was superior to placebo on the primary outcome measure. In a 10-wk randomized controlled, double-blind trial escitalopram was more effective than placebo. [27] Fluvoxamine, another SSRI, has shown positive results. [28] However, evidence for their effectiveness and acceptability is unclear. [29]

Eating disorders Edit

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa. [30] SSRIs (fluoxetine in particular) are preferred over other anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized.

Similar recommendations apply to binge eating disorder. [30] SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss. [31]

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa. [32] Treatment guidelines from the National Institute of Health and Clinical Excellence [30] recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or OCD. [31]

Stroke recovery Edit

SSRIs have been used off-label in the treatment of stroke patients, including those with and without symptoms of depression. A 2019 meta-analysis of randomized, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety but the studies had a high risk of bias. No reliable evidence points to their routine use to promote recovery following stroke. [33] Thrombosis risk is reduced because SSRIs limit serotonin availability to platelets, so benefits, such as stroke recovery, of reduced clotting go up, with SSRIs.

Premature ejaculation Edit

SSRIs are effective for the treatment of premature ejaculation. Taking SSRIs on a chronic, daily basis is more effective than taking them prior to sexual activity. [34] The increased efficacy of treatment when taking SSRIs on a daily basis is consistent with clinical observations that the therapeutic effects of SSRIs generally take several weeks to emerge. [35] Sexual dysfunction ranging from decreased libido to anorgasmia is usually considered to be a significantly distressing side effect which may lead to noncompliance in patients receiving SSRIs. [36] However, for those suffering from premature ejaculation, this very same side effect becomes the desired effect.

Other uses Edit

SSRIs such as sertraline have been found to be effective in decreasing anger. [37]

Side effects vary among the individual drugs of this class and may include:

Sexual dysfunction Edit

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm). [43] Sexual problems are common with SSRIs. [44] While initial trials showed side effects in 5-15% of users (based on spontaneous reporting by users), later studies (based on asking patients directly) have shown side effect rates from 36% to 98%. [45] [46] [47] [48] Poor sexual function is also one of the most common reasons people stop the medication. [49]

In some cases, symptoms of sexual dysfunction may persist after discontinuation of SSRIs. [43] [50] [51] : 14 [47] [52] This combination of symptoms is sometimes referred to as Post-SSRI Sexual Dysfunction (PSSD). [48] [45] On the 11th of June 2019 the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that a possible relationship exists between SSRI use and persistent sexual dysfunction after cessation of use. The committee concluded that a warning should be added to the label of SSRIs and SNRIs regarding this possible risk. [53] [54]

The mechanism by which SSRIs may cause sexual side effects is not well understood as of 2021 [update] . The range of possible mechanisms includes (1) nonspecific neurological effects (e.g., sedation) that globally impair behavior including sexual function (2) specific effects on brain systems mediating sexual function (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function and (4) direct or indirect effects on hormones mediating sexual function. [55] Management strategies include: for erectile dysfunction the addition of a PDE5 inhibitor such as sildenafil for decreased libido, possibly adding or switching to bupropion and for overall sexual dysfunction, switching to nefazodone. [56]

A number of non-SSRI drugs are not associated with sexual side effects (such as bupropion, mirtazapine, tianeptine, agomelatine and moclobemide [57] [58] ).

Several studies have suggested that SSRIs may adversely affect semen quality. [59]

While trazodone (an antidepressant with alpha adrenergic receptor blockade) is a notorious cause of priapism, cases of priapism have also been reported with certain SSRIs (e.g. fluoxetine, citalopram). [60]

Violence Edit

Researcher David Healy and others have reviewed available data, concluding that SSRIs increase violent acts, in adults and children, both on therapy and during withdrawal. [61] This view is also shared by some patient activist groups. [62]

Vision Edit

Acute narrow-angle glaucoma is the most common and important ocular side effect of SSRIs, and often goes misdiagnosed. [63] [64]

Cardiac Edit

SSRIs do not appear to affect the risk of coronary heart disease (CHD) in those without a previous diagnosis of CHD. [65] A large cohort study suggested no substantial increase in the risk of cardiac malformations attributable to SSRI usage during the first trimester of pregnancy. [66] A number of large studies of people without known pre-existing heart disease have reported no EKG changes related to SSRI use. [67] The recommended maximum daily dose of citalopram and escitalopram was reduced due to concerns with QT prolongation. [68] [69] [70] In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial infarction, junctional rhythms and trigeminy. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRIs. [71]

Bleeding Edit

SSRIs directly increase the risk of abnormal bleeding by lowering platelet serotonin levels, which are essential to platelet-driven hemostasis. [72] SSRIs interact with anticoagulants, like warfarin, and antiplatelet drugs, like aspirin. [73] [74] [75] [76] This includes an increased risk of GI bleeding, and post operative bleeding. [73] The relative risk of intracranial bleeding is increased, but the absolute risk is very low. [77] SSRIs are known to cause platelet dysfunction. [78] [79] This risk is greater in those who are also on anticoagulants, antiplatelet agents and NSAIDs (nonsteroidal anti-inflammatory drugs), as well as with the co-existence of underlying diseases such as cirrhosis of the liver or liver failure. [80] [81]

Fracture risk Edit

Evidence from longitudinal, cross-sectional, and prospective cohort studies suggests an association between SSRI usage at therapeutic doses and a decrease in bone mineral density, as well as increased fracture risk, [82] [83] [84] [85] a relationship that appears to persist even with adjuvant bisphosphonate therapy. [86] However, because the relationship between SSRIs and fractures is based on observational data as opposed to prospective trials, the phenomenon is not definitively causal. [87] There also appears to be an increase in fracture-inducing falls with SSRI use, suggesting the need for increased attention to fall risk in elderly patients using the medication. [87] The loss of bone density does not appear to occur in younger patients taking SSRIs. [88]

Bruxism Edit

SSRI and SNRI antidepressants may cause jaw pain/jaw spasm reversible syndrome (although it is not common). Buspirone appears to be successful in treating bruxism on SSRI/SNRI induced jaw clenching. [89] [90] [91] [92]

Discontinuation syndrome Edit

Serotonin reuptake inhibitors should not be abruptly discontinued after extended therapy, and whenever possible, should be tapered over several weeks to minimize discontinuation-related symptoms which may include nausea, headache, dizziness, chills, body aches, paresthesias, insomnia, and brain zaps. Paroxetine may produce discontinuation-related symptoms at a greater rate than other SSRIs, though qualitatively similar effects have been reported for all SSRIs. [93] [94] Discontinuation effects appear to be less for fluoxetine, perhaps owing to its long half-life and the natural tapering effect associated with its slow clearance from the body. One strategy for minimizing SSRI discontinuation symptoms is to switch the patient to fluoxetine and then taper and discontinue the fluoxetine. [93]

Serotonin syndrome Edit

Serotonin syndrome is typically caused by the use of two or more serotonergic drugs, including SSRIs. [95] Serotonin syndrome is a condition that can range from mild (most common) to deadly. Mild symptoms may consist of increased heart rate, shivering, sweating, dilated pupils, myoclonus (intermittent jerking or twitching), as well as overresponsive reflexes. [96] Concomitant use of an SSRI or selective norepinephrine reuptake inhibitor for depression with a triptan for migraine does not appear to heighten the risk of the serotonin syndrome. [97] The prognosis in a hospital setting is generally good if correctly diagnosed. Treatment consists of discontinuing any serotonergic drugs as well as supportive care to manage agitation and hyperthermia, usually with benzodiazepines. [98]

Suicide risk Edit

Children and adolescents Edit

Meta analyses of short duration randomized clinical trials have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents. [99] [100] [101] For instance, a 2004 U.S. Food and Drug Administration (FDA) analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation and suicidal behavior" by about 80%, and of agitation and hostility by about 130%. [102] According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment. [103] [104] [105] The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment". [106] The European Psychiatric Association places the excess risk in the first two weeks of treatment and, based on a combination of epidemiological, prospective cohort, medical claims, and randomized clinical trial data, concludes that a protective effect dominates after this early period. A 2014 Cochrane review found that at six to nine months, suicidal ideation remained higher in children treated with antidepressants compared to those treated with psychological therapy. [105]

A recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that no significant difference between the fluoxetine group and a placebo group. [107] There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational, the true nature of the relationship is unclear. [108]

In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered a favorable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation. [109] Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), and only for the treatment of obsessive–compulsive disorder. Fluoxetine is not licensed for this use. [110]

Adults Edit

It is unclear whether SSRIs affect the risk of suicidal behavior in adults.

  • A 2005 meta-analysis of drug company data found no evidence that SSRIs increased the risk of suicide however, important protective or hazardous effects could not be excluded. [111]
  • A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to placebo and compared to therapeutic interventions other than tricyclic antidepressants. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants. [112]
  • On the other hand, a 2006 review suggests that the widespread use of antidepressants in the new "SSRI-era" appears to have led to a highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide. [113]
  • A 2006 meta-analysis of random controlled trials suggests that SSRIs increase suicide ideation compared with placebo. However, the observational studies suggest that SSRIs did not increase suicide risk more than older antidepressants. The researchers stated that if SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased. [114]
  • An additional meta-analysis by the FDA in 2006 found an age-related effect of SSRI's. Among adults younger than 25 years, results indicated that there was a higher risk for suicidal behavior. For adults between 25 and 64, the effect appears neutral on suicidal behavior but possibly protective for suicidal behavior for adults between the ages of 25 and 64. For adults older than 64, SSRI's seem to reduce the risk of both suicidal behavior. [99]
  • In 2016 a study criticized the effects of the FDA Black Box suicide warning inclusion in the prescription. The authors discussed the suicide rates might increase also as a consequence of the warning. [115]

Pregnancy and breastfeeding Edit

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases. [116] In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold. [117] [118] Use is also associated preterm birth. [119]

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies. [120] [121] Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants. [122] Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies. [118]

The FDA issued a statement on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians. However, the medical literature on the safety of SSRIs has determined that some SSRIs like Sertraline and Paroxetine are considered safe for breastfeeding. [123] [124] [125]

Neonatal abstinence syndrome Edit

Several studies have documented neonatal abstinence syndrome, a syndrome of neurological, gastrointestinal, autonomic, endocrine and/or respiratory symptoms among a large minority of infants with intrauterine exposure. These syndromes are short-lived, but insufficient long-term data is available to determine whether there are long-term effects. [126] [127]

Persistent pulmonary hypertension Edit

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but very rare, lung condition that occurs soon after birth of the newborn. Newborn babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. About 1 to 2 babies per 1000 babies born in the U.S. develop PPHN shortly after birth, and often they need intensive medical care. It is associated with about a 25% risk of significant long-term neurological deficits. [128] A 2014 meta analysis found no increased risk of persistent pulmonary hypertension associated with exposure to SSRI's in early pregnancy and a slight increase in risk associates with exposure late in pregnancy "an estimated 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in an average of one additional case of persistent pulmonary hypertension of the newborn.". [129] A review published in 2012 reached conclusions very similar to those of the 2014 study. [130]

Neuropsychiatric effects in offspring Edit

According to a 2015 review available data found that "some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs (autism spectrum disorders)" [131] even though a large cohort study published in 2013 [132] and a cohort study using data from Finland's national register between the years 1996 and 2010 and published in 2016 found no significant association between SSRI use and autism in offspring. [133] The 2016 Finland study also found no association with ADHD, but did find an association with increased rates of depression diagnoses in early adolescence. [133]

Overdose Edit

SSRIs appear safer in overdose when compared with traditional antidepressants, such as the tricyclic antidepressants. This relative safety is supported both by case series and studies of deaths per numbers of prescriptions. [134] However, case reports of SSRI poisoning have indicated that severe toxicity can occur [135] and deaths have been reported following massive single ingestions, [136] although this is exceedingly uncommon when compared to the tricyclic antidepressants. [134]

Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The most commonly reported severe effect following SSRI overdose is serotonin syndrome serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion. [137] Other reported significant effects include coma, seizures, and cardiac toxicity. [134]

Bipolar switch Edit

In adults and children suffering from bipolar disorder, SSRIs may cause a bipolar switch from depression into hypomania/mania. When taken with mood stabilizers, the risk of switching is not increased, however when taking SSRI's as a monotherapy, the risk of switching may be twice or three times that of the average. [138] [139] The changes are not often easy to detect and require monitoring by family and mental health professionals. [140] This switch might happen even with no prior (hypo)manic episodes and might therefore not be foreseen by the psychiatrist.

The following drugs may precipitate serotonin syndrome in people on SSRIs: [141] [142]

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs and may compound the increased risk of gastrointestinal bleeds caused by SSRI use. [74] [76] [143] NSAIDs include:

There are a number of potential pharmacokinetic interactions between the various individual SSRIs and other medications. Most of these arise from the fact that every SSRI has the ability to inhibit certain P450 cytochromes. [144] [145] [146]

Drug name CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 CYP2B6
Citalopram + 0 0 + 0 0
Escitalopram 0 0 0 + 0 0
Fluoxetine + ++ +/++ +++ + +
Fluvoxamine +++ ++ +++ + + +
Paroxetine + + + +++ + +++
Sertraline + + +/++ + + +

Legend:
0 — no inhibition
+ — mild inhibition
++ — moderate inhibition
+++ — strong inhibition

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine [147] and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors. [148] [149] The concomitant use of some SSRIs (paroxetine and fluoxetine) with codeine may decrease the plasma concentration of active metabolite morphine, which may result in reduced analgesic efficacy. [150] [151]

Another important interaction of certain SSRIs involves paroxetine, a potent inhibitor of CYP2D6, and tamoxifen, an agent used commonly in the treatment and prevention of breast cancer. Tamoxifen is a prodrug that is metabolised by the hepatic cytochrome P450 enzyme system, especially CYP2D6, to its active metabolites. Concomitant use of paroxetine and tamoxifen in women with breast cancer is associated with a higher risk of death, as much as a 91 percent in women who used it the longest. [152]

Marketed Edit

Antidepressants Edit

Others Edit

Discontinued Edit

Antidepressants Edit

Never marketed Edit

Antidepressants Edit

    (GEA-654)
  • Centpropazine (JO-1017) (Malexil FG-4963) (CGP-15210) (WY-26002) (AY-23713) ((S)-norfluoxetine)

Related drugs Edit

Although described as SNRIs, duloxetine (Cymbalta), venlafaxine (Effexor), and desvenlafaxine (Pristiq) are in fact relatively selective as serotonin reuptake inhibitors (SRIs). [153] They are about at least 10-fold selective for inhibition of serotonin reuptake over norepinephrine reuptake. [153] The selectivity ratios are approximately 1:30 for venlafaxine, 1:10 for duloxetine, and 1:14 for desvenlafaxine. [153] [154] At low doses, these SNRIs act mostly as SSRIs only at higher doses do they also prominently inhibit norepinephrine reuptake. [155] [156] Milnacipran (Ixel, Savella) and its stereoisomer levomilnacipran (Fetzima) are the only widely marketed SNRIs that inhibit serotonin and norepinephrine to similar degrees, both with ratios close to 1:1. [153] [157]

Vilazodone (Viibryd) and vortioxetine (Trintellix) are SRIs that also act as modulators of serotonin receptors and are described as serotonin modulators and stimulators (SMS). [158] Vilazodone is a 5-HT1A receptor partial agonist while vortioxetine is a 5-HT1A receptor agonist and 5-HT3 and 5-HT7 receptor antagonist. [158] Litoxetine (SL 81-0385) and lubazodone (YM-992, YM-35995) are similar drugs that were never marketed. [159] [160] [161] [162] They are SRIs and litoxetine is also a 5-HT3 receptor antagonist [159] [160] while lubazodone is also a 5-HT2A receptor antagonist. [161] [162]

Serotonin reuptake inhibition Edit

In the brain, messages are passed from a nerve cell to another via a chemical synapse, a small gap between the cells. The presynaptic cell that sends the information releases neurotransmitters including serotonin into that gap. The neurotransmitters are then recognized by receptors on the surface of the recipient postsynaptic cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process the other 90% are released from the receptors and taken up again by monoamine transporters into the sending presynaptic cell, a process called reuptake.

SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. In the short run, this leads to an increase in signaling across synapses in which serotonin serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of post-synaptic serotonin receptors signals the pre-synaptic neuron to synthesize and release less serotonin. Serotonin levels within the synapse drop, then rise again, ultimately leading to downregulation of post-synaptic serotonin receptors. [163] Other, indirect effects may include increased norepinephrine output, increased neuronal cyclic AMP levels, and increased levels of regulatory factors such as BDNF and CREB. [164] Owing to the lack of a widely accepted comprehensive theory of the biology of mood disorders, there is no widely accepted theory of how these changes lead to the mood-elevating and anti-anxiety effects of SSRIs. [ citation needed ] . Any direct effects of SSRIs are limited by their inability to cross the blood-brain barrier their effects on serotonin blood levels, which take weeks to take effect, appear to be largely responsible for their slow-to-appear psychiatric effects. [165]

Sigma receptor ligands Edit

SSRIs at the human SERT and rat sigma receptors [166] [167]
Medication SERT σ1 σ2 σ1 / SERT
Citalopram 1.16 292–404 Agonist 5,410 252–348
Escitalopram 2.5 288 Agonist ND ND
Fluoxetine 0.81 191–240 Agonist 16,100 296–365
Fluvoxamine 2.2 17–36 Agonist 8,439 7.7–16.4
Paroxetine 0.13 ≥1,893 ND 22,870 ≥14,562
Sertraline 0.29 32–57 Antagonist 5,297 110–197
Values are Ki (nM). The smaller the value, the more strongly the
drug binds to the site.

In addition to their actions as reuptake inhibitors of serotonin, some SSRIs are also, coincidentally, ligands of the sigma receptors. [166] [167] Fluvoxamine is an agonist of the σ1 receptor, while sertraline is an antagonist of the σ1 receptor, and paroxetine does not significantly interact with the σ1 receptor. [166] [167] None of the SSRIs have significant affinity for the σ2 receptor, and the SNRIs, unlike the SSRIs, do not interact with either of the sigma receptors. [166] [167] Fluvoxamine has by far the strongest activity of the SSRIs at the σ1 receptor. [166] [167] High occupancy of the σ1 receptor by clinical dosages of fluvoxamine has been observed in the human brain in positron emission tomography (PET) research. [166] [167] It is thought that agonism of the σ1 receptor by fluvoxamine may have beneficial effects on cognition. [166] [167] In contrast to fluvoxamine, the relevance of the σ1 receptor in the actions of the other SSRIs is uncertain and questionable due to their very low affinity for the receptor relative to the SERT. [168]

Anti-inflammatory effects Edit

The role of inflammation and the immune system in depression has been extensively studied. The evidence supporting this link has been shown in numerous studies over the past ten years. Nationwide studies and meta-analyses of smaller cohort studies have uncovered a correlation between pre-existing inflammatory conditions such as type 1 diabetes, rheumatoid arthritis (RA), or hepatitis, and an increased risk of depression. Data also shows that using pro-inflammatory agents in the treatment of diseases like melanoma can lead to depression. Several meta-analytical studies have found increased levels of proinflammatory cytokines and chemokines in depressed patients. [169] This link has led scientists to investigate the effects of antidepressants on the immune system.

SSRIs were originally invented with the goal of increasing levels of available serotonin in the extracellular spaces. However, the delayed response between when patients first begin SSRI treatment to when they see effects has led scientists to believe that other molecules are involved in the efficacy of these drugs. [170] To investigate the apparent anti-inflammatory effects of SSRIs, both Kohler et al. and Więdłocha et al. conducted meta-analyses which have shown that after antidepressant treatment the levels of cytokines associated with inflammation are decreased. [171] [172] A large cohort study conducted by researchers in the Netherlands investigated the association between depressive disorders, symptoms, and antidepressants with inflammation. The study showed decreased levels of interleukin (IL)-6, a cytokine that has proinflammatory effects, in patients taking SSRIs compared to non-medicated patients. [173]

Treatment with SSRIs has shown reduced production of inflammatory cytokines such as IL-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ, which leads to a decrease in inflammation levels and subsequently a decrease in the activation level of the immune response. [174] These inflammatory cytokines have been shown to activate microglia which are specialized macrophages that reside in the brain. Macrophages are a subset of immune cells responsible for host defense in the innate immune system. Macrophages can release cytokines and other chemicals to cause an inflammatory response. Peripheral inflammation can induce an inflammatory response in microglia and can cause neuroinflammation. SSRIs inhibit proinflammatory cytokine production which leads to less activation of microglia and peripheral macrophages. SSRIs not only inhibit the production of these proinflammatory cytokines, they also have been shown to upregulate anti-inflammatory cytokines such as IL-10. Taken together, this reduces the overall inflammatory immune response. [174] [175]

In addition to affecting cytokine production, there is evidence that treatment with SSRIs has effects on the proliferation and viability of immune system cells involved in both innate and adaptive immunity. Evidence shows that SSRIs can inhibit proliferation in T-cells, which are important cells for adaptive immunity and can induce inflammation. SSRIs can also induce apoptosis, programmed cell death, in T-cells. The full mechanism of action for the anti-inflammatory effects of SSRIs is not fully known. However, there is evidence for various pathways to have a hand in the mechanism. One such possible mechanism is the increased levels of cyclic adenosine monophosphate (cAMP) as a result of interference with activation of protein kinase A (PKA), a cAMP dependent protein. Other possible pathways include interference with calcium ion channels, or inducing cell death pathways like MAPK [176] and Notch signaling pathway. [177]

The anti-inflammatory effects of SSRIs have prompted studies of the efficacy of SSRIs in the treatment of autoimmune diseases such as multiple sclerosis, RA, inflammatory bowel diseases, and septic shock. These studies have been performed in animal models but have shown consistent immune regulatory effects. Fluoxetine, an SSRI, has also shown efficacy in animal models of graft vs. host disease. [176] SSRIs have also been used successfully as pain relievers in patients undergoing oncology treatment. The effectiveness of this has been hypothesized to be at least in part due to the anti-inflammatory effects of SSRIs. [175]

Pharmacogenetics Edit

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects that will cause their discontinuation, although these tests are not yet ready for widespread clinical use. [178]

Versus TCAs Edit

SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well, and as a result, SSRIs have fewer side effects.

There appears to be no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs. [179] However, SSRIs have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. Further, they have fewer and milder side effects. Tricyclic antidepressants also have a higher risk of serious cardiovascular side effects, which SSRIs lack.

SSRIs act on signal pathways such as cyclic adenosine monophosphate (cAMP) on the postsynaptic neuronal cell, which leads to the release of brain-derived neurotrophic factor (BDNF). BDNF enhances the growth and survival of cortical neurons and synapses. [164]

Fluoxetine was introduced in 1987 and was the first major SSRI to be marketed.

A study examining publication of results from FDA-evaluated antidepressants concluded that those with favorable results were much more likely to be published than those with negative results. [180] Furthermore, an investigation of 185 meta-analyses on antidepressants found that 79% of them had authors affiliated in some way to pharmaceutical companies and that they were reluctant to report caveats for antidepressants. [181]

David Healy has argued that warning signs were available for many years prior to regulatory authorities moving to put warnings on antidepressant labels that they might cause suicidal thoughts. [182] At the time these warnings were added, others argued that the evidence for harm remained unpersuasive [183] [184] and others continued to do so after the warnings were added. [185] [186]


DISCUSSION

The major new finding from this study is that cutaneous vasodilation accompanying direct local skin warming correlates better with the sensation of heat than it does with actual skin temperature. The suggestion from this study is that local warming-induced vasodilation is mediated by heat-sensitive nociceptors. In part I, we observed that pretreatment with capsaicin shifted the relationship of vasodilation to local warming and that this effect is dose dependent. Furthermore, in part I, we noted that a correlation existed between the first sensation of nonnoxious heat and the onset of cutaneous vasodilation. In part II, we observed the same degree of vasodilation (similar blood flow) at sites with different actual temperatures but similar heat sensation. Cutaneous blood flow increases induced by combined chemical and thermal stimulation were not significantly different from those induced through only thermal stimulation, when the sensation of heat was the same. Inpart III, we found no significant difference in CVC values or local temperatures from untreated sites on different arms warmed to the same perceived temperature. These findings led us to the conclusion that an important part of the mechanism for the vasodilator response to local warming includes activation of heat-sensitive nociceptors.

In general, neural and local mechanisms are considered as independent means of control in the circulation. That the local environment of the nerve-vascular smooth muscle junction can influence efferent neural function is now well accepted in a variety of tissues and organ systems (6, 33, 37). More recently, it has been found that responses to local stimuli by the human cutaneous circulation are dependent on neural elements. That is, the relationship between local and neural control mechanisms is more than simply modulatory. For example, the cutaneous vasoconstrictor response to local cooling is dependent on intact sympathetic nerves (30, 31) and on the availability of α-2 adrenoceptors (9, 24). Currently, available findings indicate that local cooling of the skin both stimulates transmitter release from vasoconstrictor nerve terminals (30, 31) and increases postsynaptic α-2 receptor affinity for norepinephrine (10, 27, 38). Both of these elements of the remote sympathetic control of the cutaneous circulation appear to be required for the response to local skin cooling.

The response of the cutaneous circulation to local warming does not appear to require elements of sympathetic vasoconstrictor or vasodilator nerves. Local heating of the skin can cause a marked increase in blood flow with the potential for complete relaxation of cutaneous resistance vessels and a maximal vasodilation (1, 16,36). This degree of vasodilation is not achievable by modulation of vasoconstrictor nerve function. Neither sympathectomy (32), nerve block (8), stellate ganglion block (39), nor inhibition of neurotransmitter release from adrenergic nerve terminals (19), all of which raise skin blood flow by inhibiting or eliminating vasoconstrictor nerve function, will cause this degree of cutaneous vasodilation. Furthermore, presynaptic blockade of the cutaneous neurogenic active vasodilator system does not eliminate or obviously affect the vasodilator response to local heating (21). These observations effectively eliminate any major role for sympathetic efferent nerves in the cutaneous vasodilator response to local heating. Similarly, the dilator effects of topical capsaicin do not appear to involve sympathetic nerves (5).

Several have noted that the vasodilator response to direct skin heating extends beyond the heated area, suggesting a neurogenic component (6, 25). Brief heat stimuli were found to cause vasodilation at an 8-mm distance from the heated site, but only at temperatures considered to be nociceptive, whereas nociceptive sensations and vasodilation were not as closely correlated if the warm stimulus was more sustained (26). In either case, the data clearly support the role of an axon reflex from heat-sensitive nociceptors in mediating increases in blood flow up to 8 mm from the site of heating. However, information is lacking regarding the mechanisms of vasodilation at the site of heating during nonnociceptive stimulation. Lynn et al. (25) demonstrated that thermally induced vasodilation of porcine skin is mediated by a distinctive type of nociceptor that is sensitive both to heat and to capsaicin, but not to pressure. In part I, the sites of blood flow measurement, measured on the same arm, were separated by at least 10 cm. The distance of separation in our experiment is larger than the distance of axon reflex vasodilation conduction observed by Magerl and Treede (26) at noxious local temperatures. Furthermore, the local temperatures during parts I, II, and IIIwere lower than the local temperature used by Magerl and Treede (26) to induce vasodilation 8 cm distant from the site of local warming. Crockford et al. (7) showed that local warming-induced vasodilation of forearm blood flow was conducted at 10 cm. However, Crockford et al. sprayed warm water over a large area of the forearm and upper arm. The results reported in this study were collected from sites where the changes in local temperature were confined to a smaller area (12 cm 2 ), presumably stimulating a more discrete axon reflex. Thus, given the reports in the literature and the distance of separation, an axon reflex at the capsaicin-treated site is unlikely to have importantly influenced the cutaneous vascular response to local warming observed at the control site on the same arm.

A possible limitation in part I is that 5 min may not be long enough for the cutaneous vasomotor response to reach steady state at the higher local temperatures. During local temperature changes at relatively low temperatures (e.g., <40°C), vasomotor responses reach a steady state typically in 3 min. However, at higher temperatures, the time constant to reach a steady-state blood flow response in response to local temperature changes can be longer. This limitation does not change our conclusion that capsaicin pretreatment significantly lowers the threshold for local warming-induced vasodilation in a dose-dependent manner.

The origin of the hysteresis in the LDF-local temperature relationship as shown in Fig. 4 is not clear. However, it was seen only at the capsaicin-treated sites and is most likely associated with the continual stimulation by capsaicin during the 1 h before the study began. During that period, the area was simply exposed to the ambient environment, but the capsaicin may have induced significant heat-sensitive nociceptor activity. It is likely that the continued activity of those receptors over the hour caused continual secretion of calcitonin gene-related peptide (CGRP) or another axon reflex transmitter, causing an increased interstitial concentration. It follows that when the pretreated area was cooled such that the heat-sensitive nociceptor activity was abolished, the secretion of sensory transmitters was halted and the interstitial levels dissipated. In this scenario, the interstitial level of transmitter would be greater for a given local temperature during the initial cooling than during the subsequent rewarming. Another possibility is that a modulatory interaction exists between sympathetic vasoconstrictor nerves activated by local cooling and the capsaicin-induced release of vasodilatory neurotransmitters. This hypothesis arises from the observation that blood flow at capsaicin-treated sites is similar to that at untreated sites only after being cooled to a moderately cold temperature and that local skin cooling stimulates vasoconstriction through adrenergic activity (6, 10, 31).

The perception of heat sensation in the human forearm is mediated by both warm receptors and heat-sensitive C fiber nociceptors. Interestingly, Green and Cruz (11) described warmth-insensitive fields in the human forearm of up to 4.8 cm 2 , supporting the concept that heat sensation is sensitive to and coded by spatially summated sensory information. In our study, the area of application of both capsaicin and heat of ∼12 cm 2 exceeded the largest warmth-insensitivity fields described by Green and Cruz. However, although warm receptors may be stimulated in our direct heating method, the relative paucity of warm receptors in the human forearm (11, 12) and the insensitivity of warm receptors to capsaicin (3) make their having a prominent role in the vasomotor response to direct heating unlikely. Interestingly, one subject in part III did not perceive warmth at a site that was heated to 42°C. Those data were not included in the analysis, but they suggest that warmth-insensitive fields described by Green and Cruz may occasionally be larger than even the 4.8 cm 2 measured.

In our studies, we took advantage of the perception of increased temperature by capsaicin pretreatment as a means of separating heat-sensitive afferent activity from the actual local temperature. With this tool, we explored the vasodilator responses in directly heated areas where effects of local warming appear to differ from the effects found by Magerl and Treede (26) at nearby unheated sites. They found no vasodilation 8 mm from the site of local warming during heating from 30 to 35°C, a range of temperatures chosen for nonnociceptive stimulation of warm receptors. This was true for either brief, pulsatile heating or sustained heating. On the contrary, in the present study, we found significant vasodilation between local temperatures of 30 and 35°C at the heated sites (see Fig. 2). This is in keeping with earlier reports (1, 16, 36). Taken together, these observations suggest that heat-sensitive afferents, likely C fibers, mediate vasomotor responses to direct heating and that these responses are active at temperatures below those perceived to be painful.

Is the vasodilation with local heating a direct function of the temperature of the resistance vessels, or does that response require a neural element? Part II of this study supports the latter possibility. The vasodilator response to direct heating corresponded better to the perception of temperature than to the temperature itself (see Fig. 5). Our assumption was that a given level of heat-sensitive nociceptor stimulation, be it by physical heating or by chemical stimulation, would be perceived as a particular temperature. Blood flow did not differ significantly between untreated and capsaicin-treated sites when perceived as being at equal temperatures although actually being several degrees different. This suggests the major local stimulus for vasodilation to involve activity of heat-sensitive nociceptors and to be less dependent on the physical temperature of the resistance vessels. Furthermore, the VR is capable of mediating cationic currents that are induced by heat. Capsaicin sensitizes the VR to heat and thus amplifies the response to the heat stimulus. Caterina et al. (4) noted that VRs were only active at noxious temperatures (48°C). However, methodological differences with the present study are significant in that we tested intact human sensory function that likely includes endogenous physiological signaling mechanisms absent in transfected cell preparations.

To complete our investigation of the role of heat-sensitive nociceptors and cutaneous vasodilation, we tested whether subjects could accurately match heat sensation at untreated sites and whether blood flow differed significantly at untreated sites perceived to be the same temperature. We found that blood flow was not significantly different at untreated sites perceived to be the same (Fig. 6A) and that subjects could accurately match the local temperatures by heat sensation on their arms (Fig. 6B). The local temperatures in part III were similar to the local temperatures from the untreated sites in part II.

In summary, we have shown that chemical stimulation of heat-sensitive nociceptors shifts the vasodilator response to local warming to lower temperatures. Furthermore, these data indicate that similar levels of heat-sensitive nociceptor stimulation, whether by thermal or chemical means, cause similar levels of skin blood flow. Taken together, the findings strongly suggest that the cutaneous vasodilator response to local warming of the skin is dependent on the activation of sensory nerves (heat-sensitive nociceptors) in the area being warmed.


How are animal toxicity studies related back to humans when different species find different things toxic?

Let’s take raisins for example. If you were testing raisins in dogs, the LD50 would be really low compared to the LD50 in humans.

How do we account for these differences? Are there animals that have consistently had similar toxicities as humans that are used (mice? pigs?)? Are compounds tested in many different species? I know they can be tested on human cell lines, but that doesn’t necessarily equate to the whole system.

Even though it's true that different species may have different response to a certain toxic substance, it's something that we are aware of and can adjust for in toxicology studies. It's also a matter of which model is more suitable for each case. As a rule of thumb, the closest the animal is to us, the more reliable the results will be. So the best models would be large apes, like chimpanzees, gorillas or orangutans, but they are rarely used for obvious reasons. Instead, one common technique is to use two animal models, one rodent (rat, mouse, guinea pig) and one something else (dogs or pigs, for example). If both show the same toxic effect its more likely that humans will suffer it too. In any case, any LD50 should always include the model used to determineit.

Thanks for your response. That all makes sense, I just wonder about the hypothetical situation in which both animal models are fine and humans are not, or vice versa.

In case anyone is wondering LD50 is the lethal dose to kill 50% of a population.

To add to the other post about testing in multiple species like mice, dogs, and pigs, knowledge about the toxicity mechanism and pathways help to establish how universal the initial finding is going to be.

Toxin A is a synthetic chemical that interferes with a central cell function of an animal model, say DNA replication. These central functions do not vary much throughout the animal kingdom, so the likelihood is increased that it will be toxic for humans. If you then find that it's chemically simple and can slowly diffuse throughout the body without assistance, the likelihood increases further. If the body can't break it down, it must flush it out/store it somewhere out of the way, if it can. Etc. These are the kind of characteristics one would find in a universal toxin.

Toxin B is made by an spider who hunts by injecting it into prey, or defend against a predator. It then acts by paralysing the victim, by blocking nerve signals. This mechanism is more specific, but since we all have nerves there is typically an LD50. This value is different per toxin because there are small superficial changes between our evolved components. Also, many spider venoms are proteins that would just get digested if eaten. So, animals eating a spider will tend to be fine if it doesn't get bitten in the process. P.S. don't feed your pet, just in case. Exceptions always occur.

Toxin C is made by a plant, which tend to be esoteric chemicals. From a survival perspective, they don't really care if the stuff kills you or just gives you a bad itch. So the results can vary a lot. Ones like oxalic acid are tiny and easy to make by the plant, which technically has an LD50 but youɽ be okay if it was a small amount. Many plants make these. Others like theobromine (chocolate), caffeine, and capsaicin (chili) are larger and somewhat more difficult to make, but are still meant to be some sort of neurotoxin to tell a herbivore that they are not supposed to eat the seed. As it turns out, humans have developed a taste for such toxins and a metabolism to break them down. Dogs have not.

There is work being done right now to get around some of those limitations, such as humanized mice. They have cells or tissues from humans that supplant their normal cells or tissues. For instance, there are mice with livers made from human cells that should metabolize drugs more similarly to humans.

There’s no way they would use these mice to perform standard acute toxicity studies, it would be way to expensive. The possibility of screening various cancer drugs this mouse model will bring to the industry is definitely fascinating. I can’t wait to see what comes from it

For the most part LD50s are not really conducted today like they were years ago. Additionally, testing would be controlled for a single cmpd or so, therefore no studies would be run with raisins, they’d probably extract whatever chemical they were interested in or expected to see toxicity with, to verify its range. So if you’re talking about toxicity testing within Pharma, here’s how it’s broken down.

Early Discovery type studies, like MTD (maximum tolerated dose) studies will be conducted to verify if the animal model being used will be tolerated and the animals will survive the planned dose regimen. Those are generally rodent models, and are looking to maximize exposure to maximize the efficacious effect they’re exploring. Scientist will then look at the exposure vs efficacy and plot that against predictive models in humans. These predictive models look at modes of clearance/metabolism in humans and the prediction of how well it binds to the human target vs in animal. Additional efficacy studies will be conducted and when they have a cmpd of interest it then goes to Nonclinical Safety testing, which I think is what you were really asking about.

Nonclinical Safety studies are required to be conducted via strict regulations governed by the FDA (in US). The pharma companies are required to provide safety data in at least 2 species, one being a rodent model and the other non-rodent (eg dogs, pigs, primates). They will conduct numerous in vitro binding assays to determine the most sensitive species, so the animal models will contain similar efficacious sites of binding as humans, and they also have to show that there is adequate exposure (meaning drug actually gets into system and isn’t just expelled). If for some reason there isn’t a second species which show exposure, or there is no active site in the animal models, you can provide scientific justification to proceed with a single species, if warranted. Once you have your two species chosen and start conducting Tox studies, you take a step wise approach, a single dose acute study, to a 7day Tox, to 14 day Tox, until the pivotal 28 day IND studies. At each of those steps you generally have 3 different dose levels you look at (low mid high) vs a control group. The idea is to have toxic findings in high dose groups, a clean low dose, with the mid dose helping to figure out thresholds. We never want any animal deaths on these studies, as that would lose important data. So toxic findings in the high dose should be more like tissue damage identified after histopath evaluation following the necropsy, not overt adverse clinical signs. There are many known common findings in these animal models that are known to be species specific, so we can discount them effecting humans right off the bat. Next we see if we’ve identified similar toxicities in both species, and if so, then the likelihood of it occurring in humans goes up. If Tox is only in a single species, then you look at the genetic makeup of what you’re hitting, and is it similar enough to humans to cause an issue.

So once you e identified all potential toxicities, you’re then looking for an efficacious drug that has a clean toxicity profile to allow it to next move into human clinical trials. The threshold is generally a 10x safety margin, so any adverse finding you discovered in your Tox program, would need to have occurred at drug levels that were 10 times higher than what you expect to reach in humans. Additionally, those identified toxicities may have associated biomarkers that can be included on the clinical trials to ensure safety. An easy example is that if liver damage is a known finding, a simple blood test for LFT markers are easily done and highly accurate.

So in essence, there isn’t a 1:1 correlation between animal models of toxicity and humans, but there is a rigorous science behind how we keep humans safe in pharmaceutical trials and ensuring large safety windows.

Hope I didn’t miss the mark with this, i tried keeping to a basic response, but there are thousands of nuances in there. Feel free for any follow up questions, I do work directly in Nonclinical safety, and would be happy to provide more detailed answers.



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