Hyperthermia is defined as supraphysiological body temperature resulting from absorption and/or production of more heat than is dispelled. Medically, local hyperthermia is often used as an adjunct to radiation and/or chemotherapy for the treatment of cancers. It is thought that deliberate induction of hyperthermia to a cancerous region of the body increases the sensitivity of cancer cells to radiation and/or chemotherapy, thereby enhancing the respective efficacies of each intervention.
Another form of hyperthermia used on an experimental basis among cancer patients is referred to as “whole-body hyperthermia.” Unlike local hyperthermia which involves increasing the temperature in a specific region, whole-body hyperthermia increases temperature throughout the entire body – and is typically induced with radiant heat chambers. Interestingly, in addition to augmenting cancer therapies, preliminary evidence suggests that whole-body hyperthermia may be useful for the treatment of major depression.
Assuming those with major depression could simply receive a session or two of whole-body hyperthermia per week to maintain a happier mood – many may prefer this over medication. It is also possible that whole body hyperthermia could be used as an adjunct to potentiate the therapeutic efficacy of antidepressants among partial responders. That said, further investigation is required to elucidate the safety and efficacy of whole-body hyperthermia among those with major depression.
How Whole-Body Hyperthermia Treats Depression (Hypothesized Mechanisms)
It is understood that whole-body hyperthermia delivers and traps heat in a confined space around the body to elevate core temperature. As the body begins warming up, receptors within the epidermis and endothelial lining detect elevations in skin temperature and innervate peripheral nerves. Next, these peripheral nerves transmit signals to regions of the brain responsible for generation of a thermoregulatory cooling effect (this helps prevent overheating and reduce body temperature).
A region of the brain known as the dorsal raphe nucleus (DRN) is heavily implicated in facilitating this thermoregulatory cooling effect. To initiate the thermoregulatory cooling effect, a neurochemical reaction within the dorsal raphe nucleus occurs in which serotonin is released from serotonergic neurons. When a person first notices feelings of pleasant warmth (in the early stages of a whole-body hyperthermia session), the serotonin released binds to 5-HT1A and 5-HT7 receptors to help keep the body cool; 5-HT1A is involved in thermoregulation.
Continued heating of the skin from heat administration and trapping leads to further elevations in skin temperature whereby the skin-to-brain signaling necessary for the thermoregulatory cooling effect is maintained. Serotonin release in the dorsal raphe nucleus is also maintained, and since serotonin concentrations continue to rise, it begins binding to another target besides 5-HT1A receptors, namely the 5-HT2 receptors.
Thereafter, core body temperature continues to rise, and inevitably becomes sufficiently hot to trigger a thermal stress response. As a result of the thermal stress response, cortisol is released, serotonin levels drop, and sensitivities of both serotonin and mineralocorticoid receptors are normalized. Normalization of serotonin and mineralocorticoid receptors sensitivities is helpful for individuals with major depression in which receptor sensitivity imbalances are common.
This is believed to reverse abnormal function of the HPA (hypothalamic-pituitary-adrenal) axis, as well as restore stress tolerance. Following the normalization of neural activity after the thermal stress response, a person’s mood is generally elevated, and a pronounced “antidepressant effect” can be observed. This is the theory presented by a leading whole-body hyperthermia researcher Kay-u Hanusch in the book The Antidepressant Effect of Passive Whole Body Hyperthermia.
Included below is a step-by-step summary of the succinct hypothesis explained by Kay-u Hanusch in the aforestated book. For more detailed information, consider purchasing the book or reading some of his publications.
- Hyperthermia initiation: Body temperature is elevated through simultaneous administration of an exogenous heat source and reduction of peripheral heat emissions. In other words, heat is delivered to your body (such as from infrared rays) and trapped in a confined chamber. Since your body will attempt to cool itself down in effort to maintain homeostasis (and prevent hyperthermia), encapsulation of the body in a heat chamber is necessary. Devices such as the Heckel HT-3000 apparatus are commonly used due to the fact that they effectively deliver and trap heat. In some cases, hyperthermal baths are used as an alternative and are thought to deliver analogous effects.
- Skin detects temperature elevation: As a person’s core body temperature increases, thermosensitive ion channels (TRPv) within skin cells called “Merkel cells” are able to detect the temperature elevation. For reference, Merkel cells are clear receptor cells positioned at the bottom of sweat duct ridges on the epidermis of all vertebrates. They are implicated in sensing “light touch” of various textures and shapes in our environment, and are thought to influence neuroendocrine activity.
- Skin-to-brain signaling: In response to detecting an elevation in core body temperature, Merkel cells transmit signals via afferent nerve fibers to the dorsal raphe nucleus (DRI) region of the brain. The signaling is thought to activate a particular subsection of the dorsal raphe nucleus known as the interfascicular region. Activation of the interfascicular region is understood to increase serotonin release, as well as serotonin metabolism in forebrain limbic areas.
- Serotonin release: In the early minutes of a whole-body hyperthermia session, serotonin release is understood to stimulate 5-HT1A and 5-HT7 receptor sites. Stimulation of 5-HT1A receptors is associated with feelings of warmth, comfort, and pleasantness. However, the 5-HT1A receptor eventually adapts to the enhanced release of serotonin, and skin temperature continues to increase. A continued increase in skin temperature leads to binding of serotonin on 5-HT2A receptors, causing perspiration along with feelings of discomfort, anxiety, and restlessness. At this point, a user’s serotonin concentrations remain elevated, whereas cortisol concentrations have dropped.
- Thermal stress response: Eventually, as core body temperature increases to a supraphysiological level (e.g. 38.5°C), perspiration ceases to occur and a thermal stress response is triggered. The thermal stress response occurs, leading to the release of cortisol with a drop in serotonergic activity. It is the thermal stress response that is capable of reversing imbalances in serotonin and mineralocorticoid receptor sensitivities.
- Antidepressant effect: As a result of the thermal stress reaction induced by whole-body hyperthermia, stress tolerance is restored. Reversal of receptor sensitivity imbalances improves circadian rhythms, as well as restores the negative feedback loop of cortisol on HPA-axis activity. All of this leads to increased energy, as well as enhancement of mood. It is unclear exactly how long the antidepressant effect can be maintained, but some speculate that between 3 and 7 days is a reasonable estimate.
- Source: https://books.google.com/books?id=Cuo7K3iVwFAC&pg
- Source: http://www.heckel-medizintechnik.de/en/hyperthermia/products.shtml
In summary, it appears as though whole-body hyperthermia sensitizes physiological circuits associated with thermoregulatory cooling. Interestingly, the physiological circuitry involved in a thermoregulatory cooling process ends up innervating regions of the brain involved in the regulation of mood. Serotonin and cortisol are modulated in direct response to these innervations, whereby imbalance in the sensitivities of receptors is normalized to yield an antidepressant effect.
Relationship between skin temperature and serotonergic activity…
During whole-body hyperthermia, epidermal and endothelial receptors sense heat increases and send signals through nerves to regions of the brain (e.g. dorsal raphe nucleus) involved in thermoregulation. Next, thermosensitive serotonergic systems respond based upon the degree to which a person is heated. Below is an overview of how serotonergic transmission is modified in direct response to body temperature increases.
Warm temperature: At the beginning of a whole-body hyperthermia session, body temperature is elevated slightly above its homeostatic baseline. In this early stage, the warmth is comfortable and leads to release of serotonin to stimulate the 5-HT1A and 5-HT7 receptors. This may be what occurs when most people take a warm bath and/or sit briefly in a sauna. At this point the body is just starting to adapt itself to the heat increases and it feels soothing.
- Skin temperature is warm
- Serotonin release
- 5-HT1A/5-HT7 receptor binding
- Well-being, relaxation
Hot temperature: As the body continues to receive heat, it transitions from a state of warmth to one of general hotness. The 5-HT1A receptor will have adjusted to the influx of serotonin release, and as the person becomes hotter, serotonin binds to the 5-HT2 receptor. This triggers feelings of discomfort, anxiety, and irritability. In other words, most people won’t like this feeling of hotness, in part because of the fact that their 5-HT2 receptor is being stimulated.
- Serotonin release continues
- 5-HT2 receptor binding
- Discomfort, anxiety, restlessness
Very hot temperature: Inevitably, the body will transition from a state of general hotness to reach a peak temperature (as was set by a whole-body hyperthermia practitioner). This peak temperature generates a thermal stress response to release cortisol and decrease serotonin. It is thought that the thermal stress response reverses imbalanced sensitivities of serotonin and cortisol receptors, as well as normalizes HPA-axis activity. At this point, a person’s mood, energy, and motivation are thought to increase.
- Thermal stress response
- Cortisol release
- Serotonin decrease
- Mood elevation, motivation, energy increase
Cooling of temperature: In the aftermath of whole-body hyperthermia, core body temperature declines. The heat is no longer being applied nor trapped within a confined space, allowing the thermoregulatory cooling effect to decrease core body temperature. At this point, HPA-axis and serotonin receptor function remains normalized. Mood enhancement, motivational spikes, and/or increases in energy are maintained for a minimum of several days.
- Thermoregulatory cooling
- Normalization of HPA-axis
- Correction of MR and 5-HT receptor sensitivities
- Circadian rhythm improves
- Restoration of stress tolerance
- Psychological mood improvements maintained
Whole-Body Hyperthermia for Depression (Other Possible Mechanisms)
The aforementioned theory presented by Hanusch regarding the mechanisms by which whole-body hyperthermia treats depression is highly plausible. In his theory, neurotransmission of serotonin and cortisol change in response to the elevated heat. Imbalances in sensitivity of receptors is normalized with a thermal stress response, and HPA-axis dysfunction is reversed. It is possible that his theory may be slightly incomplete. There may be other mechanisms by which whole-body hyperthermia is exerting an antidepressant effect, including by: altering neural connectivity, modulating regional cerebral blood flow and glucose metabolism, as well as by generating an anti-inflammatory response via heat-shock proteins.
Brain connectivity alterations: Another means by which whole-body hyperthermia may treat depression is by altering neural connectivity. Researchers Ye et al. (2015) analyzed disruptions in topological structure of functional brain networks among individuals with major depressive disorder. They used fMRI scans to compare the brains of 42 patients with depression to 42 healthy controls.
Results from their analysis revealed that patients with major depression exhibited structural and connectivity abnormalities in many regions including the: hippocampus, temporal cortex, anterior cingulate gyrus, and dorsolateral prefrontal gyrus. A systematic review by Gudayol-Ferré et al. (2015) discovered that when patients with major depression receive treatment, brain connectivity is altered. While depressed, abnormalities are presented in the Default Mode Network (DMN), Affective Network (AN), Cognitive Control Network (CCN), as well as many others.
The degree of improvement in antidepressant symptoms following treatment is relatively proportional to the degree in brain connectivity changes. Specifically, it seems as though connectivity alterations consistently occur in the Default Mode Network as well as cortical-limbic structures when mood improves. Based on these findings, it could be suspected that any changes in neural connectivity induced by antidepressant therapies may be critical for alleviation of depressive symptoms.
Interestingly, it appears as though hyperthermia is capable of disrupting connectivity of various brain networks. A study by Sun et al. (2013) tested the effect of 1-hour of environmental heat exposure on 36 participants at either: 122°F (hyperthermia) or 86°F (control) and assessed brain activity. Individuals exposed to the hyperthermia temperature exhibited 65 alterations in neural connectivity: 50 connections were weakened, whereas 15 were strengthened.
Weakening of connections occurred chiefly in the medial orbitofrontal cortex, temporal lobe, and occipital lobe. Strengthening of connections occurred limbic areas of the brain. Researchers noted that the number of altered functional connections resulting from hyperthermia was associated with enhancement of executive control reaction time.
Knowing these findings, it is reasonable to assume that hyperthermia could reverse dysfunctional neural connectivity implicated in major depressive disorder. The reorganization of brain connections may enhance executive function, modify behavior, as well as improve mood. Although it is unclear as to whether hyperthermia-induced reorganization of neural connectivity interferes with depression-related connections OR rewires the brain for positive emotion, and unknown as to how long this reorganization can be maintained – reorganization of neural connectivity may be a mechanism by which hyperthermia improves mood.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26327292
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26578927
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23593416
Cerebral blood flow: Researchers have documented abnormalities in regional cerebral blood flow among patients with depression compared to euthymic (non-depressed) individuals. Some findings suggest that depressed individuals may exhibit differences in cerebral blood flow to the: anterior ventral and dorsal medial prefrontal cortex (PFC), anterior cingulate cortices, temporal cortices, and lateral parieto-occipital lobes. Successful treatment with antidepressants is also understood to modulate cerebral blood flow, indicating that cerebral blood flow changes may be an important mechanism of antidepressant action.
As an example, a study by Ishizaki et al. (2008) analyzed 25 patients with late-life depression discovered that pharmacotherapy enhanced cerebral blood flow from the left dorsolateral prefrontal cortex to precentral and right parieto-occipital regions. Results from a study by Qian et al. (2014) indicate that short-term hyperthermia can modulate cerebral blood flow. In this study, researchers analyzed the effect of short-term environmental hyperthermia on regional cerebral blood flow.
It appeared as though hyperthermia significantly modified regional cerebral blood flow in the prefrontal cortex, somatosensory cortex, and limbic system. Researchers concluded that these blood flow modifications could affect cognitive performance as well as mood. Based on these findings, it is reasonable to hypothesize that whole-body hyperthermia could modulate regional cerebral blood flow to uplift mood.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/18214999
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24530482
Cerebral glucose metabolism: A mechanism by which whole-body hyperthermia may improve mood among those with depression is through enhancement of cerebral glucose metabolism. It is understood that the brain is among the most metabolically active organs in the entire body, consuming over half of the body’s energy requirements. The brain stores some energy in the form of glycogen, but predominantly relies upon circulating glucose for energy.
As glucose enters neurons, it is metabolized by mitochondria for cellular energy (adenosine triphosphate). This energy helps the brain maintain optimal neuronal and synaptic function. Hosokawa, Momose, and Kasai (2009) noted that neuroimaging brain scans of individuals with mood disorders reveal abnormalities in cerebral glucose metabolism in regions such as the prefrontal cortex.
In their research, Hosokawa, Momose, and Kasai (2009) discovered significantly lower glucose metabolism in multiple brain regions among those with major depression compared to euthymic (non-depressed) persons. Interestingly, as depressive symptoms tend to subside, cerebral glucose metabolism speeds back up to normal. A study by Mickley, Cobb, and Farrell (1997) notes that brain hyperthermia expedites brain glucose metabolism.
It is possible that whole-brain hyperthermia reverses hypometabolism of cerebral glucose to deliver its antidepressant effect. Understand that this is unlikely a standalone mechanism by which whole-body hyperthermia works, but it could play a critical role in the reversal of depressive symptoms. Further research is warranted to determine whether the degree of mood improvement from whole-body hyperthermia is related to the significance of upregulation in cerebral glucose metabolism.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/19100808
- Source: http://www.ncbi.nlm.nih.gov/pubmed/9024931
Inflammation reduction (with HSPs): Manipulation of body temperature is understood to have an effect on inflammation and the presence of inflammatory biomarkers. Emerging literature suggests that inflammation and depression are bidirectionally linked. This bidirectional link results in a vicious circle in that as inflammation increases, depression worsens – and as depression worsens, inflammation increases.
Researchers Zunszain, Hepgul, and Pariante (2013) suggest that major depressive disorders may be caused by altered peripheral immune function, impaired cellular immunity, and increased concentrations of proinflammatory cytokines. Administration of exogenous inflammation-inducing cytokines causes sickness as well as depressed mood. Conversely, a report by Köhler et al. (2015) notes that anti-inflammatory agents (e.g. NSAIDs) and cytokine inhibitors appear efficacious as antidepressant adjuncts, as well as monotherapies for the treatment of depression.
Perhaps the controlled induction of whole-body hyperthermia generates a direct anti-inflammatory response or yields a thermoregulatory cooling effect to combat inflammation. A study by Ostberg et al. (2000) documented the effect of whole-body hyperthermia in animal models. Results indicated that in the strain-specific mice, elevations in body temperature lead to an immunoregulatory effect and modulated markers of inflammation.
A report by Grisé, Kim, and McFadden (2000) mentions that hyperthermia increases expression of heat-shock protein-70 (HSP-70) in mice, and ultimately their survival with necrotizing pancreatitis. In humans, hyperthermia is also associated with an upregulation in the expression of HSP-70, which likely modulates inflammatory markers. Researchers van Eden, van der Zee, and Prakken (2005) document that heat shock proteins facilitate T cell-mediated reduction of chronic inflammation.
Based on these findings, it is reasonable to speculate that whole-body hyperthermia increases expression of heat shock proteins (HSPs). These heat shock proteins combat proinflammatory responses within the body and mood is improved. Although it is unlikely that heat-shock proteins account for the majority of whole-body hyperthermia’s antidepressant effect, they may contribute to the reduction in depressive symptoms, especially among those with high markers of inflammation.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26644153
- Source: http://www.ncbi.nlm.nih.gov/pubmed/22553073
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26711676
- Source: http://www.ncbi.nlm.nih.gov/pubmed/11129648
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10975704
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15803151
Reactive oxygen species (ROS): Another modality by which whole-body hyperthermia may treat depression is via reduction of reactive oxygen species (ROS). Some have theorized that abnormally high oxidative stress could be a causal underpinning of depressive disorders. Whole-body hyperthermia is known to induce a protective, hormetic stress response in which heat shock proteins (HSPs) are enhanced.
Though these heat-shock proteins are thought to decrease inflammation by acting upon the immune system, they also scavenge free radicals and support cellular antioxidant action through maintenance of glutathione. A study by Thomas, Pulimood, and Balasubramanian (2003) discovered that preconditioning with heat inhibits oxidative stress-inflicted damage to the intestine and lung after a surgical modification.
Researchers concluded that whole-body hyperthermia prior to a surgery may protect against postoperative complications in which reactive oxygen species may induce damage. A study by Medina-Navarro and Guerrero-Linares (2009) discovered that the heat shock of whole-body hyperthermia acts like a neuroprotective agent in animal models of mitochondrial toxicity. It protected the animal brains by reducing oxidative stress in the striatum region.
Reflecting upon these findings, it is reasonable to assume that whole-body hyperthermia may enhance antioxidant capacity of cells, reduce reactive oxygen species (ROS), and/or prevent neural abnormalities resulting from reactive oxygen species. Though this antioxidant-like effect is unlikely to be the chief mood-elevating mechanism of whole-body hyperthermia, it should be considered as playing a small, contributing role.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12673751
- Source: http://www.ncbi.nlm.nih.gov/pubmed/19440936
Growth Hormone: Whole-body hyperthermia is known to significantly increase concentrations of growth hormone, possibly improving mood among individuals with suboptimal concentrations or outright deficiencies. A publication by Mahajan et al. (2004) discussed the fact that adults with growth hormone deficits have a poorer quality of life than those with normative concentrations of growth hormone concentrations.
Research by Mahajan et al. demonstrated that over half of all patients with adult onset growth hormone deficiencies exhibit symptoms of atypical depression. Within 2 months of growth hormone therapy, improvements can be observed in: emotional reactivity, socialization, sleep quality, energy level, and mood. Based on this evidence, it appears as though atypical cases of depression in adults may benefit from assessing concentrations of growth hormone, and increasing these concentrations if deficient.
Although using whole-body hyperthermia to increase growth hormone concentrations is likely inefficient and less effective than pharmacological interventions, it may make enough of a difference to improve mood. A study by Kappel et al. (1997) discovered that hyperthermia for 2 hours (induced by a hot water bath at 39.5°C) significantly increased growth hormone concentrations to a peak of 48.4 mU/L compared to 0.3 mU/l at baseline. At 1-hour post-intervention, growth hormone concentrations dropped back to 7.4 mU/l.
Another study by Blazícková et a. (2000) noted that a whole-body hyperthermic bath significantly increased concentrations of somatotropic hormone (STH), [also known as growth hormone], in 8 out of 10 participants. It is speculated that biomarkers of immune function such as NK (natural killer) cells and CD+ T lymphocyte cells may be dependent upon production of growth hormone. Researchers Atanackovic et al. (2006) conducted a study investigating the therapeutic effect of whole-body hyperthermia among cancer patients and discovered that it significantly increases human growth hormone (hGH).
It is unclear as to whether growth hormone increases are maintained for a sustained duration post-WBH. Furthermore, if growth hormone concentrations plummet within several hours of receiving whole-body hyperthermia, it is unknown as to whether the transient spike in growth hormone [during WBH] is sufficient to facilitate lasting mood enhancement. While increasing growth hormone may not be a mechanism by which whole-body hyperthermia improves mood in the majority of recipients, it may offer some sort of benefit among those with atypical depression induced by growth hormone deficits.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15362961
- Source: https://www.researchgate.net/publication/51746946
- Source: http://www.ncbi.nlm.nih.gov/pubmed/9278770
- Source: http://www.ncbi.nlm.nih.gov/pubmed/11146901/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/16254130
Benefits of Whole-Body Hyperthermia for Depression (Possibilities)
There may be numerous benefits associated with using whole-body hyperthermia (WBH) as a treatment for depression. Arguably the most notable benefit of whole-body hyperthermia is that it rapidly delivers an antidepressant effect, boosting a person’s mood within 24 hours of a session. In addition to the rapid onset of its action, whole-body hyperthermia appears to facilitate a sustained antidepressant effect, lasting between several days and a full week after a single session. Moreover, it may be advantageous over pharmacological interventions in that it isn’t associated with side effects nor deleterious long-term effects.
- Adjunctive option: Though untested as an antidepressant augmentation strategy, it is possible that whole-body hyperthermia may accelerate and/or potentiate the effect of conventional antidepressant medications (e.g. SSRIs, SNRIs, TCAs, MAOIs, etc.). Furthermore, since whole-body hyperthermia is understood to enhance the release of serotonin in various regions of the brain, it may complement pharmacological interventions, especially among patients who respond partially or insufficiently to a first-line neuromodulator. It may also be a favorable adjunct in that it is unlikely to interact with the pharmacokinetics or pharmacodynamics of neuropsychiatric medications.
- “As-needed” sessions: It seems as though to attain a therapeutic antidepressant effect, whole-body hyperthermia sessions are only needed on an “as-needed” basis. Some studies compared the effect of 2 whole-body hyperthermia sessions per week to just 1 session and discovered that the standalone session was significantly more effective for improving mood. It may be that more than a single session per week is excessive, whereas a single session may induce just enough of a hormetic effect to improve mood. Studies of whole-body hyperthermia documented that its antidepressant effect is sustained between 5 days and 6 weeks post-intervention. It is reasonable to speculate that certain patients may only need whole-body hyperthermia sessions once every week, 2 weeks, 3 weeks, or month.
- Efficacy: Emerging evidence from randomized controlled trials (RCTs) suggests that whole-body hyperthermia is effective for the treatment of major depression. Induction of whole-body hyperthermia appears to significantly reduce depressive symptoms compared to a sham-control intervention. The effect size reported in preliminary findings appears more substantial than many pharmacological medications. It is possible that whole-body hyperthermia may promote a more pronounced antidepressant effect than other antidepressant therapies (by comparison).
- Fast-acting: Among the most promising aspects of whole-body hyperthermia for the treatment of depression is that it’s rapid-acting. After a single 2-hour session of whole-body hyperthermia, mood improvements are typically reported within 24 hours. By comparison, most first-line antidepressant medications take between 4 and 8 weeks to deliver their full effect. (This is because it takes weeks for the 5-HT1A autoreceptors to desensitize [disinhibiting serotonergic neurons for increased serotonin release] and BDNF to increase for induction of hippocampal neurogenesis). Rapid-acting antidepressants are especially helpful among those feeling suicidal and/or who want to die because these individuals often cannot afford to wait “weeks” to feel better.
- Few side effects: Some side effects from whole-body hyperthermia were reported, but for the most part, they were mild. No significant adverse effects have been reported from whole-body hyperthermia when delivered by a professional with the intent of mitigating depression. Unlike conventional antidepressant side effects such as: brain fog, dry mouth, increased depression, sexual dysfunction, and weight gain – side effects associated with whole-body hyperthermia seem favorable. It may also turn out that whole-body hyperthermia is safer over a long-term than antidepressant medications (which are associated with a host of long-term complications).
- Non-pharmacological: Another appealing aspect of whole-body hyperthermia is that’s classified as a non-pharmacological therapy. If effective, you won’t need to worry about popping an antidepressant pill every day to normalize your mood. You also won’t need to worry about potentially missing your antidepressant pill and experiencing acute withdrawal symptoms or dreaded “brain zaps.” Unlike pharmacological therapies, non-pharmacological approaches such as whole-body hyperthermia may be easier to tolerate with fewer side effects and/or unwanted long-term complications.
- Refractory depression: Some sources estimate that around 1 in 3 patients with major depression fail to derive benefit from first-line antidepressants. Among individuals with treatment-resistant depression, medications and/or medication combinations are tested, but symptomatic relief remains inadequate. These individuals may pursue alternative antidepressant therapies such as electroconvulsive therapy (ECT), yet continuously relapse into depressive states. It is necessary to consider that whole-body hyperthermia may deliver therapeutic effects for a subset of patients resistant to all other antidepressant interventions that they’ve tried.
- Sustained antidepressant effect: All studies testing the effect of whole-body hyperthermia discovered that it delivers a sustained antidepressant effect. In a study among cancer patients in which whole-body hyperthermia heated core body temperature to 107.24°F for a duration of 60 minutes, mood was elevated for 72-hours post-intervention. Another study among individuals with major depression documented that ~2.11 hours of whole-body hyperthermia (101.3°F) significantly reduced depressive symptoms for up to 5-days post-intervention. Moreover, a randomized controlled trial documented that whole-body hyperthermia (101.3°F) for 2 to 3 hours significantly alleviated depressive symptoms (among individuals with major depressive disorder) for up to 6-weeks post-intervention.
- Unique mechanism of action: The mechanism by which whole-body hyperthermia improves mood is unique compared to currently-available interventions. It seems as thought heat-sensitive skin receptors detect heat delivered through whole-body hyperthermia and innervate nerves to signal areas of the brain to induce thermoregulatory cooling. The areas of the brain involved in thermoregulatory cooling happen to be similar regions involved in mood regulation. This leads to an upregulation in the release of serotonin, enhanced serotonin metabolism, and binding of serotonin to receptor sites (5-HT1A, 5-HT2, 5-HT7). Thereafter, a thermal stress response is triggered whereby sensitivity of receptor sites is reversed and mood is enhanced.
Drawbacks of Whole-Body Hyperthermia for Depression (Possibilities)
While there may be benefits associated with using whole-body hyperthermia (WBH) for depression, it is necessary to highlight potential drawbacks. Among the most significant of drawbacks is that whole-body hyperthermia is currently unproven as an antidepressant therapy. Sure there’s preliminary evidence from a small randomized controlled trial (RCT) suggesting it’s likely to improve mood, but it hasn’t been subject to rigorous scientific evaluation. Moreover, it is possible that whole-body hyperthermia is: expensive, unsafe for certain patients, cause unwanted side effects, or yield deleterious long-term effects.
- Cost: Since whole-body hyperthermia needs to be conducted in a controlled setting by a medical professional with specialized training, it is likely that treatment could be highly expensive. Not only does a single session usually take multiple hours to properly deliver, but the device [and software] necessary to administer and trap the heat (e.g. Heckel HT-3000) is expensive. Professionals will need to be financially reimbursed for the time of administration and specialized training to operate the device. Clinics will also want compensation for purchasing the latest and greatest whole-body hyperthermia apparatus. In addition to a professional inducing the hyperthermia, recipients of the hyperthermia will necessitate monitoring (such as from other healthcare professionals) during the session to avoid serious adverse events – this monitoring costs additional money. When considering that patients may need up to one session per week, it may be far more expensive than conventional antidepressant therapies. Finally, since it is currently nothing more than an experimental antidepressant intervention, it will not be covered by health insurance. Rough estimates suggest that this type of therapy may cost patients up to $800 per hour.
- Discomfort: While having your body heated up with whole-body hyperthermia may not sound like a bad option compared to conventional antidepressant medications, it is likely to be uncomfortable. In the early minutes of a session, the body heats up and the warmth feels somewhat pleasant – similar to sitting in a hot tub or sauna. However, as core body temperature continues to heat, the person feels more uncomfortable. Rather than feeling calm and relaxed throughout a session, individuals may become irritable, restless, and highly uncomfortable. It is the discomfort that eventually leads to a thermal stress reaction for mood enhancement. It would be a mistake to assume that whole-body hyperthermia is pleasant and/or tolerable for everyone.
- Efficacy unknown: There’s evidence from animal models, as well as uncontrolled studies suggesting that whole-body hyperthermia could enhance mood. However, there’s only one published randomized controlled trial (RCT) to support its antidepressant efficacy for the treatment of major depression. More research is clearly warranted with larger sample sizes, as well as more convincing sham-controls. While the media may extrapolate results from a small RCT to suggest that whole-body hyperthermia is definitively effective for those who are depressed, others know that more research is necessary before efficacy can be supported. Since the efficacy remains unknown, those using the therapy for depression may find that it has no favorable effect on mood.
- Frequency of sessions: Not only could the costs quickly add up if you needed to fork over an excess of $800 weekly, bi-weekly, or even monthly for whole-body hyperthermia sessions – but some patients may dislike the idea of experiencing hyperthermia on a frequent basis just to improve their mood. In an ideal scenario, whole-body hyperthermia would only be necessary on a monthly basis (or even less frequent) to alleviate depression. In a less ideal scenario, individuals may require one session per week for the antidepressant effect. Patients may dislike the fact that they need to invest time and money, while simultaneously experiencing discomfort (from the heat) just to lift mood.
- Ineffective adjunct: Though it may turn out that whole-body hyperthermia is a useful therapy when combined with current-market antidepressant medications, preliminary evidence suggests that it may be ineffective as an adjunct. A small-scale study tested the effect of whole-body hyperthermia on 3 individuals that were taking an SSRI and found that it provided zero antidepressant effect. Since whole-body hyperthermia is thought to facilitate mood improvement through serotonergic mechanisms, perhaps combining it with a serotonergic antidepressant offers no extra benefit.
- Long-term effects: The long-term effects of frequent whole-body hyperthermia remain unknown. Although the technique doesn’t involve swallowing an exogenous chemical such as in the form of an antidepressant pill, we cannot automatically assume that it’s devoid of causing potentially deleterious long-term effects. For example, it is possible that the technique may expedite brain aging, impair cognitive function, provoke neuroinflammation, or even kill brain cells. Recipients of whole-body hyperthermia over a long-term would need to be monitored before we know whether its long-term effects are safe.
- Less effective: Although the size of effect reported from the first randomized controlled trial of whole-body hyperthermia was large, this was a small-scale study. It is possible that further studies reveal that whole-body hyperthermia is less effective than initially hypothesized. It may also be that while whole-body hyperthermia can significantly reduce depressive symptoms, it turns out to be less effective than current first-line antidepressant medications and/or therapies. Until comparative studies are conducted we won’t know how its efficacy compares to other options.
- Safety: Not everyone experiencing major depressive disorder may be able to safely partake in whole-body hyperthermia to alleviate their unwanted symptoms. Individuals with a history of certain medical conditions such as brain injuries may be at risk for serious adverse reactions as a result of hyperthermia induction. Studies have shown that hyperthermia following a brain injury such as transient ischemic attack is associated with worse outcomes than hypothermia. It is also possible that hyperthermia is unsafe among a subset of the healthy populations devoid of medical comorbidities.
- Side effects: Lying in a heat chamber doesn’t sound so bad compared to taking an antidepressant medication, however, it may be associated with more side effects than you expected. Not only can administration of heat induce burns on the skin, it could inflict damage upon tissues and/or injure certain organs (e.g. lungs, heart, brain). Some reports suggest that whole-body hyperthermia may cause bleeding, blood clots, and swelling. In rare cases, whole-body hyperthermia could trigger systemic shock or even cardiovascular toxicity. Other side effects may include fatigue and drowsiness.
- Symptomatic exacerbation: Most research indicates that whole-body hyperthermia either enhances mood to alleviate depression or that it has no effect. However, it is known that the skin-to-brain signaling induced by increasing core body temperature leads to modulation of neurochemicals such as serotonin and hormones such as cortisol. It is possible that for a subset of individuals with depression, the WBH-induced modulation of serotonergic transmission ends up exacerbating depressive symptoms. For this reason, anyone receiving the technique should be cognizant that their mood could (unfortunately) worsen.
- Tolerance: It is possible that the antidepressant effects of whole-body hyperthermia diminish as a result of regularly therapy. It is possible that the body could adapt itself to expect whole-body hyperthermia and develop some sort of tolerance to its effect. In other words, while whole-body hyperthermia may be effective as a single session once every few months, if administered once per week for several months, the therapeutic antidepressant effect may decline. Although tolerance is highly unlikely to develop from WBH, if it did develop, perhaps a person could experience a worsening of depression and/or withdrawal symptoms if they discontinued receiving the hyperthermia therapy.
Whole Body Hyperthermia for Depression (Review of Evidence)
Included below are studies investigating the effect of whole-body hyperthermia on mood. Keep in mind that the research of whole-body hyperthermia as an intervention for depression is relatively new. For this reason, there aren’t many well-designed randomized controlled trials (RCTs) with optimal methods and large samples. Nevertheless, it is interesting to reflect upon the literature, as well as other evidence documenting associations between brain temperature, core body temperature, thermoregulatory circuits, and mood.
2016: Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder: A Randomized Clinical Trial.
It is understood that current antidepressant therapies are limited in that they are not effective for all patients and are often associated with unwanted side effects. In effort to discover novel interventions for major depressive disorder, researchers Janssen et al. stumbled upon the concept of whole-body hyperthermia. Preliminary evidence from an open-label study suggested that just one session of whole-body hyperthermia could significantly alleviate depression.
Other evidence suggested that induction of hyperthermia could affect mood. To further investigate the efficacy of hyperthermia for depression, Janssen et al. (2016) conducted a trial of their own. Unlike prior trials, researchers implemented a randomized, sham-controlled, double-blind study – and recruited adult participants (age 18 to 65) diagnosed with major depression.
It was noted that all participants included in the study were considered healthy (with no medical issues other than depression) and none used psychiatric medications (e.g. antidepressants). For the study, participants were assigned at random to receive either: whole-body hyperthermia (heating core body temperature to 101.3°F) or a sham-control (heating core body temperature to 99.86°F). The sham-control was identical to the whole-body hyperthermia in all aspects other than temperature – it delivered less heat by comparison.
To gauge the efficacy of whole-body hyperthermia for depression, researchers compared mood changes from pre-treatment (baseline) through a 6-week post-treatment period using the Hamilton Depression Rating Scale (17-item). Results indicated that whole-body hyperthermia significantly reduced depressive symptoms compared to the sham-control. What’s more, those that received whole-body hyperthermia experienced a sustained mood improvement for the full 6-week post-intervention period when compared to the control group.
Researchers concluded that whole-body hyperthermia appears promising as a safe, rapid-acting antidepressant with sustained therapeutic effect. Critics have been quick to attack this study based on its potentially unconvincing sham-control, small sample size (30 participants), lack of secondary measures, and erroneous effect size. Documentation indicated that 10 of 14 sham-control recipients (71.4%) believed they had received the real treatment – meaning 4 were unconvinced that they received a legitimate intervention.
By comparison, in the active group 15 of 16 participants (93.8%) were convinced that they received the real treatment. Nevertheless, even after researchers accounted for differences in expectancy scores (as to whether the intervention was perceived as legitimate), outcomes remained significant. While not much can be done to make the sham intervention more convincing, researchers already addressed the fact that there was an initial editorial error resulting in the intriguingly large effect size.
Furthermore, secondary measures (e.g. self-reported depressive symptoms, function and quality of life) were recommended to be excluded during the revision process – hence the reason they were not included in the results. Despite an exclusion of secondary measures, self-reported depressive symptoms were significantly reduced at 1-week post-treatment among those receiving the whole-body hyperthermia compared to the sham-control. Function and quality of life (QOL) had significantly improved for up to 2 weeks post-treatment among the recipients of whole-body hyperthermia versus the controls.
However, unlike the sustained changes in depression scores (as measured by the Hamilton Depression Rating Scale), improvements on secondary measures were not sustained for 6 weeks. Authors also admit that they didn’t expect a single whole-body hyperthermia session to enhance mood for a prolonged duration. Though this trial cannot confirm the efficacy of whole-body hyperthermia for major depression, results were favorable.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/27172277
2013: Whole-body hyperthermia for the treatment of major depression: associations with thermoregulatory cooling.
A trial by Hanusch et al. (2013) documented the therapeutic potential of whole-body hyperthermia for major depression. It should be noted that authors of this trial (Hanusch, Janssen, etc.) were involved in the randomized controlled trial discussed above (published in 2016). That said, in this report, researchers discuss the mechanisms by which hyperthermia or heat induction may enhance mood.
Among those with depression, a multitude of physiological abnormalities have been identified, including: deficits in spinoparabrachial thermal afferent pathway signaling, poor thermoregulatory cooling, elevations in core body temperature, and reduced peripheral serotonergic activity. It is hypothesized that impairments in skin-to-brain and brain-to-skin signaling may be to blame for some of the aforestated physiological abnormalities associated implicated in depression. That said, it appears as though these abnormalities could be improved, at least transiently, with whole-body hyperthermia.
Induction of whole-body hyperthermia is understood to stimulate the temperature-sensitive spinoparabrachial thermal afferent pathway (through the skin), to prompt a thermoregulatory cooling effect (mediated by the brain). It just so happens that the same areas of the brain responsible for generating this thermoregulatory cooling effect may play a role in regulating mood. As whole-body hyperthermia takes effect, spinoparabrachial thermal afferent pathway signaling to serotonergic nuclei in the midbrain is altered, which facilitates a thermoregulatory cooling response and simultaneous antidepressant effects.
Knowing that whole-body hyperthermia could be a useful antidepressant, researchers opted to conduct a trial to test its effect upon 16 healthy adults diagnosed with major depression – each of whom were inpatients at private alternative treatment hospitals. Whole-body mild-hyperthermia was induced for an average of 126.7 minutes (~2.11 hours) with a device referred to as the “Heckel 2000.” This particular device is manufactured in Germany and utilizes water-cooled infrared lamps to administer heat.
To determine the effect of mild-hyperthermia (induced by the Heckel 2000) on depressive symptoms, researchers documented mood changes from pre-treatment (baseline) to post-treatment using the Centers for Epidemiological Studies Depression Scale (CES-D). Results indicated that CES-D scores significantly decreased as a result of a single whole-body mild-hyperthermia session. Specifically, CES-D scores dropped from ~29.9 (baseline) to ~19.2 (five days after treatment).
It was reported that 13 of the 16 participants received no psychotherapeutic nor pharmacological therapies during the trial. However, 3 participants were receiving an SSRI without dosing changes throughout the trial. Of interest to researchers was the fact that whole-body hyperthermia appeared ineffective as an antidepressant among the 3 SSRI users compared to the other participants.
In addition to tracking mood changes, researchers also measured core body temperature changes in 12 participants [using a temperature sensor]. Core body temperatures of these 12 participants were compared pre-treatment to 5-days post-treatment. Data revealed that core body temperature significantly decreased as a result of whole-body hyperthermia, changing from approximately 99.14°F (pre-treatment) to 98.6°F (5-days post-treatment).
The change in core body temperature is evidence to suggest that the antidepressant effect of whole-body hyperthermia may result from thermoregulatory cooling. Hanusch et al. (2013) mentioned that reduction in depressive symptoms was directly correlated with reduction in core body temperature. Another correlation discovered was that, the greater a person’s core body temperature prior to the whole-body hyperthermia, the more pronounced his/her mood improvement.
Authors concluded that whole-body hyperthermia appears to act as a rapid antidepressant with an extended therapeutic effect. They speculate that its antidepressant efficacy results from sensitization of physiological pathways involved in thermoregulatory cooling. This trial provided preliminary evidence that whole-body hyperthermia may serve as a novel treatment for major depressive disorder. That said, since this was not a randomized controlled trial (RCT), it’s difficult to know whether mood improvements were attributable due to whole-body hyperthermia.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23820835
2013: Whole body hyperthermia in pain therapy. A controlled trial on patients with fibromyalgia.
A study conducted by Walz et al. (2013) analyzed the effect of whole body hyperthermia (WBH) among individuals with fibromyalgia. They specifically sought to test whether mild water-filtered near-infrared whole-body hyperthermia could improve pain as an adjunct to conventional rehabilitation modalities. A total of 67 patients were recruited to participate and assigned to receive either: WBH (once per week), WBH (twice per week), or standalone conventional rehabilitation.
The primary measure of efficacy was changes in pain intensity from baseline to 6 months post-treatment. Results indicated that individuals receiving WBH once per week experienced significant reductions in pain compared to those receiving WBH twice per week and the controls. What’s more, once-per-week WBH appeared to reduce depression and improve quality of life.
This suggests that whole-body hyperthermia may be effective for mitigating pain and enhancing mood among those with fibromyalgia. It remains unclear as to why WBH once-per-week was more effective than twice-per-week, perhaps just a single session per week triggers a hormetic response whereas multiple sessions per week is physiologically taxing. Although mood wasn’t the primary outcome measure of this study, it was documented as a secondary measure and was said to improve among recipients of once-weekly WBH.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23354314
2008: Brain temperature may influence mood: a hypothesis.
Salerian, Saleri, and Salerian (2008) proposed a hypothesis that brain temperature may have a direct influence upon mood. In their publication, it was noted that reductions in body and brain temperature often facilitate therapeutic benefit among individuals with medical conditions such as: multiple sclerosis (MS), myocardial infarction, traumatic brain injury (TBI). Researchers reference the importance of understanding Svante Arrhenius’ rate law (1889) in that it dictates internal thermoregulatory and biochemical processes implicated in mood.
Thereafter, they reviewed literature of studies that established relationships between temperature (core body and brain temperature), mood disorders, and treatments. It was discovered that most interventions to combat mania (elevated mood) involved reducing temperature, whereas interventions to alleviate depression involved increasing temperature. Based on their findings, Salerian, Saleri, and Salerian believe that brain temperature is suboptimally high in manic states and low in depressive states.
Researchers suspect that, since temperature has a significant impact on biological processes (in accordance with Svante Arrhenius’ rate law), deliberate modulation of brain temperature could effectively treat mood disorders. Modulation of brain and/or core body temperature may be a novel non-pharmacological intervention for both major depression and mania. Specifically, depression may respond best to heat induction whereas mania respond best to cold induction.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/17951014
2003: Chronic treatment with antidepressants decreases intraoperative core hypothermia.
Research by Kudoh, Takase, and Takazawa (2003) assessed temperature regulation during anesthesia and postoperative shivering among 70 patients subject to orthopedic surgery. Of these 70 patients, 35 patients were diagnosed with major depression and received antidepressant medication, whereas the remaining 35 patients were considered healthy controls. Researchers measured temperature of each patient via the tympanic membrane (a region separating the ear canal from middle ear).
Among those diagnosed with major depression, temperatures of the tympanic membrane were significantly greater than the healthy controls. While there were no differences in skin temperature between the depressed and healthy controls, more individuals with depression exhibited shivering after anesthesia administration. Researchers concluded that induction of hypothermia among individuals with depression was reduced compared to healthy controls.
This finding may have been due to the fact that persons with major depression exhibit higher core body temperatures than non-depressed individuals, making them less susceptible to anesthesia-induced hypothermia. It was also mentioned that depressed individuals appear more susceptible to shivering as a result of anesthesia compared to others. Researchers suggest that among those with depression, thermoregulatory function deviates from the norm.
In this study, individuals taking clomipramine, exhibited greater temperatures than patients taking maprotiline. Based on this finding, it can be inferred that antidepressants alter body temperature, and that the extent of these alterations is contingent upon the specific antidepressant administered. Moreover, this research supports the idea that depression is associated with temperature and/or thermoregulatory abnormalities.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12818981
1992: Changes in mood state following whole-body hyperthermia.
A study by Koltyn et al. (1992) published in the International Journal of Hyperthermia documented changes in mood resulting from whole-body hyperthermia. A total of 7 patients (4 males, 3 females) diagnosed with cancer participated in the study. All participants received a session of whole-body hyperthermia in which core body temperature was heated to 107.24°F for a duration of 60 minutes.
To determine the effect of whole-body hyperthermia on mood of the patients, researchers administered the Profile of Mood States (POMS) questionnaire – before and after treatment. Based on change in POMS scores from pre- to post-treatment, it appeared as though mood of the participants significantly improved. Within 24 hours of treatment depression significantly decreased and feelings of well-being increased.
What’s more, the mood elevation appeared to last for approximately 72 hours post-intervention. In addition to documenting mood changes, researchers measured changes in plasma beta-endorphin levels. They discovered that following the whole-body hyperthermia session, plasma beta-endorphin concentrations markedly increased. Despite mood improvements resulting from whole-body hyperthermia, significant increases in fatigue were reported.
It is possible that the fatigue induced by the whole-body hyperthermia may be related to enhanced release of serotonin and/or other neurochemical modulation. Interestingly, the fatigue antidepressant effect and fatigue diminished simultaneously – within 72 hours. This study suggests that whole-body hyperthermia may be useful for improving mood, however, it is limited by it’s non-RCT design, small sample, and highly specific sample of cancer patients.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/1607735
1985: Effects of raised body temperature on reasoning, memory, and mood.
A study by Holland et al. (1985) assessed the effect of elevated body temperature on reasoning, memory, and mood. Participants in the study were assigned at random to receive either warm water immersion at a temperature of 105.8°F OR a control water immersion at 98.6°F. Core body temperatures of those receiving the warm water immersion reached between 101.84°F and 102.29°F within just minutes of the immersion.
Conversely, participants that received the control water immersion maintained core body temperatures between 97.88°F and 99.32°F. An hour prior to the water immersion, participants were administered several tests including: memory, verbal logic problems, and mood. After the change in core body temperature (with water immersion), tests were readministered and scores were compared to pre-treatment baseline.
Results indicated that neither memory (registration and recall) nor cognitive performance was affected by elevations in core body temperature. Interestingly, increased core body temperature was associated with significantly faster performance on the tests. Moreover, elevations in core body temperature reduced alertness and provoked irritability, suggesting that it may have had a deleterious effect upon mood.
Despite the fact that participants exposed to heat experienced greater irritability, it was unclear as to whether this irritability was sustained for a prolonged period after the heat exposure. Furthermore, this irritability may have preceded a thermal stress response in which cortisol was released. It is possible that if mood of participants would’ve been monitored 24 hours after the core body temperature elevation, that their mood may have been increased.
There may be some delay between the thermal stress response and the mood enhancement. It is important to note that participants in this study were considered to be healthy adults as opposed to those diagnosed with major depressive disorder. Perhaps healthy adults do not need the skin-to-brain induced neuromodulation (of serotonin) and for this reason, it may not affect their mood.
It is possible that perhaps the elevation in core body temperature was not maintained for long enough to trigger a thermal stress response to improve mood. Finally, since the temperature of the experimental group was set at 105.8°F, this may have been overly hot. This study doesn’t help us understand as to whether WBH could improve mood, but it does suggest that in the process of heating, people may experience irritability.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/4077790
Limitations of research associated with WBH for Depression
The research of whole-body hyperthermia as a treatment for depression is riddled with limitations. As of 2016, there appears to be just one single small-scale randomized controlled trial (RCT) testing whole-body hyperthermia as a treatment for depression. Not only is research limited in that there are few randomized-controlled trials, but the optimal parameters of whole-body hyperthermia specifically to treat depression remain unclear. Moreover, safety of the technique, as well as its comparative efficacy to other therapeutic interventions is warranted.
- Adjunct efficacy: The effectiveness of whole-body hyperthermia as an adjunct to first-line antidepressants hasn’t been thoroughly investigated. It may turn out that WBH is a highly-effective adjunct in that it accelerates and/or potentiates conventional antidepressant medications. Oppositely, it may also turn out that WBH offers zero benefit as an adjunct. Since there’s preclinical evidence suggesting that WBH as a standalone could significantly improve mood among those with major depression, perhaps it would be worth investigating as an adjunct therapy (especially among partial responders to medication). No studies have analyzed its efficacy as an antidepressant adjunct.
- Comparative efficacy: None of the literature has compared the antidepressant efficacy of whole-body hyperthermia to that of other interventions. Though the large effect size in currently-published trials may lead some to believe that WBH is more effective than antidepressant medications, superior efficacy cannot be confirmed. For this reason, future research should aim to directly compare the efficacy of whole-body hyperthermia with that of antidepressant drugs. If whole-body hyperthermia consistently yields a significantly larger effect size than medications, it may be the superior antidepressant option.
- Depressive subtypes: Despite common overarching symptoms of major depression such as extreme sadness, weight changes, fatigue, and sleep disturbances – not all individuals with depression exhibit similar neurochemical and physiological signatures. One individual with depression may hypersecrete cortisol and have low serotonin signaling, whereas another may struggle more as a result of low dopamine. Since whole-body hyperthermia is hypothesized to target the serotonin system, perhaps it may only benefit individuals with neurochemical signatures of depression in which serotonin abnormalities are implicated. Assuming the technique continues to show efficacy, it may be worth distinguishing the depressive subtypes are likely to benefit more from WBH than others.
- Designs: A majority of studies documenting the effect of WBH on mood lack robust designs in that they are not randomized, sham-controlled, or double-blinded. To accurately know whether WBH could be a promising intervention for the management of major depression, further research needs to incorporate randomized controlled designs. As of current, there are just 2 published controlled trials documenting the effect of WBH on mood. Of those 2 controlled trials, only 1 study specifically recruited individuals with major depression and used mood as the primary outcome measure. It would also be helpful to conduct research over a longer-term (e.g. several months) to understand the average duration of antidepressant effect resulting from WBH.
- Methods: Critics have argued that the research of WBH for depression is limited as a result of the methods. In particular, critics suggest that the sham-control used in randomized-controlled trials is too unconvincing for participants, and as a result, needs to be improved before efficacy of the technique can be established. Some also have a problem with the fact that, in nearly all studies, just a single session of WBH was administered for the management of depressive symptoms. This makes it difficult to know whether multiple sessions of WBH per week would be more or less therapeutically effective. Additionally, not all studies testing the effect of WBH on mood were conducted among those with major depression – some were conducted with cancer patients.
- Safety: Many are unsure as to whether whole-body hyperthermia is definitively safe, especially if administered regularly over a long-term. More data should be compiled regarding the potential risks of whole-body hyperthermia. It appears as though hyperthermia could aggravate preexisting brain injuries, trigger cardiac events, and/or damage neurons. Researchers should attempt to elucidate the optimal parameters (frequency of sessions, length of sessions, temperature setting) without compromising safety of patients. Furthermore, risks of using hyperthermia with comorbid medical conditions warrant investigation.
- Samples: The largest sample size of a randomized trial specifically investigating whole-body hyperthermia (WBH) for the treatment of major depression was 30 participants. Another controlled trial tested WBH for the treatment of fibromyalgia among 67 participants and found that it improved mood of the participants when conducted once per week, however, mood was not the primary outcome measure. To determine whether WBH is legitimately effective for the treatment of depression, it is necessary to conduct research with larger sample sizes solely consisting of individuals that meet diagnostic criteria for major depressive disorder. It may also be helpful to know if the efficacy of WBH varies based on the severity of depression (mild, moderate, severe) and/or whether treatment-naïve patients respond better to WBH compared to recent or current users of antidepressant medication.
- Unclear parameters: There is convincing evidence to suggest that heating core body temperature to 101.3°F with a Heckel HT-3000 apparatus for a duration of ~2 hours is sufficient for treating symptoms of depression. That said, it isn’t known as to whether the WBH parameters including: temperature (101.3°F), the heating method (Heckel HT-3000 device), or duration (~2 hours) are optimal for the treatment of depression and/or safety of the patient. Further research is warranted to determine whether temperatures above 101.3°F, alternative heating modalities, and/or adjusted durations (other than ~2 hours) could prove more effective and/or safer than the current set of effective parameters. Researchers may also want to determine the average frequency of WBH sessions (e.g. weekly, bi-weekly, etc.) for the most prominent therapeutic effects.
Verdict: Whole-body hyperthermia may be useful for depression
Based on the body of scientific literature investigating the effect of whole-body hyperthermia on mood, it appears as though it may be an effective intervention for the treatment of depression. While evidence to support its efficacy is limited, there’s zero evidence to suggest that it may be ineffective and/or that it could exacerbate symptomatic severity of depression. It appears as though when administered by a professional, whole-body hyperthermia is able to facilitate safe, rapid, and sustained antidepressant effects.
The randomized controlled trial (RCT) by Janssen et al. (2016) documented antidepressant effects lasting up to 6 weeks from a single session of mild, whole-body hyperthermia (~2-3 hours at 101.3°F induced by a Heckel apparatus). Research by Hanusch et al. (2013) suggested that one session of whole-body hyperthermia (at 101.3°F induced by a Heckel apparatus for ~2.11 hours) was able to significantly improve the mood of 13 individuals with major depression. Further evidence from a controlled trial by Walz et al. (2013) documents significant benefit from once weekly, water-filtered, near-infrared, mild whole-body hyperthermia among those with fibromyalgia.
Not only was the whole-body hyperthermia able to reduce symptoms of pain, but it also improved mood of the patients. An earlier study by Koltyn et al. (1992) noted that whole-body hyperthermia (at a temperature of 107.24°F for 60 minutes) enhanced mood and quality of life among cancer patients. Reflecting upon the available evidence, it becomes obvious that whole-body hyperthermia may facilitate therapeutic effects.
Moreover, the hypothesized mechanism by which whole-body hyperthermia is thought to enhance mood involves modulation of serotonergic activity. Skin receptors detect heat, signal to the brain to activate thermoregulatory cooling, which in turn releases serotonin. Thereafter a thermal stress reaction is triggered, antidepressant effects emerge within 24 hours of WBH, and are sustained for between 72 hours (3 days) and 6 weeks of a single session.
Using Whole-Body Hyperthermia for Depression (Parameters)
It is difficult to determine the optimal parameters of whole-body hyperthermia (delivery, temperature, duration, frequency) most suitable for treating depression without risk of serious adverse reactions. Emerging trends in the research indicate that milder temperatures of WBH for a duration between 2 and 3 hours may be safe and effective. Other research suggests that higher temperatures for a shorter duration (e.g. 1 hour) may be safe and effective. Most research notes that a single session can improve mood for between 3 days and 6 weeks post-therapy.
- Temperature: 101.3°F to 107.24°F
- Duration: 1 to 3 hours
- Modality: Heckel apparatus, water-filtered near-infrared heater
- Frequency: 1 session per week (at most)
Who may benefit most from whole-body hyperthermia for depression?
It isn’t known as to who is most likely to benefit from whole-body hyperthermia for depression. At this juncture, it cannot be confirmed that WBH definitively facilitates an antidepressant effect. Assuming it is an effective antidepressant therapy, whole-body hyperthermia may only be efficacious in a subset of depressed individuals. Some biomarkers of individuals that may be most likely to derive benefit from whole-body hyperthermia include: high core body temperature, thermoregulatory dysfunction, serotonergic abnormalities, cortisol irregularities, and HPA-axis dysfunction.
- High core body temperature: Research has shown that individuals with depression exhibit core body temperatures between 0.2°C and 0.4°C greater than healthy non-depressed individuals. This may be due to dysfunction in circuitry implicated in skin-to-brain communication and/or related to abnormalities in serotonergic transmission necessary to facilitate a thermoregulatory cooling effect. Regardless of the definitive reasons as to why individuals with depression have higher core body temperatures, evidence from a study by Hanusch et al. (2013) indicates that the greater a person’s core body temperature prior to whole-body hyperthermia therapy – the more substantial the antidepressant effect is likely to be. It is possible that individuals with lower core body temperatures at baseline may not attain as much benefit from whole-body hyperthermia.
- Serotonergic abnormalities: A longstanding hypothesis is that depression is caused by dysfunction in the neurotransmission of serotonin. Specifically, it is suspected that there’s insufficient serotonin in the synaptic cleft to stimulate postsynaptic receptors. The suboptimal concentrations of intrasynaptic serotonin lead the postsynaptic receptors to develop sensitivities. Whole-body hyperthermia is thought to increase concentrations of intrasynaptic serotonin to stimulate postsynaptic receptors. By the end of a whole-body hyperthermia session, it is theorized that serotonin will have corrected imbalanced sensitivities of the postsynaptic receptors to alleviate depression. That said, not everyone with major depression exhibits abnormalities in serotonergic neurotransmission. For this reason, it could be postulated that whole-body hyperthermia would be of most benefit to individuals with depression in which serotonergic dysfunction is implicated.
- Thermoregulatory dysfunction: It is suspected that among many individuals with major depression, thermoregulatory cooling responses are compromised. Thermoregulatory dysfunction leads individuals to exhibit abnormally high body temperatures throughout the day (an average of 0.2°C to 0.4°C higher than non-depressed individuals). Whole-body hyperthermia is capable of reversing thermoregulatory dysfunction by sensitizing and/or reviving suboptimally functional skin-to-brain thermoregulatory circuitry. Since not everyone with depression may exhibit thermoregulatory abnormalities, only those with underlying thermoregulatory dysfunction may benefit from whole-body hyperthermia.
- Cortisol irregularities: Individuals with major depression often exhibit irregularities in secretion, reactivity, and concentrations of circulating cortisol. Depression can be associated with lack of cortisol production, but is typically associated with excessive cortisol production. Research shows that most individuals with major depression have high basal cortisol concentrations, decreased cortisol responses to stress, and elevations in waking cortisol levels. It is suspected that cortisol irregularities are a byproduct of HPA-axis dysfunction. Nevertheless, whole-body hyperthermia is hypothesized to correct cortisol irregularities to normalize the HPA axis and improve mood. For this reason, anyone with depression in which cortisol abnormalities are implicated may benefit more from WBH than those with seemingly normative cortisol function.
- HPA-axis dysfunction: Heightened activation within the HPA-axis is associated with depression, as well as suicidal ideation. In states of depression, it is hyperactivity of the HPA-axis that maintains elevations in cortisol and CRH (corticotropin-releasing hormone), impaired ACTH (adrenocorticotropic hormone) responses to CRH, as well as decreased hippocampal volume. Whole-body hyperthermia is thought to normalize receptor sensitivity to serotonin and cortisol, thereby ameliorating HPA-axis dysfunction. Amelioration of HPA-axis dysfunction (via modulation of serotonin and cortisol) restores stress tolerance and enhances mood. Based on this hypothesized mechanism, we can suspect that persons presenting HPA-axis hyperactivity would stand to benefit more from whole-body hyperthermia than those with seemingly normative HPA-axis activity.
- Unipolar depression: Preliminary evidence indicates that whole-body hyperthermia is likely to benefit healthy adults diagnosed with unipolar major depression. It remains unclear as to whether whole-body hyperthermia would serve as a useful intervention among individuals with bipolar depression or major depression with neuropsychiatric comorbidities (e.g. anxiety disorder). Until evidence suggests otherwise, it should be assumed that healthy adults with standalone diagnoses of unipolar depression are likely to derive most benefit from whole-body hyperthermia. It is possible that the technique may aggravate neuropsychiatric comorbidities and/or be contraindicated among adults with certain health conditions.
- Treatment-naïve patients: It isn’t known as to whether the antidepressant efficacy of whole-body hyperthermia is affected by recent and/or ongoing treatment with antidepressant medications. Some evidence indicates that among SSRI users, whole-body hyperthermia is ineffective. Perhaps serotonergic medications induce analogous therapeutic changes in neural activity to WBH, leaving no additional benefit to be attained from WBH. However, it is also possible that serotonergic antidepressants somehow interfere with or impair the therapeutic action of WBH. It could be suspected that treatment with non-serotonergic antidepressants (e.g. bupropion) may be less likely to interfere with whole-body hyperthermia. That said, it appears as though whole-body hyperthermia may be most effective for treatment-naïve patients and/or those who haven’t recently used an antidepressant.
Have you tried Whole-Body Hyperthermia (WBH)?
If you’ve had the chance to try whole-body hyperthermia, share your experience in the comments section below. To help others get a better understanding of your experience, provide additional details such as: why you received whole-body hyperthermia (e.g. clinical trial, medical treatment, etc.), modality of hyperthermia induction (e.g. Heckel device) session parameters (temperature and duration), as well as the frequency of your sessions. After the hyperthermia therapy, did you notice any positive changes in mood or an antidepressant effect?
In the event that your mood improved after hyperthermia therapy, how long did the mood enhancement last before you reverted back to your baseline mood? Be sure to mention any other therapeutic effects of whole-body hyperthermia that you experienced such as: pain reduction, relaxation, energy increases, etc. Also document any unfavorable side effects that you incurred as a result of the therapy such as: burning, drowsiness, or irritability.
For individuals that haven’t had the opportunity to try whole-body hyperthermia, would you volunteer to test it for managing depression? (Explain why or why not). Although a “fever” is caused by infection [involving pyrogenic molecules] and is not the same as whole-body hyperthermia, have you ever noticed a reduction in depressive symptoms while experiencing a fever? Overall, it is clear that induction of whole-body hyperthermia radically alters neurochemical and physiological processes.
Whether the neurochemical and physiological alterations deliver a significant antidepressant effect is currently unknown. Further evaluation in randomized controlled trials should reveal whether deliberate manipulation of core body temperature delivers a robust antidepressant effect. Should whole-body hyperthermia prove effective for the management of depression, it may serve as a viable, non-pharmacological alternative to the often intolerable lineup of antidepressant medications.