tag:theconversation.com,2011:/id/topics/anti-depressants-26521/articlesAnti-depressants – The Conversation2022-10-26T14:08:29Ztag:theconversation.com,2011:article/1931352022-10-26T14:08:29Z2022-10-26T14:08:29ZHow does ketamine help fight depressive beliefs?<figure><img src="https://images.theconversation.com/files/491306/original/file-20221024-5750-jrh41.jpg?ixlib=rb-1.1.0&rect=0%2C35%2C4728%2C3085&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A depressive episode traps the patient in a negative view of the world around them.</span> <span class="attribution"><span class="source">KieferPix/Shutterstock</span></span></figcaption></figure><p>Which factors determine what we believe about our world, ourselves, our past, and our future? Cognitive neuroscience suggests that our beliefs are dependent on brain activity, specifically on the way our brains process <a href="https://theconversation.com/lesprit-est-il-une-machine-predictive-introduction-a-la-theorie-du-cerveau-bayesien-173707">sensory information in order to make sense of our environment</a>.</p>
<p>These beliefs (defined as <em>probability estimates</em>) are central to our brain’s <a href="https://pubmed.ncbi.nlm.nih.gov/30483088/">predictive processing</a> function, which enables it to predict the probabilistic structure of the world around us. These predictions could even be the fundamental building blocks of <a href="https://pubmed.ncbi.nlm.nih.gov/36056173/">mental states</a>, such as perceptions and emotions.</p>
<p>Many psychiatric disorders, such as depression and schizophrenia, are characterised by irregular beliefs <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969668/">whose origins we still don’t fully understand</a>. But if we can identify the cerebral systems governing them, we could target those very areas in a bid to alleviate the pain associated to these illnesses.</p>
<h2>Decoding belief mechanisms in psychiatry</h2>
<p>This is one of the findings of our study recently published in the journal <a href="https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2796906"><em>JAMA Psychiatry</em></a>. For this study, I explored with my team how the dissociative psychotropic, ketamine, affects mechanisms of <a href="https://plato.stanford.edu/entries/logic-belief-revision/">belief updating</a> (i.e., how we change our beliefs upon receiving information) in patients with treatment-resistant depression.</p>
<p>While traditional antidepressants take weeks to show any results, ketamine – an antagonist molecule that acts on the NMDA (N-methyl-D-aspartate) receptors – produces <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416968/">antidepressant effects</a> within hours. When administered, it also causes a <a href="https://pubmed.ncbi.nlm.nih.gov/24679390/">dissociative experience of depersonalisation</a> typically associated with a sensation of leaving the body (known as “autoscopy”).</p>
<p>Given that ketamine’s rapid action and unexpected dissociative effects make it a potentially worthwhile option for treating mental health problems, we are on a mission to unpack this mystery, at the crossroads between pharmacology and neuroscience.</p>
<h2>Cognitive-affective biases in depression</h2>
<p>According to the <a href="https://www.who.int/news-room/fact-sheets/detail/depression">World Health Organization</a>, depression affects approximately 280 million people in the world and 700 000 people die due to <a href="https://pubmed.ncbi.nlm.nih.gov/34753436/">suicide</a> every year. One of the most specific symptoms of depression is <a href="https://pubmed.ncbi.nlm.nih.gov/34916079/">depressive beliefs</a> (e.g., pessimism, self-deprecation, rejection, and feelings of failure), described as “mood-congruent” beliefs when their content matches the subject’s affective state.</p>
<p>By influencing the patient’s perception and action, these beliefs play a vital role in triggering the phenomenon of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241292/">negative auto-reinforcement</a>. For example, the belief that we have been rejected by our peers gradually makes us more withdrawn, which in turn reinforces feelings of worthlessness. Once this feedback loop has been closed, it can be difficult not to spiral downward.</p>
<p>Ever since the pioneering research of psychiatrist <a href="https://www.nytimes.com/2021/11/01/health/dr-aaron-t-beck-dead.html">Aaron Beck</a>, many studies have suggested that the ways in which information is encoded in belief networks according to their valence (i.e., their positive or negative nature) could be linked to the <a href="https://www.sciencedirect.com/science/article/abs/pii/S0005796719301950">emergence of depressive beliefs</a>.</p>
<p>This innovative research has shown that our brains are <a href="https://www.sciencedirect.com/science/article/pii/S0960982211011912">likelier to encode positive information</a>. Known as “affective bias”, this phenomenon is responsible for generating beliefs that are <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467896/">slightly more positive than reality</a>. For instance, we tend to think we are more intelligent, more attractive, better drivers or better lovers than what is shown in statistical reality.</p>
<p>However, with depression, this <a href="https://pubmed.ncbi.nlm.nih.gov/23672737/">bias disappears or flips</a>, with patients taking in more negative-valence information that gradually generates gloomier beliefs about the world, themselves, or the future. This phenomenon of an inverted affective bias could well be key to understanding the origins of depressive beliefs.</p>
<h2>How ketamine acts on belief systems</h2>
<p>We launched our study on the back of a surprising clinical observation made at our unit at Paris’s Hôpital de la Pitié-Salpêtrière. When given ketamine as an antidepressant, patients with treatment-resistant depression reported feeling a strange sensation whereby their perspectives on the world seemed to have shifted, almost <a href="https://www.sciencedirect.com/science/article/abs/pii/S0013700621002244">as though their very point of view had been altered</a>.</p>
<p>The negative beliefs that they had been carrying for several months appeared to have faded. Some patients even expressed a feeling of foreignness, as if their thoughts belonged to someone else. Even more intriguingly, these changes appeared to result from the drug’s antidepressant effect, although we still don’t understand the causality of this.</p>
<p>In light of our patients’ accounts, we suspected that ketamine had affected the brain’s belief-updating mechanisms. In an effort to understand this phenomenon, we conducted an experiment intended to assess <a href="https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2796906">ketamine’s influence on the ways we generate beliefs</a>, using pre- and post-treatment experimental task and <a href="https://www.nature.com/articles/nn.4238">computational modelling</a>.</p>
<p>Prior to the <a href="https://institutducerveau-icm.org/en/actualite/ketamine-and-depression-a-mechanism-of-the-antidepressant-effect-revealed/">ketamine administrations</a>, we asked patients and healthy subjects to assess their likelihood of experiencing 40 different future negative events (e.g., being bitten by a dog or having a car accident). After being informed of the actual occurrence risks in the general population, the two groups were again asked to assess the probability of these events occurring in their lives. Results show healthy subjects took into account new positive facts to update their beliefs, whereas this was not the case for depressed persons.</p>
<p>However, this changed only four hours after receiving the first ketamine dose: patients were far <a href="https://institutducerveau-icm.org/en/actualite/ketamine-and-depression-a-mechanism-of-the-antidepressant-effect-revealed/">less sensitive to negative information and recovered their ability to update their beliefs</a>. This meant the positive affective bias had been restored among patients with treatment-resistant depression. All the more surprisingly, this effect was directly linked to a reduction in depressive symptoms after one week, which suggests that these cognitive changes may even occur prior to clinical improvement.</p>
<h2>Avenues of future research</h2>
<figure class="align-right ">
<img alt="3D structure of a NMDA receptor" src="https://images.theconversation.com/files/490120/original/file-20221017-6684-ujmh1q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/490120/original/file-20221017-6684-ujmh1q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=747&fit=crop&dpr=1 600w, https://images.theconversation.com/files/490120/original/file-20221017-6684-ujmh1q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=747&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/490120/original/file-20221017-6684-ujmh1q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=747&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/490120/original/file-20221017-6684-ujmh1q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=939&fit=crop&dpr=1 754w, https://images.theconversation.com/files/490120/original/file-20221017-6684-ujmh1q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=939&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/490120/original/file-20221017-6684-ujmh1q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=939&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Ketamine molecules attach themselves to NMDA neuronal receptors, which play an important role in brain plasticity and predictive processing.</span>
<span class="attribution"><span class="source">C22H31NO2</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Further research is needed to understand the brain processes associated with these changes, but many clues point to the involvement of <a href="https://www.nature.com/articles/s41467-021-27876-3">NMDA receptor-mediated signalling</a>. These neuronal receptors contribute to the brain’s excitation-inhibition balance, and appear to be essential to <a href="https://pubmed.ncbi.nlm.nih.gov/23177956/">predictive processing</a> and <a href="https://pubmed.ncbi.nlm.nih.gov/26726120/">brain plasticity</a>.</p>
<p>Ketamine’s direct action on the activity of these receptors may constitute a direct pharmacological pathway that regulates <a href="https://pubmed.ncbi.nlm.nih.gov/32818386/">predictive mechanisms</a>, which would explain the drug’s rapid-onset antidepressant effects and its dissociative properties. By controlling the way the brain uses its sensory building blocks to generate beliefs, ketamine could help change the mechanisms behind depressive symptoms.</p>
<p>These hypotheses open up numerous perspectives for developing treatments targeting brain processing, or for combining these molecules with <a href="https://pubmed.ncbi.nlm.nih.gov/34876279/">augmented psychotherapy</a>, protocols that focus specifically on belief systems. This goal is at the core of debates in so-called psychedelic medicine, particularly in treatment using <a href="https://pubmed.ncbi.nlm.nih.gov/35360137/">psilocybin</a>, a hallucinogenic molecule that also presents rapid antidepressant effects. Could theses researches help bring pharmacological and psychotherapeutic approaches together in psychiatry?</p>
<hr>
<p><em>This article is based on the results of <a href="https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2796906">“Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression”</a>, a study that was recently published in the journal JAMA Psychiatry.</em></p>
<p><em>Translated from the French by Enda Boorman for <a href="http://www.fastforword.fr/en">Fast ForWord</a>.</em></p><img src="https://counter.theconversation.com/content/193135/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hugo Bottemanne ne travaille pas, ne conseille pas, ne possède pas de parts, ne reçoit pas de fonds d'une organisation qui pourrait tirer profit de cet article, et n'a déclaré aucune autre affiliation que son organisme de recherche.</span></em></p>Approximately 280 million people in the world suffer for depression. Despite this, the disorder remains poorly explained and is often difficult to treat. Ketamine could offer an innovative approach.Hugo Bottemanne, Psychiatre à la Pitié-Salpêtrière & chercheur à l'Institut du Cerveau - Sorbonne Université AP-HP, Sorbonne UniversitéLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1487212020-12-21T13:05:44Z2020-12-21T13:05:44ZNew antidepressants can lift depression and suicidal thoughts fast, but don’t expect magic cures<figure><img src="https://images.theconversation.com/files/374930/original/file-20201214-20-vhn4py.jpg?ixlib=rb-1.1.0&rect=302%2C33%2C2899%2C1918&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Alleviating major depression for the long term involves more than just drugs.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/worried-woman-royalty-free-image/563853729">Rafa Elias via Getty Images</a></span></figcaption></figure><p>Depression is the <a href="https://www.who.int/news-room/fact-sheets/detail/depression">most common cause of disability</a> in the world. Chances are high that you or someone you know will experience a period when depression gets in the way of work, social life or family life. Nearly two in three people with depression will experience <a href="https://www.nimh.nih.gov/health/statistics/major-depression.shtml#part_155030">severe effects</a>.</p>
<p>As a <a href="https://scholar.google.com/citations?user=5DzjK7QAAAAJ&hl=en">psychiatrist</a> specializing in behavioral neuroscience, I help patients who suffer from mood disorders. Many have “<a href="http://doi.org/10.1016/s0193-953x(05)70283-5">treatment-resistant</a>” depression and are on a nearly constant search for relief. </p>
<p>There have been some exciting developments in treating depression recently, particularly new rapid-acting antidepressants. But it’s important to understand that these medications aren’t cure-alls.</p>
<p>The new treatments for depression <a href="https://www.nytimes.com/2019/03/05/health/depression-treatment-ketamine-fda.html">promise</a> to relieve distressing symptoms, including <a href="https://www.npr.org/sections/health-shots/2020/08/07/900272454/nasal-spray-is-a-new-antidepressant-option-for-people-at-high-risk-of-suicide">suicidal thinking</a>, faster than any previous treatment. They include ketamine, an anesthetic that is also abused as a street drug, and a derivative of ketamine called esketamine. These drugs have been shown to help relieve symptoms of depression <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534172/">within hours</a>, but each dose only works for a few days. <a href="https://doi.org/10.1080/15622975.2020.1836399">They also carry risks</a>, including the potential for drug abuse.</p>
<p>With the <a href="https://www.cdc.gov/mmwr/volumes/69/wr/mm6932a1.htm">coronavirus pandemic taking a toll</a> on mental health, patients are looking for fast relief. Medication can help, but to effectively treat depression long term, with its mix of biological, psychological, social and cultural components, requires more than just drugs. </p>
<h2>Depression medications have evolved</h2>
<p>The early history of depression treatments focused on the psychological components of illness. The goal in the early 20th century was for a patient to understand unconscious urges established during childhood. </p>
<p><a href="http://library.law.columbia.edu/urlmirror/CJAL/14CJAL1/shock_i.htm">Biological treatments at the time</a> seem frightening today. They included insulin coma therapy and primitive, frequently misused versions of a modern lifesaving procedure – electroconvulsive therapy.</p>
<p>In the middle of the 20th century, medicines that affected behavior were discovered. The first medicines were sedatives and antipsychotic medicines. <a href="https://pubmed.ncbi.nlm.nih.gov/16433053/">Chlorpromazine</a>, marketed as “Thorazine,” led the way in the 1950s. In 1951, imipramine was discovered and would become one of the first antidepressants. The <a href="https://archive.fortune.com/magazines/fortune/fortune_archive/2004/06/28/374398/index.htm">“blockbuster”</a> antidepressant Prozac, a selective serotonin reuptake inhibitor, or SSRI, was approved in 1987. </p>
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<img alt="Man in therapy session." src="https://images.theconversation.com/files/374921/original/file-20201214-15-6n0f22.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/374921/original/file-20201214-15-6n0f22.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/374921/original/file-20201214-15-6n0f22.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/374921/original/file-20201214-15-6n0f22.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/374921/original/file-20201214-15-6n0f22.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/374921/original/file-20201214-15-6n0f22.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/374921/original/file-20201214-15-6n0f22.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">The physician-patient relationship can help ensure all components of major depression are being addressed.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/youre-not-alone-royalty-free-image/1048189084">SolStock via Getty Images</a></span>
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<p>It’s been over 30 years since we’ve seen a novel class of antidepressant medicine. That’s one reason rapid-acting antidepressants are exciting.</p>
<h2>What depression looks like inside the brain</h2>
<p>Medical treatments for depression affect certain processing cells in the brain area above your eyes and under your forehead. This area, called the prefrontal cortex, processes complex information including emotional expressions and social behavior. </p>
<p>Brain cells called neurons are chemically controlled by <a href="https://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana.html">two opposing messenger</a> molecules, glutamate and gamma-amino-butyric acid (GABA). Glutamate works like a gas pedal and GABA is the brake. They tell the neurons to speed up or slow down.</p>
<p>Rapid-acting medicines for depression decrease the action of glutamate, the gas pedal. </p>
<p>Other treatments have been developed to rebalance GABA. A neurosteroid called <a href="https://doi.org/10.3389/fendo.2020.00236">allopregnanolone</a> affects GABA and applies the brake. Both allopregnanolone and esketamine have federal approval for treatment of depression, allopregnanolone <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-post-partum-depression">for postpartum depression</a> and esketamine for <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified">major depressive disorder and suicidal thinking</a>.</p>
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<h2>Not so fast</h2>
<p>Around 2016-2017, young psychiatrists like myself were rushing to implement these novel antidepressant treatments. Our training supervisors said, “not so fast.” They explained why we should wait to see how studies of the new drugs turn out.</p>
<p>Several years before, the medical community experienced similar excitement over Vivitrol to treat opioid addiction. Vivitrol is a monthly injected form of naltrexone, an opioid-blocking medicine. </p>
<p>Clinical trials are executed in a highly controlled and clean environment, while the real world can be highly uncontrolled and very messy. Without risk reduction, education and psychosocial treatment, the potential <a href="https://www.vivitrol.com/important-safety-information">risks of medications like Vivitrol</a> can be magnified. Vivitrol can help reduce relapses, but isn’t a panacea on its own. The National Institute on Drug Abuse <a href="https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/principles-effective-treatment">recommends integrated treatment</a> for addiction. </p>
<p>Treating depression may be <a href="http://doi.org/10.1176/appi.ajp.2015.15040476">similar</a>. Medication and psychological support together work better than either on its own.</p>
<h2>The risks</h2>
<p>In depression, the more treatments a person tries that don’t work, the less likely that person is to have success with the next treatment option. This was a main message of the largest clinical trial studying depression medications, the <a href="https://www.nimh.nih.gov/funding/clinical-research/practical/stard/index.shtml">National Institutes of Health-directed STAR-D study</a>, completed in 2006.</p>
<p>Providing a more effective option for patients who don’t respond to a first or second antidepressant may turn that STAR-D message on its head. However, when dealing with an illness that is affected by <a href="http://doi.org/10.2174/1570159x1304150831150507">external stress</a> like trauma and loss, treatment is more likely to succeed with both medication and psychological support. </p>
<p>A real-world treatment approach called the <a href="https://www.psychiatrictimes.com/view/can-we-salvage-biopsychosocial-model">biopsychosocial paradigm</a> accounts for the wide range of relevant biological, psychological and social components of mental illnesses. The patient and physician work together to process the patient’s problematic experiences, thoughts and feelings. </p>
<p>A hyperfocus on novel drugs may overlook the importance of addressing and monitoring all those components, which could mean problems surface in the future. Medications like opiates or other substances that provide rapid relief of physical or psychological pain can also be physically and psychologically addictive, and novel rapid-acting antidepressants <a href="http://doi.org/10.1177/0897190014525754">can have the same risks</a>.</p>
<p>Rapid-acting antidepressants can be powerful tools for treating major depression when used with other forms of therapy, but are they the answer? Not so fast.</p>
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<p class="fine-print"><em><span>Nicholas Mischel receives or has received funding from the American Heart Association, National Institutes of Health, and Wayne State University. He is employed by Wayne State University and member of the American Psychiatric Association, Society of Biological Psychiatry, North American Neuromodulation Society, the Clinical TMS Society, and the American Society of Ketamine
Physicians, Psychotherapists & Practitioners.</span></em></p>Drugs like ketamine can relieve depression symptoms, including suicidal thoughts, within hours, but they also carry risks that patients need to understand.Nicholas Mischel, Assistant Professor of Psychiatry and Behavioral Neurosciences; Director, Interventional Psychiatry and Neuromodulation Research Program, Wayne State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1419582020-07-21T15:24:06Z2020-07-21T15:24:06ZNeurostimulation may herald a new treatment for depression<figure><img src="https://images.theconversation.com/files/345669/original/file-20200705-33943-161gsv0.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1356%2C667&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Medical treatments involving neurostimulation, or cerebral electromagnetic stimulation, are resurfacing and appear to be more effective than drugs for treating depression.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/">Shutterstock</a></span></figcaption></figure><p>Depression is a growing problem in Canada and elsewhere, and one of the <a href="https://doi.org/10.1038/475027a">most important public health issues today</a>, says the World Health Organization (WHO). The COVID-19 pandemic and the ensuing containment measures <a href="https://www.cbc.ca/news/health/camh-mental-health-canadians-1.5614447">have had an impact on the mental health of Canadians</a> and have created conditions that are associated with <a href="https://dx.doi.org/10.1016%2Fj.psychres.2020.113104">increased rates of suicide</a>.</p>
<p>Unfortunately, front-line treatments for depression, such as psychotherapy and medication, <a href="https://doi.org/10.1126/science.338.6103.32">remain ineffective</a> for a large portion of patients receiving care.</p>
<p>However, a new type of treatment is promising: <a href="https://doi.org/10.1001/archgenpsychiatry.2010.46">neurostimulation</a>. Here, a technician in a clinic directs a magnetic coil and delivers a few hundred electromagnetic pulses to a specific area of the brain. Treatments are painless, involve no surgery or significant side-effects and take less than an hour a day. The results are impressive. But is this too good to be true?</p>
<p>As a professor of neuroscience in the department of biology at the University of Ottawa and an affiliated researcher at the Krembil Research Institute in Toronto, my research in nonlinear physics has led me to the incredible complexity and richness of biological systems, especially in neuroscience.</p>
<p>Using mathematics and the power of numerical computation, it is possible to better understand not only how the brain works at the cellular level but also how its vast network is organized and what may be lacking because in presence of diseases, such as depression. This can help identify new avenues for treatment and test their effectiveness through simulations. It’s a huge task that I’m working on in collaboration with an interdisciplinary team of researchers around the world.</p>
<h2>The return of neuron stimulation</h2>
<p>During the past decade, medical treatments involving neurostimulation, or cerebral electromagnetic stimulation, have resurfaced in neuroscience and psychiatry. </p>
<p>After the murky days of electroconvulsive therapy and other techniques, which had rather bad press, electrical or magnetic stimulation of neurons is attempting a comeback, using a much more sophisticated approach and much lower electrical currents. As a result, neurostimulation is becoming increasingly important in the treatment of depression, and its effectiveness seems to surpass that of medication in many patients.</p>
<p>Methods such as <a href="https://doi.org/10.4088/jcp.16cs10905">transcranial magnetic stimulation</a> (TMS) are safe and painless alternatives to traditional pharmacological treatments. In addition, they have virtually no side-effects and offer new insights into the manipulation and control of cognitive processes.</p>
<p>Recent <a href="http://dx.doi.org/10.1136/gpsych-2019-100074">meta-analyses</a> have identified positive and lasting effects of TMS neurostimulation treatments on patients with depression, some of whom experienced benefits up to one year after treatment.</p>
<h2>Proven treatments</h2>
<p>These treatments are now approved by many regulatory agencies and the clinical use of neurostimulation is on the rise in many countries. In particular, portable TMS devices <a href="https://www.theglobeandmail.com/canada/article-can-researchers-bring-a-brain-stimulation-remedy-for-depression-out-of/">are in development</a> and in the process of being approved by Health Canada for wider, accessible deployment. These devices would allow patients to treat themselves at home, without having to go to the clinic every day as is currently the case.</p>
<figure class="align-center ">
<img alt="A woman is seated in front of a machine with an arm of the machine extended next to her head" src="https://images.theconversation.com/files/321373/original/file-20200318-1953-1c5vtp8.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/321373/original/file-20200318-1953-1c5vtp8.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=429&fit=crop&dpr=1 600w, https://images.theconversation.com/files/321373/original/file-20200318-1953-1c5vtp8.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=429&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/321373/original/file-20200318-1953-1c5vtp8.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=429&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/321373/original/file-20200318-1953-1c5vtp8.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=539&fit=crop&dpr=1 754w, https://images.theconversation.com/files/321373/original/file-20200318-1953-1c5vtp8.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=539&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/321373/original/file-20200318-1953-1c5vtp8.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=539&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Intracranial neurostimulation.</span>
<span class="attribution"><span class="source">(Baburov/Wikimedia)</span></span>
</figcaption>
</figure>
<p>However, a major challenge remains: how to control brain activity accurately. What areas and types of magnetic signals should be used to relieve patients’ symptoms? For despite amazing results and promising advances, the mechanisms of neurostimulation remain poorly understood. Why?</p>
<p>TMS uses a coil to create a magnetic field that induces electric currents in the brain. Neurons are cells that communicate by means of repeated electrochemical impulses; the brain is an organ with essentially electrical functions. Magnetic fields can therefore influence the dialogue between different areas of the brain and — in theory — restore or balance their function.</p>
<p>The brain, composed of billions of neurons with continuously changing dynamics, is an incredibly complex network. Neurostimulation therefore poses quite a problem for researchers and clinicians, such as where to stimulate and how. The problem is so great that many advances are being made empirically using the trial-and-error method.</p>
<h2>A mathematical calculation</h2>
<p>Mathematics is involved in this interdisciplinary adventure. What if, through mathematical models of brain circuits, we could understand how stimulation influences neurons and how its effects propagate?</p>
<p>By integrating brain imaging data such as magnetic resonance and electroencephalograms, mathematics can be used to create numerical simulations to better understand the influence of neurostimulation on neuronal activity. It’s a promising approach that could indeed allow us to unravel the mystery of considering the brain as a pendulum!</p>
<p>To better understand, let’s go back a bit.</p>
<p>The activity of neurons in the brain is far from being random and irregular. On the contrary, the neurons in certain parts of the brain co-ordinate their activity and react at the same time. They synchronize. This synchronization of the neurons in the brain appears in the magnifying glass of medical imaging as waves, or very characteristic oscillations, which are also called brain rhythms.</p>
<p>Brain activity oscillates like a pendulum and this constant to-and-fro movement allows us to see neuronal processes in action. Like ripples on a pond, brain rhythms are dynamic, changing according to our cognitive states. They will be different during a sustained mental effort, during physical activity and during sleep or meditation.</p>
<h2>Hope for tackling neurodegenerative diseases</h2>
<p>Researchers believe that brain waves are involved in the majority of brain processes. It is also these same rhythms that seem to be lacking in many neurodegenerative diseases. They are absent, too strong or too slow.</p>
<p>What if we could control these rhythms with the help of neurostimulation? This is the <a href="https://doi.org/10.7554/eLife.32054.001">emerging hypothesis</a> put forward by some neurostimulation researchers. Using advanced mathematics and computer simulations, they want to understand how co-ordination between networked neurons can be influenced and to what extent electromagnetic stimulation can be used to control brain rhythms and to develop treatments for neurological disorders such as multiple sclerosis, Parkinson’s, schizophrenia and depression.</p>
<p>This research may lead to a better understanding of the role of these rhythms in brain function, the code used by neurons to communicate with each other and a better understanding of what is lacking in certain diseases. It may also allow us to use neurostimulation to increase the computational capacity of these neural networks, thereby increasing cognitive abilities and creativity. Science fiction? Maybe … but not completely.</p><img src="https://counter.theconversation.com/content/141958/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jérémie Lefebvre received funding from the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. </span></em></p>Medical treatments involving neurostimulation are resurfacing and appear to be more effective than drugs in treating depression.Jérémie Lefebvre, Professeur agrégé de neurosciences computationnelles et neurophysiologie, L’Université d’Ottawa/University of OttawaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/813512017-08-14T16:25:36Z2017-08-14T16:25:36ZDespair and depression at law school are real, and need attention<figure><img src="https://images.theconversation.com/files/181958/original/file-20170814-12098-1ephtac.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Law school and the legal profession present their own distinct challenges.</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Pursuing a professional degree can be extremely stressful for students, who often experience it as a time riddled with anxiety, uncertainty, fear and financial challenge. </p>
<p>The emotional health of law students was recently brought to my attention in an email from a student at the University of Cape Town’s law faculty where I am the dean. The student noted a perceived hyper competitive, overly demanding and alienating environment. This, he told me, was putting the mental health of some law students under severe strain. He stated that because of the atmosphere, “the use of anti-anxiety and antidepressant medication has become the norm amongst students” and alcohol is being consumed in alarming proportions.</p>
<p>The disturbing email had me pondering: was this an individual case of emotional distress or did it suggest a wider problem that required urgent attention? And what kind of attention? Is there something about law school in particular that drives its students to mental health problems and substance abuse? And, if so, how can it be addressed? </p>
<p>In seeking answers to these questions I first looked into the University of Cape Town’s policies and practices on addressing mental health and substance abuse. I then began an investigation into the issue of mental health among law students specifically, looking at South Africa and other countries. Though most of the rigorous, scientific research on the subject has been conducted in the US, it does offer some valuable insight into what’s driving the issue and how it may be addressed. </p>
<h2>What we know</h2>
<p>The American media has drawn attention to issues of substance abuse and mental health among law students and lawyers. One article written about the high <a href="http://edition.cnn.com/2014/01/19/us/lawyer-suicides/">instances of suicides</a> among law students and lawyers cites a study by the American Psychology Association showing that lawyers are <a href="http://edition.cnn.com/2014/01/19/us/lawyer-suicides/">3.6 times more likely</a> to suffer from depression than non lawyers. </p>
<p>In 2014 a comprehensive study, <a href="http://jle.aals.org/cgi/viewcontent.cgi?article=1370&context=home">The Survey of Law Student Well-Being</a>, was conducted at 15 law schools across the US. It was designed to examine and address the incidence of alcoholism and drug use, as well as mental health concerns of law students. The study found that a quarter to a third of law students reported misuse of alcohol and drugs, as well as experiencing mental health problems. </p>
<p>What was particularly disturbing about the findings was that a sizeable group of the students experiencing problems were reluctant to seek help. The factors that stopped them included social stigma, potential threat to job status, financial reasons, the idea that they could handle the problem themselves, or not having the time. </p>
<p>At South African universities, the question of student emotional wellness has been <a href="http://mentalhealthsa.org.za/international-study-on-students-health-and-wellness/">acknowledged and examined</a> in some depth. These studies do not focus on law specifically but anecdotal evidence suggest that some law students may be experiencing similar pressure, requiring both personal and professional support and care.</p>
<p>All the signs seem to suggest that there is something particular to the education and training of lawyers that makes students and graduates prone to mental health problems and substance abuse. But knowing how to intervene requires a better understanding of what is driving this disturbing phenomenon.</p>
<h2>Stresses in law</h2>
<p>Studying law is fulfilling, rewarding and fun. But law studies are also academically tough. Success is predicated on hard work, long hours and emotional persistence. The skills of successful law graduates include resilience, perseverance and the determination and capacity to succeed despite obstacles. </p>
<p>This is true of other professions, but law is distinct in a few key ways. </p>
<p>In many ways law operates as an adversarial system with clear winners and losers. The combative prosecutor, the shrewd defence lawyer, the ruthless negotiator, the tough judge – these are all images of the strong, successful lawyer. Learning law therefore feels combative, not collaborative. This leads to a culture of competitiveness in law school, where the pressure to emulate successful lawyers is strong. </p>
<p>The practice of lawyering is also a more public endeavour than in other professions. Lawyers are open to public ridicule. </p>
<p>And because law students have to certify that they are “fit and proper” persons to practice they may feel particularly constrained to demonstrate any emotional problem, fearing that it may have an impact on their ability to be licensed to practice. They may also perceive seeking help as a sign of weakness – anathema to the perceived image of the strong lawyer. </p>
<h2>Where to from here?</h2>
<p>In response to the mental health challenges of its students, the University of Cape Town is pursuing a revised <a href="https://www.news.uct.ac.za/article/-2017-07-04-help-along-the-way">mental health policy</a> for students that’s responsive to their needs and attuned to issues of inclusiveness and care. </p>
<p>In the law faculty, in line with the broader <a href="https://www.uct.ac.za/downloads/email/MentalhealthpolicyDRAFT.APRIL2017.pdf">university-wide initiative</a>, we are focusing on the question of how to encourage students to seek help when they need it. This means making mental health services visible, accessible, affordable and socially acceptable. </p>
<p>We are also addressing the way we teach law. Some aspects of the legal profession are inherently stressful. But our aim is to develop a caring institutional culture as well as solid academic support structures.</p><img src="https://counter.theconversation.com/content/81351/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Penelope Andrews does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Some signs seem to suggest that students studying law are prone to mental health problems and substance abuse.Penelope Andrews, Dean of Law and Professor, University of Cape TownLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/812712017-07-20T06:53:45Z2017-07-20T06:53:45ZAntidepressants and pregnancy: study didn’t find they actually cause autism<figure><img src="https://images.theconversation.com/files/178961/original/file-20170720-23985-en5ukt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Most important for now is that we look after pregnant women experiencing depression.</span> <span class="attribution"><span class="source">from www.shutterstock.com.au</span></span></figcaption></figure><p>A <a href="http://www.bmj.com/content/358/bmj.j2811">new paper published today</a> has reported a small increase in the number of children born with autism in mothers who were using antidepressant medication while pregnant. But the increase was small, and the study did not find one caused the other. So we shouldn’t be changing the way we treat depression during pregnancy.</p>
<p><a href="http://pediatrics.aappublications.org/content/121/5/e1357.long?sso=1&sso_redirect_count=1&nfstatus=401&nftoken=00000000-0000-0000-0000-000000000000&nfstatusdescription=ERROR%3a+No+local+token">Previous research has identified</a> a greater than expected presence of psychiatric disorders in the families of children with autism. This could suggest the presence of common underlying genetic factors. <a href="http://dx.doi.org/10.1007/s10803-015-2594-3">Western Australian research</a> also found that prior to the birth of their infant, mothers of children who later developed autism had a higher rate of contact with the mental health system than other mothers. This could have been equally explained by environmental factors such as medication used during pregnancy.</p>
<p>In an attempt to disentangle the potential genetic and environmental factors, and further to previous inconclusive research, this most recent study was conducted on 254,610 people aged 4-17 years living in Stockholm, Sweden from 2001-2011. Given the <a href="http://dx.doi.org/10.5694/mja12.11783">ever-increasing prevalence of mental health disorders</a> in mothers this is a very important research question.</p>
<p>In order to ensure their findings were as valid and unbiased as possible, the authors adjusted the results for other relevant variables such as parental age and family income and repeated their analysis using several different methods. Their results showed a slightly increased risk (from 2.9% to 4.1%) for mothers who had taken antidepressant medication during pregnancy. </p>
<p>But the paper also showed more than 95% of women who took antidepressants did not have a child with autism.</p>
<p>Interestingly, the risks were observed only for autism without, rather than with, an associated intellectual disability. This shows the findings could have been attributable to genetic factors rather than the effects of the medication, as <a href="http://www.pnas.org/content/111/42/15161">previous research has found</a> genes appear to be more linked to autism <em>without</em> intellectual disability.</p>
<h2>So what should we take from this study?</h2>
<p>Clearly, health care providers, pregnant women and those planning a pregnancy will want to know what the results of this new study mean for them. We already know there is a <a href="http://dx.doi.org/10.1007/s10803-015-2594-3">slightly increased risk of autism</a> in the children of women with mental health disorders. Any additional risk from the use of antidepressant medication has been shown in this study to be extremely small.</p>
<p>It’s also important to distinguish between a study that finds a <em>correlation</em> (autism diagnoses increased in the children of mothers who had taken antidepressant medication) and one that finds <em>causation</em> (antidepressants during pregnancy cause autism). </p>
<p>But there is still a need for further research using much larger samples to better investigate the type of antidepressant as well as to take into account the severity of the depression and other aspects of maternal health. Knowing the type of antidepressant would help to understand the mechanism through which any effect may be acting.</p>
<p>In the meantime, it’s extremely important that appropriate clinical management of depression in pregnancy not be compromised in any way by the results of the current study. Pregnant women experiencing depression should stick to their current management plan until we know more.</p><img src="https://counter.theconversation.com/content/81271/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Helen Leonard has received funding from the NIH in the US. </span></em></p>A new paper published today has reported a small increase in the number of children born with autism from mothers who were using antidepressant medication while pregnant.Helen Leonard, Associate Professor, Telethon Kids InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/673462016-10-24T15:02:41Z2016-10-24T15:02:41ZHow an old antidepressant could provide the next brain cancer breakthrough<figure><img src="https://images.theconversation.com/files/142909/original/image-20161024-28382-6t8lqg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>In 1998, I received an intriguing handwritten note. It came from David Wilkie, emeritus professor at University College London, and asked if I thought the antidepressant drug clomipramine could affect brain tumours. I had been investigating how brain cancer spreads and Wilkie wondered if his own work on how clomipramine could kill cells might be of relevance.</p>
<p>This sparked a series of investigations over the last 18 years into how this old drug that was once commonly used as an antidepressant might find a new purpose in cancer treatment. <a href="http://meeting.ascopubs.org/cgi/content/short/23/16_suppl/1535">Research has now linked</a> it to increased survival rates for brain tumour patients and, because its patent has expired, it is cheaply available at less than <a href="http://www.evidence.nhs.uk/formulary/bnf/current/4-central-nervous-system/43-antidepressant-drugs/431-tricyclic-and-related-antidepressant-drugs/tricyclic-antidepressants/clomipramine-hydrochloride">10p a tablet</a>. Clomipramine (sold under the brand name Anafranil) has been used for decades to treat patients with depression. Yet surprisingly – some might say scandalously – it has still not been through the clinical trials that would allow it to be prescribed for brain tumour patients.</p>
<p>Clomipramine’s use as an antidepressant has somewhat declined since it was first introduced in the 1950s, due to the development of selective serotonin reuptake inhibitor (SSRI) drugs such as Prozac. But its potential use as a brain cancer drug comes from the fact that it can cross the blood-brain barrier, which protects the brain from toxins in the blood but can also prevent drugs from entering.</p>
<p>The <a href="http://europepmc.org/theses/eth/272349">first piece of research</a>, carried out by a PhD student in my lab, made the important discovery that clomipramine specifically targeted brain tumour cells – but not healthy brain cells. <a href="http://eprints.port.ac.uk/7632/">Additional studies</a> confirmed that clomipramine worked by targeting these cells’ energy source (mitochondria). Depending on the dose used, this would set up <a href="https://theconversation.com/how-self-destructing-cells-may-hold-key-to-cancer-cure-31707">cell death</a> in a way that was reversible after 24 hours but irreversible after 48 hours, even at a relatively low dose.</p>
<p>This is very different from the way that current gold-standard brain tumour therapy works, which <a href="http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/cancer-drugs/temozolomide">typically involves</a> killing both cancer and normal cells by targeting their nuclei.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=377&fit=crop&dpr=1 600w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=377&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=377&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=474&fit=crop&dpr=1 754w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=474&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/142910/original/image-20161024-28376-2j90bw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=474&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Brain barrier.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p><a href="http://www.nature.com/bjc/journal/v104/n1/full/6605996a.html">Research has shown</a> that clomipramine is linked to a reduction in the likelihood of developing a tumour by 40%-50% depending on the dose, and 64% for patients taking the drug long-term. We (<a href="https://www.ncbi.nlm.nih.gov/pubmed/8927228">and others</a>) <a href="https://www.ncbi.nlm.nih.gov/pubmed/20332444">have also shown</a> that using other repurposed drugs as well can make cancer cells more sensitive to clomipramine and enhance its anti-tumour effect.</p>
<p>But the evidence needed to change a drug’s licence so it can be prescribed for a specific condition can only be obtained with a robust clinical trial. <a href="http://meeting.ascopubs.org/cgi/content/short/23/16_suppl/1535">The trials</a> that have so far been carried out with brain tumour patients unfortunately are not enough. One was a pilot with a small sample size (50 patients) and the second was halted because it had too few patients who complied with the trial rules after the initial 12 months.</p>
<h2>Anecdotal evidence</h2>
<p>Publicity for the drug has resulted in many doctors giving their brain tumour patients clomipramine anyway. In these anecdotal cases, some patients have gone on to survive for periods of up to ten years – and even 17 years in a couple of instances.</p>
<p>But because these patients were not controlled by a clinical trial – for example taking recorded doses and consistent biological measurements – any results can’t be used to change the licence. So even with compelling laboratory and anecdotal evidence, many doctors still only prescribe within the existing guidelines. This helps them to avoid being liable for negligence if a patient is harmed.</p>
<p>Some politicians in the UK have tried to alter the law to make it easier to for promising off-patent drugs to be used for cancer treatment within the regulations. But the <a href="http://services.parliament.uk/bills/2015-16/accesstomedicaltreatmentsinnovation/documents.html">latest law</a>, which came into effect in March 2016, was very watered down. Its main outcome was a searchable database that will record doctor’s medical innovations. This could be a useful reference but doesn’t provide any protection against negligence to encourage more doctors to trial drugs like clomipramine.</p>
<p>So this brings us back to the need for a robust clinical trial. Our laboratory research aims to find partner drugs that can target multiple specific biological pathways and to personalise patient therapies. But finding the funds for a clinical trial is difficult, especially <a href="https://www.braintumourresearch.org/statistics">less than 2%</a> of national cancer research money may be spent on brain tumour research. But without this funding, we won’t be able to reveal the full potential of clomipramine to save the lives of brain cancer patients.</p>
<p><em>Listen to Geoff talk in more depth about clomipramine on The Conversation’s podcast, The Anthill.</em></p>
<iframe width="100%" height="166" scrolling="no" frameborder="no" src="https://w.soundcloud.com/player/?url=https%3A//api.soundcloud.com/tracks/283008303&color=ff5500&auto_play=false&hide_related=false&show_comments=true&show_user=true&show_reposts=false"></iframe><img src="https://counter.theconversation.com/content/67346/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Geoff Pilkington receives funding from Brain Tumour Research. </span></em></p>The well-used drug clomipramine could target tumour cells and leave normal cells healthy – if scientists could get enough evidence for it.Geoff Pilkington, Professor of Cellular and Molecular Neuro-Oncology, University of PortsmouthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/592362016-05-15T19:47:43Z2016-05-15T19:47:43ZAntidepressants may not be as effective as we thought, and shouldn’t be the only treatment for depression<figure><img src="https://images.theconversation.com/files/122425/original/image-20160513-27212-99b17t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Australians are some of the biggest anti-depressant users in the world.</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/wESKMSgZJDo">Volkan Olmez/Unsplash</a>, <a class="license" href="http://artlibre.org/licence/lal/en">FAL</a></span></figcaption></figure><p>The treatment of depression too often means treatment with antidepressants. Australia has one of the <a href="http://www.abc.net.au/news/2013-11-22/australia-second-in-world-in-anti-depressant-prescriptions/5110084">highest rates of antidepressant use in the world</a>. This continues to increase despite mounting evidence they are not especially effective. </p>
<p>My colleague <a href="https://theconversation.com/profiles/andrew-chanen-22382">Andrew Chanen</a> and I have just published <a href="https://www.mja.com.au/journal/2016/204/09/">an article that describes</a> the apparent falling effectiveness of the medications. We argue that doctors have become too reliant on them. When medications are used to treat depression they should be part of an overall treatment plan and shouldn’t be <em>the</em> treatment plan.</p>
<h2>The falling effectiveness of antidepressants</h2>
<p>Why are antidepressants becoming less effective? Partly because we haven’t always had all of the data. The clinical sciences have <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341407/">a problem with negative trial results</a> – trials where the experimental treatments don’t appear to work. They are seen as uninteresting, and as undesirable by drug companies, and have often gone unpublished. </p>
<p>Drug trials are, however, regulated and require registration with authorities before they begin. So, over the past decade, researchers have tracked them down. Once they have found the registered-but-unpublished trials, they have included the data in their overall assessment of the medications’ effectiveness. Unsurprisingly, the result has been that the recorded <a href="http://www.ncbi.nlm.nih.gov/pubmed/18199864">effectiveness of the medications has fallen</a>.</p>
<p>Early drug trials are usually conducted in highly controlled university research environments. The researchers, often working in partnership with the pharmaceutical companies, enrol uncomplicated, motivated, middle-class patients into the trials in an effort to give the trial medications the best chance of success. </p>
<p>Later, researchers are keen to see if the medications work in “real world” patients: the sorts of patients we see in mental health clinics and GP practices, who may not only be depressed but also anxious, drinking too much and distressed about their mounting bills. The medications don’t work as well in these patients.</p>
<h2>The increasing effectiveness of placebos</h2>
<p>Perhaps the biggest reason for the declining effectiveness of the antidepressant medications is that placebos are becoming more effective. The gap between the medications and placebos is steadily narrowing.</p>
<p>The <a href="https://theconversation.com/explainer-what-is-the-placebo-effect-and-are-doctors-allowed-to-prescribe-them-55219">placebo response</a> is a complicated phenomenon. In part it illustrates the statistical concept of “regression to the mean”, where a measure that is extreme when first measured (depressive symptoms in this case) will tend to be less extreme when remeasured.</p>
<hr>
<p><em><a href="https://theconversation.com/explainer-what-is-the-placebo-effect-and-are-doctors-allowed-to-prescribe-them-55219">Explainer: what is the placebo effect?</a></em></p>
<hr>
<p>The other component of the placebo response is a positive expectation bias. When people expect to improve, this makes it more likely they will improve. This is particularly important for depression, because by providing someone with treatment, if only a placebo pill, we are directly addressing the sense of hopelessness that is one of depression’s core symptoms. </p>
<p>The increasing placebo response rate in depression is likely driven by an increasing expectation that treatment will work. Notwithstanding recent evidence about the <a href="http://www.ncbi.nlm.nih.gov/pubmed/22169941">declining effectiveness </a>of antidepressant medications, there is a broad cultural belief – one that has been emphasised in recent decades – that taking a pill can help depression.</p>
<h2>Combining treatments</h2>
<p>Antidepressants might not be as effective as we once believed. But, overall, they are effective. </p>
<p>Other treatments have <a href="http://www.theguardian.com/lifeandstyle/2015/jul/03/why-cbt-is-falling-out-of-favour-oliver-burkeman">similar problems with declining effectiveness</a>. In fact, there are no well-studied treatments for depression that have consistently strong effects.</p>
<p>This suggests combining treatments might be the best approach. And the evidence bears this out: combined treatment with medication and psychotherapy is <a href="http://www.ncbi.nlm.nih.gov/pubmed/24497254">more effective than either alone</a>. We should be moving beyond a simplistic view of alternative treatments as competition for medications and consider whether they might be usefully combined to deliver even more effective treatment.</p>
<h2>Treatment recommendations</h2>
<p>When medications are used they should be part of a broader treatment plan. When therapy is available – and it isn’t always – there can be few good reasons for not recommending it. Medication should be considered when the depression is reasonably severe, when psychotherapy is refused (not everyone wants to see a therapist), or when psychotherapy hasn’t been effective.</p>
<p>When medication is used, it should be used in a way that maximises its chances of being effective. This means not remaining on the same ineffective low dose for months and months. It means close monitoring by a doctor, so when the medication isn’t effective there is consideration of a dose increase or a change to an alternative medication.</p>
<p>Other treatments can also be added. Improving diet and exercising more are good for depression, and combining antidepressants with nutraceuticals – food-derived nutrients such as fish oil and vitamin D – <a href="https://theconversation.com/supplements-including-fish-oil-and-vitamin-d-can-boost-effects-of-antidepressant-medications-58484">has been shown to improve</a> the effectiveness of the medications. </p>
<h2>Future treatment approaches</h2>
<p>It is unlikely we are going to see treatments with significantly greater effectiveness than existing treatments in the near future. Drug companies <a href="http://www.news.com.au/lifestyle/health/big-pharmaceutical-cuts-investment-in-depression-meds/story-fneuzlbd-1226769133716">have reduced their investment</a> in developing new drug treatments for mental illnesses, largely because they have been burnt by so many failures.</p>
<p>And the psychotherapies, while requiring a lot of training and skill to deliver competently, essentially comprise two people in a room talking. It is difficult to see how new therapies could be much more effective than existing ones.</p>
<p>Our task as clinicians is to consider the broad range of treatments that are available, and how they might best be combined in treating the particular patient in front of us. Our task as researchers is to work out the characteristics of the patients who are most likely to respond to particular treatments, so that we provide evidence for delivering the treatments to those patients. There is still much work to do.</p><img src="https://counter.theconversation.com/content/59236/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Christopher Davey has received funding from the NHMRC.</span></em></p>The increasing placebo response rate in depression is likely driven by an increasing expectation that treatment will work.Christopher Davey, Consultant Psychiatrist and Head of Mood Disorders Research at Orygen, The National Centre of Excellence in Youth Mental Health, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/560662016-04-20T02:49:29Z2016-04-20T02:49:29ZWeekly Dose: St John’s Wort, the flower that can treat depression<figure><img src="https://images.theconversation.com/files/118263/original/image-20160412-15871-1841ulh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">St John's Wort has been proven to be as effective as medicinal anti-depressants in treating mild to moderate depression. </span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/widnr/6516047651/">Wisconsin Department of Natural Resources/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>St John’s Wort, botanical name <em>Hypericum perforatum</em>, is considered a weed in temperate climates outside its native homelands of Europe, Asia and North Africa. The flowering tops and aerial parts of the plant are used medicinally in the form of tinctures and tablets to treat a number of conditions affecting the nervous and immune systems.</p>
<p>Records of the medicinal use of St John’s Wort date back to ancient Greece. <a href="https://books.google.com.au/books?id=Y951BwAAQBAJ&pg=PA933&lpg=PA933&dq=Dioscorides+and+Hippocrates+used+St+John%E2%80%99s+Wort&source=bl&ots=GC7eQWOhxX&sig=B1tSFK-DBSn8Fn0WlnEUY8AGWlI&hl=en&sa=X&ved=0ahUKEwi_6tq1o4jMAhWEF5QKHUthBIoQ6AEIITAB#v=onepage&q=Dioscorides%20and%20Hippocrates%20used%20St%20John%E2%80%99s%20Wort&f=false">It is believed</a> Dioscorides and Hippocrates used it to cleanse the body of evil spirits. Since the times of the Swiss physician and botanist Paracelsus (1493-1541), St John’s Wort has traditionally been used to treat nerve pain, anxiety, neurosis and depression and externally for bruises, wounds and shingles.</p>
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<a href="https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=795&fit=crop&dpr=1 600w, https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=795&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=795&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=999&fit=crop&dpr=1 754w, https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=999&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/119066/original/image-20160418-23633-k3h14l.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=999&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<h2>How is it used today?</h2>
<p>In modern times, St John’s Wort <a href="http://www.cochrane.org/CD000448/DEPRESSN_st.-johns-wort-for-treating-depression">has been shown</a> to be as effective as placebo and standard antidepressants in the treatment of mild to moderate depression. </p>
<p>In Australia, St John’s Wort is mainly purchased through pharmacies and health food stores with or without the guidance of a health-care professional. </p>
<p>The St John’s Wort products vary in the amount of key constituents they contain. Only a few products actually match what was trialled in the studies with positive clinical outcomes. Variations in the active constituent content will affect the strength and effectiveness of the medicine and its possible safety. </p>
<p>It has become more common for complementary medicine manufacturers to include a standardised amount of the herb constituents on the label. The daily dose range for total hypericin content is 0.75mg to 2.7mg of hypericin daily. The <a href="http://www.cochrane.org/CD000448/DEPRESSN_st.-johns-wort-for-treating-depression">published studies</a> generally used standardised extracts to contain 0.3% hypericin and 2-5% hyperforin.</p>
<p>In 2000, St John’s Wort made up <a>25% of all antidepressant prescriptions</a> in Europe. A more recent <a href="http://www.australianprescriber.com/magazine/22/5/112/3">Australian study</a> reported 4.3% or 17,780 patients who had visited a GP for depression had taken or were taking St John’s Wort.</p>
<h2>How does it work?</h2>
<p>St John’s Wort has been <a href="https://books.google.com.au/books?hl=en&lr=&id=Ca3QAQAAQBAJ&oi=fnd&pg=PP1&dq=principles+and+practice+of+phytotherapy&ots=QcYsnTUCQK&sig=tZWHP8otW965bvi6-SEznx0R30Y#v=onepage&q=principles%20and%20practice%20of%20phytotherapy&f=false">reported as containing</a> many constituents and demonstrating multiple and simultaneous mechanisms of action. </p>
<p>While individual key constituents have been identified as hypericin (a naturally occurring substance with a few different applications including antidepressive), pseudohypericin and hyperforin (a phytochemical produced in some plants), collectively they exert a number of pharmacological effects including antidepressant activity. </p>
<p>The hypericin and flavonoids (namely hyperforin) and other flavonoid molecules that are found in some fruits and vegetables are thought to play a role in exerting an antidepressant effect by altering nerve chemical messengers known as neurotransmitters. It is considered important available products contain standardised amounts of these components.</p>
<p>St John’s Wort has been shown in <a href="https://books.google.com.au/books?hl=en&lr=&id=Ca3QAQAAQBAJ&oi=fnd&pg=PP1&dq=principles+and+practice+of+phytotherapy&ots=QcYsnTUCQK&sig=tZWHP8otW965bvi6-SEznx0R30Y#v=onepage&q=principles%20and%20practice%20of%20phytotherapy&f=false">non-human studies</a> to assist in keeping the circulating levels of four key neurotransmitters (serotonin, noradrenaline, dopamine and gamma-aminobutyric acid) at levels that improve depressive symptoms. </p>
<p>This is a very distinctive feature of St John’s Wort. No other drug has been demonstrated to affect all four of these chemical messengers with similar potencies. <a href="http://www.cochrane.org/CD000448/DEPRESSN_st.-johns-wort-for-treating-depression">Studies</a> comparing the effectiveness of St John’s Wort with different classes of other anti-depressants that target these neurotransmitters support the proposed multi-targeted mechanism of action of St John’s Wort.</p>
<p>Antidepressants Citalopram (Celexa) and Sertraline (Zoloft) belong to a class of antidepressants known as selective serotonin re-uptake inhibitors (SSRIs). These block the reabsorption of the neurotransmitter serotonin in the brain, making more serotonin available to assist the brain cells to send and receive chemical messages. This in turn boosts mood.</p>
<p>A <a href="http://www.cochrane.org/CD000448/DEPRESSN_st.-johns-wort-for-treating-depression">high-standard systematic review</a> conducted in 2009 concluded St John’s Wort extract was superior to placebo in patients with major depression and similarly effective to standard treatment with SSRIs. They also found fewer people taking St John’s Wort discontinued their treatment. This was due to them experiencing fewer side effects.</p>
<p>The same review also found no significant difference in the effectiveness of St John’s Wort and the older class of antidepressants known as “tri-cyclic”. These work by blocking the absorption of serotonin to improve their availability for sending and receiving chemical messages that improve our mood.</p>
<p>St John’s Wort was reported as more effective in <a href="http://www.cochrane.org/CD000448/DEPRESSN_st.-johns-wort-for-treating-depression">German studies</a> compared to those in non-European-based populations, but it is thought these results were over-optimistic.</p>
<h2>Safety and side-effects</h2>
<p>Like standard antidepressants, it may take up to four weeks to judge how effective St John’s Wort has been. It is generally well tolerated, but adverse effects may occur. These include mild gastrointestinal symptoms, skin reactions, increased sensitivity to sunlight, fatigue, sedation, restlessness, dizziness, headache and dry mouth.</p>
<p>St John’s Wort affects enzymes in the gastrointestinal tract and liver that are involved in drug metabolism. It can reduce how much of a drug is available in the body by reducing how much is absorbed and excreted. Therefore the potential effectiveness of many drugs can be limited. </p>
<p>This includes drugs used to treat serious conditions such as AIDs, cancer and epilepsy. St John’s Wort can also reduce the effectiveness of the oral contraceptive pill. It should not be taken along with standard antidepressant drugs.</p>
<p>Anyone suspecting they may have symptoms of depression should consult their doctor to ensure a correct diagnosis is made. The use of St John’s Wort should be guided by a health-care professional who is knowledgeable about the quality of available products, effective dosing and safety considerations, including known drug interactions associated with its use.</p><img src="https://counter.theconversation.com/content/56066/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The author's current role is entirely funded by a philanthropic donation from a manufacturer of complementary medicines, Blackmores Pty Ltd. Blackmores does not have any involvement in any of the academic teaching, research or publication activities of the author.</span></em></p>The flowering tops and aerial parts of the St John’s Wort plant are used medicinally in the form of tinctures and tablets to treat a number of conditions affecting the nervous and immune systems.Joanna Harnett, Associate Lecturer Faculty of Pharmacy - Complementary Medicine, University of SydneyLicensed as Creative Commons – attribution, no derivatives.