tag:theconversation.com,2011:/id/topics/ssri-4651/articlesSSRI – The Conversation2023-10-23T13:43:49Ztag:theconversation.com,2011:article/2160252023-10-23T13:43:49Z2023-10-23T13:43:49ZHow antidepressants, ketamine and psychedelic drugs may make brains more flexible – new research<figure><img src="https://images.theconversation.com/files/555238/original/file-20231023-19-78v8r3.jpg?ixlib=rb-1.1.0&rect=263%2C203%2C7724%2C5784&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/neurons-marked-by-fluorescence-354063143">Juan Gaertner/Shutterstock</a></span></figcaption></figure><p>The first-line pharmacological treatment for major depressive disorder (MDD) are antidepressant drugs known as selective serotonin re-uptake inhibitors (SSRIs). But a significant proportion of people <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3363299/">don’t respond</a> to these drugs. </p>
<p>Given that major depression is a global mental health problem that is <a href="https://www.nature.com/articles/475027a">on the increase</a>, it is important to find novel pharmacological treatments for those who do not respond to the current ones. But to do that, we need to understand exactly how the drugs work – which we currently don’t.</p>
<p>MDD is a debilitating and distressing mental health disorder, trapping sufferers in a rigid and negative state of mind. There’s even evidence suggesting that this lack of flexibility is <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238070/">associated with cognitive changes</a>, including negative thoughts and biases, and problems with learning and memory.</p>
<p>In our new study, <a href="https://www.nature.com/articles/s41380-023-02285-8">published in Molecular Psychiatry</a>, we show that an SSRI called ecitalopram may actually make brains more “plastic” – meaning more flexible and adaptive; more able to facilitate communication between neurons (brain cells). Brain plasticity is simply the ability of neural circuits to change through growth and reorganisation. Learning involves brain plasticity, including changes in neural circuits, and can help people to recover from depression.</p>
<p>One novel treatment option for depression, approved by the US Food and Drug Administration, is intranasal esketamine (an anaesthetic made from ketamine), although it has not as yet been approved for use by the NHS. The psychedelic drugs LSD and psilocybin <a href="https://pubmed.ncbi.nlm.nih.gov/31636488/">are also being investigated</a> for treatment resistant depression in research studies, but are not yet approved by regulatory bodies. When these studies are conducted, there is careful monitoring by a medical professional to ensure participant safety.</p>
<p>We know that both SSRIs and psychedelics <a href="https://www.sciencedirect.com/science/article/pii/S0028390822003161">target the same brain receptor</a> (known as the 5HT-2A). By contrast, eskatamine, similar to ketamine, works on a different receptor (N-methyl-D-aspartate or NMDA) and affects the brain chemical glutamate.</p>
<p>So how do SSRIs and psychedelics work to reduce symptoms of depression? At present, we don’t have the full picture. But the 5HT-2A receptor is linked to the brain chemical serotonin, increasing levels of it in the brain. And a recent study has indeed shown that serotonin <a href="https://www.biologicalpsychiatryjournal.com/article/S0006-3223(22)01704-8/fulltext">appears to be reduced</a> in people with depression.</p>
<p>SSRIs, however, also affect the neurotransmitters GABA and glutamate. The latter has been linked to learning, cognition and memory – suggesting SSRI may actually <a href="https://pubmed.ncbi.nlm.nih.gov/33657450/">help to restore cognitive function</a>. Although the exact mechanisms of psychedelics are not yet fully understood, their antidepressant effects seem to work in a similar way to SSRIs given their effects on 5HT-2A receptors. However, there are also <a href="https://link.springer.com/article/10.1007/s40263-021-00877-y">other reactions</a> to psychedelics, such as hallucinations.</p>
<h2>Measuring brain plasticity</h2>
<p>All these drugs have therefore been suggested to affect brain plasticity. However, in humans, it can be difficult to estimate levels of brain plasticity. One common method that scientists have used is to measure a protein called the brain-derived neurotrophic factor (BDNF) in blood samples. </p>
<p>BDNF helps <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174655/">brain plasticity</a> by increasing the number of synapses (locations where neurons can communicate with each other), as well as the branches and growth of developing neurons. Synapses are particularly important in brain functioning as they allow transmission of chemical and electrical signals from one neuron to another. Similarly, synapses also store brain chemicals for release. </p>
<p>There have been some studies <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328267/#:%7E:text=While%20both%20SSRIs%20and%20SNRIs,0.93%3B%20P%20%3D%200.009">showing that</a> antidepressant drugs increase BDNF. However, better techniques are required to study plasticity in the human brain. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Antidepressant pill with smiling face in blister pack." src="https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/555242/original/file-20231023-25-dkmk19.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">It is unknown exactly how SSRIs treat depression.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/antidepressant-pill-smiling-face-blister-pack-786910729">DestinaDesign-Shutterstock</a></span>
</figcaption>
</figure>
<p>To develop better drugs, one approach is to find anti-depressant drugs with a faster mechanism of action. According to the NHS website, SSRIs <a href="https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/medicines-and-psychiatry/ssri-antidepressants/overview/#:%7E:text=When%20they're%20prescribed%2C%20you,t%20stop%20taking%20the%20medicine">usually need to be taken</a> for two to four weeks before any benefit is felt. </p>
<p>We suspected that one reason for this delayed effect may be that brain plasticity needs to occur with SSRI treatment. As this process involves rewiring, such as the creation of synapses and circuits, it isn’t instant, but <a href="https://www.sciencedirect.com/science/article/pii/S0306452204005366?casa_token=YYK8O5aH_CYAAAAA:yHDNSHP6HJjbMelk3gvE-WGnvgeHkzusUszIhnS8TySOUH9gK2B2q3rt38QB8lj-uEAR3QtEPg">is thought to take</a> approximately 14-21 days.</p>
<p>In our study, which was a collaboration between the University of Cambridge and the University of Copenhagen, we used a novel technique to measure plasticity in the human brain, following SSRI treatment, for the first time. </p>
<p>Thirty-two participants underwent positron emission tomography (PET) scanning to detect the amount of a protein called “synaptic vesicle glycoprotein 2A”, or SV2A, in the brain. We know that <a href="https://www.science.org/doi/full/10.1126/scitranslmed.aaf6667?casa_token=MyIx6zmoLm8AAAAA:TKIwzV_Xlsi4_3Ny40uwK-WWaUKHzSJUIyDGQw8byzbhG_B38Gk2sGmhR6zap7B1ARr36NUaynmZOA">SV2A is a marker</a> of the presence of synapses. An increased amount would suggest that more synapses are present and therefore that brain plasticity is higher. </p>
<p>Our results showed a rise in this protein as a result of taking escitalopram (an SSRI). We found that, in those taking escitalopram, increased SV2A was associated with increased duration on the drug. Our findings suggest that brain plasticity increases over three to five weeks in healthy humans following daily intake of escitalopram. </p>
<p>This is the first real evidence in humans that SSRIs really do boost neuroplasticity – seen in the brain – and that this is one of the reasons it can treat depression. Similar evidence from studies in the human brain are still required for the psychedelics. </p>
<p>It makes sense that if antidepressant treatment facilitates brain plasticity, this should make it easier for people taking these treatments to learn new things. And we know that the ability to adopt new strategies, and change them if they don’t work (supported by what researchers call cognitive flexibility), is <a href="https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=ee3e78f5e20bd9019d41a4e820bbdb597ac9a2d8">key to recovering from depression</a>.</p><img src="https://counter.theconversation.com/content/216025/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Barbara Jacquelyn Sahakian receives funding from the Leverhulme Trust and the Lundbeck Foundation. Her research work is conducted within the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health and Neurodegeneration Themes and the NIHR MedTech and in vitro diagnostic Co-operative (MIC). She consults for Cambridge Cognition.</span></em></p><p class="fine-print"><em><span>Christelle Langley receives funding from the Leverhulme Trust. Her research work is conducted within the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health and Neurodegeneration Themes and the NIHR MedTech and in vitro diagnostic Co-operative (MIC).</span></em></p>It is unknown exactly how SSRIs and psychedelics treat depression, but their ability to boost flexibility may be more important than previously thought.Barbara Jacquelyn Sahakian, Professor of Clinical Neuropsychology, University of CambridgeChristelle Langley, Postdoctoral Research Associate, Cognitive Neuroscience, University of CambridgeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1982822023-03-15T12:21:41Z2023-03-15T12:21:41ZDepression too often gets deemed ‘hard to treat’ when medication falls short<figure><img src="https://images.theconversation.com/files/514748/original/file-20230310-29-jqe5vl.jpg?ixlib=rb-1.1.0&rect=0%2C45%2C5106%2C3332&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A diagnosis of treatment-resistant depression can lead to a sense of hopelessness and despair in some patients.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/worried-young-woman-sitting-on-bed-at-home-royalty-free-image/1393174810">Maria Korneeva/Moment via Getty Images</a></span></figcaption></figure><p>A plumber who shows up to fix a leaking toilet with a single tool is not likely to succeed. The same is true if a mental health professional offers only one approach for a complex problem like depression.</p>
<p>Sadly, the number of people <a href="https://www.who.int/news-room/fact-sheets/detail/depression">struggling with depression</a> <a href="https://www.who.int/news/item/02-03-2022-covid-19-pandemic-triggers-25-increase-in-prevalence-of-anxiety-and-depression-worldwide">increased dramatically</a> at the height of the COVID-19 pandemic. <a href="https://doi.org/10.1016/j.jad.2023.01.050">Stress</a> – from school closures to job losses to the death of loved ones – made life more challenging and increased the risk of developing emotional difficulties. For some groups that have experienced discrimination, <a href="https://doi.org/10.1007/s40615-022-01284-9">ongoing inequities</a> made their mental health even worse. </p>
<p>There is a professional debate about <a href="https://doi.org/10.1353/pbm.0.0009">whether depression is a social problem</a> <a href="https://www.psychiatry.org/patients-families/depression/what-is-depression">or a disease</a>. Despite this debate, a 62% increase in <a href="https://www.finance.senate.gov/imo/media/doc/SFC%20Mental%20Health%20Report%20March%202022.pdf">yearly spending on U.S. mental health care</a>, from US$131 billion in 2006 to $212 billion in 2015, has not led to the intended level of improvement for patients. </p>
<p>This makes it clear that the <a href="https://www.hsph.harvard.edu/ecpe/why-leadership-in-mental-health-care-is-needed-now-more-than-ever-and-how-to-implement-change/">current approach is falling short</a>, but there are a host of viable alternatives for helping to treat patients who are suffering with depression.</p>
<p>We are a <a href="https://scholar.google.com/citations?hl=en&user=LFOKsvwAAAAJ&view_op=list_works&sortby=pubdate">health and biological psychologist</a> who treats hospitalized patients with depression and anxiety and a <a href="https://scholar.google.com/citations?user=p3SsTKUAAAAJ&hl=en&oi=ao">doctoral student in social work</a> studying how to improve the lives of socially isolated older adults.</p>
<p>As mental health professionals, we see the effects of the <a href="https://www.psychiatrictimes.com/view/mental-health-america-crisis">ongoing mental health crisis</a> on a daily basis. </p>
<h2>An overreliance on medication causes harm</h2>
<p>More than <a href="https://pubmed.ncbi.nlm.nih.gov/33054926/">13% of U.S. adults take an antidepressant medication</a> for depression or for other reasons. <a href="https://doi.org/10.3389/fpsyt.2019.00407">Many people report feeling better</a> on antidepressants, though there is <a href="https://theconversation.com/in-research-studies-and-in-real-life-placebos-have-a-powerful-healing-effect-on-the-body-and-mind-173845">debate about what causes the improvements</a>. </p>
<p>Unfortunately, nearly 3 in 4 who take these drugs <a href="https://psycnet.apa.org/doi/10.1037/cns0000261">do not get complete relief from antidepressants</a>. As we discussed in a recent paper, people who do not feel better on antidepressants are usually categorized as having a <a href="https://doi.org/10.1016/j.ssmmh.2022.100081">difficult-to-treat type of depression</a> referred to, controversially, as “treatment-resistant depression.” </p>
<p>We see patients <a href="https://doi.org/10.1016/j.psc.2011.11.004">who feel demoralized</a> by the implied and untrue notion that their depression is “incurable” after only trying medication but not <a href="https://doi.org/10.1176/appi.ajp.2021.21050535">lower-risk treatments</a> like psychotherapy and <a href="https://doi.org/10.1016/S2215-0366(20)30036-5">other effective alternatives</a>. We help them find hope again.</p>
<p>The U.S. health care system <a href="https://www.usnews.com/news/health-news/articles/2022-04-20/in-long-run-antidepressants-dont-improve-quality-of-life-study">relies heavily on medication</a> and other <a href="https://pubmed.ncbi.nlm.nih.gov/31612847/">biomedical treatments</a> for depression. But in fact there are numerous non-drug-based solutions for prevention and treatment of depression. </p>
<p>Holistic concepts that promote <a href="https://doi.org/10.1016/j.ssmmh.2021.100052">flourishing</a> and <a href="https://doi.org/10.1027/1016-9040/a000294">thriving</a>, as well as <a href="https://www.va.gov/wholehealth/">whole-health initiatives</a> and <a href="https://doi.org/10.1056%2FNEJMp1917461">mind-body medicine</a> focus on the entire person. These concepts have not yet been fully integrated into approaches to public mental health. </p>
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<figcaption><span class="caption">The word ‘heal’ is derived from the same Latin and Greek words that mean ‘whole.’</span></figcaption>
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<h2>The quest to understand well-being and depression</h2>
<p>There are many hardworking, highly successful people who do not feel fulfilled with life from time to time. When this internal lack of fulfillment also includes other symptoms like a loss of hope and becomes severe enough to disrupt daily life for a period of two weeks or more, it may be medically diagnosed as depression. </p>
<p>In the 1960s, researchers proposed that <a href="https://doi.org/10.1016/j.ssmmh.2022.100098">depression was caused by a chemical imbalance</a> of a neurotransmitter called serotonin in the brain. In 1988, the pharmaceutical company Eli Lilly introduced <a href="https://doi.org/10.1037%2Fa0038550">an antidepressant medication based on that idea</a>.</p>
<p>However, after decades of experiments, researchers have failed to find evidence showing support for the chemical imbalance theory. A recent study highlights the <a href="https://www.ucl.ac.uk/news/2022/aug/opinion-chemical-imbalance-theory-depression-clearing-some-misconceptions">growing realization that antidepressant medications</a> do not work <a href="https://doi.org/10.1038/s41380-022-01661-0">in the simplistic way</a> in which they <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313530/">have been advertised</a> for decades. </p>
<p>This is important because antidepressants have <a href="https://www.karger.com/Article/Abstract/447034">side effects</a> that can be serious. For a doctor and patient to weigh the risks and benefits of taking an antidepressant, they need accurate information about both. The chemical imbalance theory interfered with that conversation.</p>
<h2>Tools to heal depression</h2>
<p>So what exactly does contribute to overall well-being and happiness to help stave off depression?</p>
<p>A large body of research shows that <a href="https://doi.org/10.3390%2Fbrainsci11121633">biological, psychological and social factors</a> contribute to feeling satisfied in life or to developing depression. Because each individual is unique, there is not a one-size-fits-all formula for well-being. </p>
<p>Many people find relief from depression by talking to a psychotherapist. <a href="https://doi.org/10.1002%2Fwps.20238">High-quality psychotherapy</a> has been shown to be as effective as and <a href="http://dx.doi.org/10.1136/bmjopen-2012-002542">longer-lasting</a> <a href="https://doi.org/10.1038%2Fnrn2345">than antidepressant medication</a> when treating depression. </p>
<p>Therapy <a href="https://psycnet.apa.org/record/2017-55500-019">activates an individual’s hope</a> and natural resilience by <a href="https://doi.org/10.3389/fnint.2022.871227">creating a safe</a> and emotionally warm relationship through which the therapist and client work together toward common goals. In addition to helping clients learn about their emotions, thoughts, relationships and patterns of behavior, a good therapist explores how to help their clients identify everyday activities that can improve wellness.</p>
<p>The things we do on a day-to-day basis, called <a href="https://doi.org/10.1186/1471-244x-14-107">lifestyle factors</a>, function as building blocks for a life without depression. <a href="https://www.johnwbrickfoundation.org/move-your-mental-health-report/">Physical movement</a>, <a href="https://www.health.harvard.edu/blog/diet-and-depression-2018022213309">good nutrition</a>, <a href="https://www.nytimes.com/2013/11/19/health/treating-insomnia-to-heal-depression.html">healthy sleep</a>, <a href="https://www.apa.org/topics/mindfulness/meditation">healthy levels of stress</a> and <a href="https://doi.org/10.1037%2Fa0018555">stress management</a>, <a href="https://doi.org/10.1016/j.jad.2017.04.043">social connection</a>, <a href="https://www.healthexperiencesusa.org/Depression-in-Young-Adults/having-a-purpose-in-life">finding meaning and purpose</a> and <a href="https://doi.org/10.1007/s11126-020-09881-9">spiritual practices</a> all play important roles in preventing and treating depression. </p>
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<figcaption><span class="caption">Exercise is a powerful antidote against depression, anxiety and stress.</span></figcaption>
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<p>These are too often wrongly trivialized as less effective than professional treatment. In fact, though, a <a href="https://theconversation.com/exercise-is-even-more-effective-than-counselling-or-medication-for-depression-but-how-much-do-you-need-200717">recent study</a> showed that exercise is <a href="http://dx.doi.org/10.1136/bjsports-2022-106195">even more effective than medication or counseling</a>. Another eye-opening study showed that <a href="https://doi.org/10.1097/01.nmd.0000217820.33841.53">85% of people who received no treatment</a> still recovered from depression within one year. </p>
<p>As mental health professionals, we find these results both humbling and inspiring. It means that the general public has solutions for depression that the mental health system has too often overlooked. This is consistent with the <a href="https://www.ifm.org/news-insights/healing-works-means-health-care-wayne-jonas-md/">scientific study of healing</a>, which shows that the body has a tremendous and overlooked <a href="https://www.youtube.com/watch?v=gcai0i2tJt0">ability to repair and heal itself</a> under the right circumstances. </p>
<p>Consider the example of <a href="https://doi.org/10.1016%2Fj.crphys.2021.04.002">laughter therapy</a>, a stress hormone-reducing, mood-lifting practice used in 120 countries. Laughter leaders guide <a href="https://laughteryogausa.org/">groups of people</a> in exercises that stimulate contagious laughter. Not everyone will react the same way to laughter therapy, but it is <a href="https://www.yogajournal.com/lifestyle/laughter-cure/">effective at increasing well-being for some people</a>, so it belongs in the tool box of therapies to try.</p>
<h2>Hope comes in many forms</h2>
<p>One research initiative has identified communities, <a href="https://doi.org/10.1177%2F1559827616637066">called blue zones</a>, where people tend to live long, healthy and satisfying lives. The lifestyles of people living in these areas, like Ikaria, Greece, and Okinawa, Japan, are characterized by social connection, consumption of mostly plant-based foods, a high sense of purpose, environments that support physical movement and intentional relaxation. Customs in different countries and environments show that these principles are visible across the globe in many different forms.</p>
<p>Many cultures extol the benefits of being in nature. <a href="https://www.bbc.com/worklife/article/20171211-friluftsliv-the-nordic-concept-of-getting-outdoors">Nordic countries use the word friluftsliv</a>, which means “outdoor life,” to describe the practice of getting outdoors to improve well-being. In Japan, <a href="https://www.japan.travel/en/guide/forest-bathing/">some people practice shinrin-yoku</a>, translated as forest bathing or opening up the senses to <a href="https://www.degruyter.com/document/doi/10.1515/revneuro-2015-0009/html">the natural world’s scents</a>, sights and sounds. </p>
<p>Researchers have also found that access to green space is associated with <a href="https://doi.org/10.3390%2Fijerph110303453">lower levels of depression symptoms</a>. Other studies <a href="https://doi.org/10.1016%2Fj.pmedr.2016.11.007">show that gardening is linked with</a> less depression, stronger social connections and improvement in quality of life. Gardening also gives those with access a chance to move their bodies and eat more homegrown vegetables as part of an <a href="https://doi.org/10.1186/s12888-022-03771-z">anti-depression nutrition plan</a>. </p>
<p>We cannot describe everything on the endless list of life-affirming, research-supported and low-risk methods to decrease stress, boost mood and enhance fulfillment. But here are a few more examples: </p>
<ul>
<li><a href="https://doi.org/10.1155/2017/5869315">aromatherapy</a></li>
<li><a href="https://www.health.harvard.edu/blog/light-therapy-not-just-for-seasonal-depression-202210282840">light therapy</a></li>
<li><a href="https://doi.org/10.1177%2F2156587217715927">yoga</a></li>
<li><a href="https://doi.org/10.3389/fpsyg.2021.647879">music</a></li>
<li><a href="https://www.helpguide.org/articles/mental-health/mood-boosting-power-of-dogs.htm">animals</a></li>
<li><a href="https://www.artandhealing.org/health-concerns/">making art</a> </li>
<li><a href="https://www.cdc.gov/howrightnow/gratitude/index.html#">gratitude practice</a> </li>
<li><a href="https://psycnet.apa.org/doi/10.1037/emo0000324">sexual activity</a> </li>
<li><a href="https://ppc.sas.upenn.edu/">positive psychology</a></li>
<li><a href="https://www.psychologytoday.com/us/blog/the-athletes-way/202008/beyond-fun-and-games-playfulness-may-help-combat-depression#">playfulness enhancement</a></li>
<li><a href="https://doi.org/10.2196%2Fjmir.6482">mobile</a> <a href="https://screening.mhanational.org/content/what-are-best-apps-depression/">apps</a></li>
<li>self-help <a href="https://doi.org/10.1177%2F2515690X18823691">tools like “tapping”</a> to help with strong emotions</li>
<li><a href="https://www.artandhealing.org/unlonely-project/">peer and social</a> <a href="https://mystrength.com/">support programs</a> </li>
</ul>
<p>These seemingly simple interventions are powerful because they lead to health-promoting psychological and <a href="https://www.ncbi.nlm.nih.gov/books/NBK541120/">physiological changes</a>. </p>
<h2>Staying true to what works</h2>
<p>Clinicians, researchers and <a href="https://www.wired.com/2017/05/star-neuroscientist-tom-insel-leaves-google-spawned-verily-startup/">leaders</a> have been trying to identify the <a href="https://clinicaltrials.gov/ct2/show/NCT00021528">best treatment for depression</a> for at least two decades. </p>
<p>This is an unanswerable question. Some treatments work extremely well for certain people and cause terrible reactions for others. When <a href="http://dx.doi.org/10.1136/adc.2004.058222">standard research protocols</a> try to capture these effects, it can <a href="https://doi.org/10.1111/j.0887-378X.2004.00327.x">look like there is no effect of the treatment</a> because the positive effects average out with the negative effects. </p>
<p>A search for the holy grail of a <a href="https://doi.org/10.1016/j.neubiorev.2017.08.019">neurobiological cause for depression</a> has drawn attention away from efforts to implement what is already known about how to <a href="https://www.who.int/europe/about-us/our-work/core-priorities/promoting-health-and-well-being">promote health</a>. </p>
<p>To <a href="https://www.cdc.gov/hrqol/wellbeing.htm#one">live one’s best life</a>, everyone needs safety, shelter, clothing, good nutrition, good sleep, physical movement, <a href="https://doi.org/10.1007/s12671-020-01375-w">loving and kind social connection</a> and a sense of meaning and purpose. There are many ways to help people get there.</p><img src="https://counter.theconversation.com/content/198282/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>An overreliance on medication as the first-line treatment for depression can lead some people to be labeled with treatment-resistant depression when there are other viable alternatives for relief.Elissa H. Patterson, Clinical Assistant Professor of Psychiatry and Neurology, University of MichiganJay Kayser, PhD Student in Social Work and Developmental Psychology, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1982642023-01-25T13:08:07Z2023-01-25T13:08:07ZSSRIs: emotional ‘blunting’ may be part of the process – new research<figure><img src="https://images.theconversation.com/files/505953/original/file-20230123-10641-eqsjzj.jpg?ixlib=rb-1.1.0&rect=15%2C0%2C5187%2C3471&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Antidepressants can help people function in daily life.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/millennial-man-taking-antibiotic-antidepressant-painkiller-1095874340">fizkes/Shutterstock</a></span></figcaption></figure><p>Reinforcement sensitivity is an important behavioural process that allows us to learn from our environment through either positive/rewarding or negative feedback. When we get together with friends or go for a run, chemicals in our brains send us signals that in turn make us feel good about what we’re doing. We know that depressed patients commonly report “emotional blunting” after longer use of antidepressants, in which they experience a dulling of both positive and negative emotions. But it can be difficult to tell if these symptoms are due to the depression itself or the drug treatment. </p>
<p>Using healthy volunteers, <a href="https://www.nature.com/articles/s41386-022-01523-x">our new study</a> is the first to show that chronic use of antidepressants does decrease sensitivity to positive reward as well as negative feedback, and this finding may explain the dulling feeling experienced by some depressed patients. </p>
<p>The WHO estimates that about 350 million adults, or 5% of the global population, have depression. It is the <a href="https://www.who.int/news-room/fact-sheets/detail/depression">leading cause</a> for disability worldwide. </p>
<p>Since patients with depression may be prescribed selective serotonin reuptake inhibitor (SSRI) drugs indefinitely, it is important to understand their long-term effects. Our recent article, published in Neuropsychopharmacology, is the first to examine the cognitive, behavioural and emotional effects of long-term SSRIs in healthy people. Without studies on healthy volunteers, it’s difficult to pinpoint the cause of patients’ symptoms. For example, non-medicated patients with depression frequently have <a href="https://pubmed.ncbi.nlm.nih.gov/21976044/">cognitive impairments</a>, including <a href="https://www.sciencedirect.com/science/article/abs/pii/S1053811908007106">heightened sensitivity to negative feedback</a>, which may suggest depression not antidepressants as the cause. </p>
<p><a href="https://www.nhs.uk/medicines/escitalopram/about-escitalopram/">Escitalopram</a> is an effective treatment for many people with moderate-to-severe depression and is one of the <a href="https://link.springer.com/article/10.2165/11204760-000000000-00000">best-tolerated SSRIs</a>. Our study tested 66 healthy volunteers who were either given a placebo or the SSRI drug, escitalopram, for at least 21 days. </p>
<p>We found escitalopram reduced participants’ reinforcement sensitivity compared to those on placebo.</p>
<p>These findings also showed that the brain chemical serotonin, known as the “happy chemical” is involved in reinforcement learning in healthy people. The lower reinforcement sensitivity noted in the escitalopram group may be similar to the blunting effect (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650205/">feeling emotionally numb</a>) often reported by patients during SSRI treatment. </p>
<p>The blunting effect may contribute to patients wanting to stop their treatment too early. However, not everyone taking SSRIs will experience the emotional blunting. In addition, this blunting may also be an important part of the therapeutic process by dampening down the negative emotions and distress felt by depressed patients.</p>
<h2>One treatment doesn’t fit all</h2>
<p>Depression can have many causes, including genetics - which <a href="https://doi.org/10.1016/j.bpsgos.2021.07.008">may also affect our response to drugs</a> used for recreational purposes as well as those used for prescription medications. A study in 2022 showed depressed patients have <a href="https://pubmed.ncbi.nlm.nih.gov/36347845/">individual cognitive profiles</a>, which doctors may be able to use to help determine which patients would likely benefit from SSRI treatment. However, as yet, there is not enough research to allow for personalised drug treatments.</p>
<figure class="align-center ">
<img alt="Close-up view of female doctor hand holding bottle with pills and writing prescription" src="https://images.theconversation.com/files/505955/original/file-20230123-13-qnsx40.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/505955/original/file-20230123-13-qnsx40.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/505955/original/file-20230123-13-qnsx40.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/505955/original/file-20230123-13-qnsx40.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/505955/original/file-20230123-13-qnsx40.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/505955/original/file-20230123-13-qnsx40.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/505955/original/file-20230123-13-qnsx40.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">It’s not easy to tell who will benefit from antidepressants.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/close-view-female-doctor-hand-holding-444089281">ldutko/Shutterstock</a></span>
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<p>While there has been much debate among scientists about how SSRI treatments work, they are effective treatments for moderate and severe depression. A recent study <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext">reviewed 21 different antidepressant drugs</a> and found that all of them were more effective when compared to placebo. The <a href="https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/medicines-and-psychiatry/ssri-antidepressants/overview/">first line of treatment</a> for moderate to severe major depressive disorder is SSRIs, which increase serotonin levels in the brain. Importantly, a separate study in 2022 assessed the brain’s <a href="https://www.biologicalpsychiatryjournal.com/article/S0006-3223(22)01704-8/fulltext">serotonin release</a> and found that it is reduced in patients with depression compared to healthy people. Serotonin is involved in a number of cognitive, behavioural and emotional functions. </p>
<h2>New approaches</h2>
<p>Not all patients with depression respond to psychological treatments or SSRIs and for this reason scientists are searching for other novel treatments. For example, <a href="https://pubmed.ncbi.nlm.nih.gov/31548292/">Esketamine</a> is a new drug designed for treatment resistant depression and has recently been approved by the <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified">regulatory body in the USA (FDA)</a>. It works on a different set of receptors in the brain called NMDA, which are associated with glutamate, a different brain chemical.</p>
<p>For many people suffering from depression, SSRIs improve their condition significantly. It gives them a better quality of life and improves their ability to function in everyday life. It may be that if we are able to detect depression early, we can treat it effectively with psychological treatments only. Science has shown that there are <a href="https://theconversation.com/six-ways-to-reboot-your-brain-after-a-hard-year-of-covid-19-according-to-science-151332">activities and methods</a>, such as exercise, life long learning and social interaction, that can boost cognition and wellbeing. If we use these methods starting from an early age, we may find that in future we have better mental health and wellbeing as a society.</p><img src="https://counter.theconversation.com/content/198264/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Barbara Jacquelyn Sahakian receives funding from the Leverhulme Trust and the Lundbeck Foundation. Her research work is conducted within the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health and Neurodegeneration Themes and the NIHR MedTech and in vitro diagnostic Co-operative (MIC). She consults for Cambridge Cognition.</span></em></p><p class="fine-print"><em><span>Christelle Langley is funded by the Leverhulme Trust.</span></em></p><p class="fine-print"><em><span>Gitte Knudsen has been a speaker for H Lundbeck and Sage Biogen. She is also past president of the ECNP and act as a consultant for Onsero, Sanos and Pangea.
She receives research funding from EU, The Danish Research Council and several private foundations provide unrestricted grants for her research, eg, The Lundbeck and the Novo Nordisk Foundation. </span></em></p>Antidepressants may take away some of the pain of depression but that can also sap away people’s enjoyment of life.Barbara Jacquelyn Sahakian, Professor of Clinical Neuropsychology, University of CambridgeChristelle Langley, Postdoctoral Research Associate, Cognitive Neuroscience, University of CambridgeGitte Knudsen, Clinical Professor of Neurology, Copenhagen University HospitalLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1861092022-09-28T12:32:58Z2022-09-28T12:32:58ZDeep brain stimulation can be life-altering for OCD sufferers when other treatment options fall short<figure><img src="https://images.theconversation.com/files/486344/original/file-20220923-8064-5j7otz.jpg?ixlib=rb-1.1.0&rect=1161%2C23%2C6826%2C4467&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Deep brain stimulation relies on thin electrodes implanted deep in the brain that deliver electrical currents. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/artificial-intelligence-digital-concept-royalty-free-image/1283240410">Olemedia/E+ via Getty Images</a></span></figcaption></figure><p>Imagine growing up tormented by fears and life-consuming rituals that make no sense to you or those around you. Then imagine the shame of being told by mental health providers that, because you understand that your behaviors are illogical but keep doing them anyway, you must want to stay sick. </p>
<p>One of my patients, Moksha Patel, who is a doctor himself, endured this from childhood until his early 30s. In September 2021, Patel underwent deep brain stimulation surgery, a rare neurosurgical procedure that can be used for severe obsessive-compulsive disorder, or OCD, when it has been resistant to less invasive treatments. </p>
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<p><em>You can listen to more articles from The Conversation, narrated by Noa, <a href="https://theconversation.com/us/topics/audio-narrated-99682">here</a>.</em></p>
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<p>Patel has consented to this publication of his medical information. He <a href="https://news.cuanschutz.edu/news-stories/ocd-ruled-moksha-patels-life-until-a-rare-surgical-procedure-changed-everything">shares his story publicly</a> to combat stigma and to provide hope for other sufferers that relief is possible. </p>
<p>The term OCD is thrown around casually, often by someone joking about how organized they are: “I’m so OCD.” But true <a href="https://doi.org/10.1176/ajp.153.6.783">obsessive-compulsive disorder is debilitating</a> and leads to <a href="https://doi.org/10.1007/s40263-013-0056-z">significant suffering</a>. </p>
<p>I <a href="https://som.ucdenver.edu/Profiles/Faculty/Profile/13845">lead a team</a> that treats people with OCD using <a href="https://medschool.cuanschutz.edu/psychiatry/PatientCare/obsessive-compulsive-disorder-program">evidence-based approaches</a>. I am also co-director of the <a href="https://medschool.cuanschutz.edu/psychiatry/PatientCare/obsessive-compulsive-disorder-program/reclaim-deep-brain-stimulation-therapy-for-ocd">OCD surgical program</a> at the University of Colorado, Anschutz campus, and UC Health, a nonprofit health care system in Colorado. </p>
<p>Our surgical program is one of the few academic centers in the U.S. that offer deep brain stimulation for the treatment of OCD. My experience and research have given me insight into how a rare procedure can be used in <a href="https://doi.org/10.3389/fpsyt.2021.568932">real-world settings</a> to provide relief to those who suffer from OCD when other less invasive treatments have not been successful.</p>
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<figcaption><span class="caption">Dr. Sabine Wilhelm of Mass General Hospital answers the most commonly searched questions about obsessive-compulsive disorder.</span></figcaption>
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<h2>What does OCD feel like for a sufferer?</h2>
<p>A brain with OCD is primed to detect any signs of potential danger. Many people with OCD <a href="https://iocdf.org/blog/2019/04/22/what-it-feels-like-to-live-with-ocd/">wake up every day with a sense of dread</a> and an expectation of bad things happening. Daily life is overshadowed by ever-present guilt, shame, fear and doubt. As a result, they carry out compulsive and repetitive activities to attempt to forestall disaster and manage the painful emotions. </p>
<p>OCD fears most often involve the things and people that matter the most to the sufferer, such as their values, loved ones or purpose in life. For example, someone who values kindness and compassion might fear that they will offend, betray or somehow hurt the people they care about.</p>
<p>Sometimes what is hardest for someone who suffers with OCD is a recognition that the fears and behaviors are illogical – insight that provides no relief. </p>
<p>And because other people usually don’t understand, those with OCD do their best to hide their illness so they won’t be judged as ridiculous or “crazy,” which often leads to long delays in diagnosis and treatment. This is a painful and lonely life for the approximately <a href="https://www.psychiatrist.com/jcp/ocd/ocd-prevalence-and-gender/">1%-2% of the world population with OCD</a>. </p>
<h2>Current OCD treatment options</h2>
<p>The best initial treatment for OCD is a type of mental health therapy called <a href="https://www.erp4ocd.com/">exposure and response prevention</a>. During these sessions, OCD sufferers are supported in gradually confronting their fears while also limiting the behaviors they have come to associate with providing safety. </p>
<p>For instance, someone with a fear of harming others might start by sitting near a butter knife and work their way up to holding a sharper knife to their therapist’s throat. They either learn that their fear does not play out, or – in the case of fears that cannot be disproved – that they can tolerate their anxiety or distress and move forward even in the absence of certainty. </p>
<p>The primary <a href="https://iocdf.org/about-ocd/ocd-treatment/meds/">medications used to treat OCD</a> are <a href="https://www.fda.gov/drugs/information-drug-class/selective-serotonin-reuptake-inhibitors-ssris-information">serotonin reuptake inhibitors, or SRIs/SSRIs</a>, which are commonly prescribed for treatment of depression and anxiety. But when used for OCD, these medications are typically prescribed at much higher dosages.</p>
<p>Unfortunately, <a href="https://doi.org/10.4088/jcp.v67n0214">OCD is a chronic condition</a> for most; studies show that only 65% of people with OCD respond to standard treatment, which is a combination of therapy and medication, and only about 35% recover completely. About 10% of individuals with OCD <a href="https://doi.org/10.1186/s12888-014-0214-y">remain severely impaired</a>, regardless of how intensively they are treated.</p>
<h2>The potential of deep brain stimulation</h2>
<p>For this small group of individuals with severe and persistent OCD, deep brain stimulation – a procedure that <a href="http://dx.doi.org/10.5498/wjp.v11.i9.659">fewer than 400 people</a> with OCD have undergone worldwide – provides hope. </p>
<p>Patel, an internal medicine doctor, first came to my office in 2019. He is one of 13 patients I’ve worked with to provide deep brain stimulation for OCD and other psychiatric illnesses.</p>
<p>He has suffered with OCD since the age of 4 or 5, with obsessive fears about germs, contamination and social interactions, among other things. He learned to function and succeed by shaping his life around his rituals – for example, by not consuming water or food at work so that he would not need to use public restrooms. </p>
<p>Patel, like many others with OCD, is conscientious, thorough and compassionate, traits that contribute to his success as a physician. However, before deep brain stimulation, most of his life outside of work was occupied by painful, consuming rituals. These included scrubbing himself with harsh chemicals for hours. </p>
<p>He had explored every treatment he could find, seeing 13 mental health providers since high school and participating in years of exposure therapy. He had tried at least 15 different medications, all with little benefit. Then he learned that deep brain stimulation was available at the hospital where we both work. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A neurosurgeon prepares his patient, who is lying down, for deep brain stimulation surgery." src="https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=800&fit=crop&dpr=1 600w, https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=800&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=800&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1005&fit=crop&dpr=1 754w, https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1005&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/486645/original/file-20220926-8644-62d70o.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1005&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Dr. Steven Ojemann, a CU Anschutz/UCHealth neurosurgeon, preparing Dr. Moksha Patel for deep brain stimulation surgery on Sept. 15, 2021.</span>
<span class="attribution"><span class="source">Radhika Patel</span>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
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<h2>How deep brain stimulation works</h2>
<p>Deep brain stimulation requires a neurosurgical procedure to place thin electrodes into deep structures of the brain, specifically a region known as the <a href="https://doi.org/10.1016/j.wneu.2019.01.254">ventral capsule/ventral striatum</a>. These <a href="https://www.youtube.com/watch?v=wYLJGuUt4iI">electrodes deliver electrical currents to the brain</a>. The current is produced by pulse generators in the chest that look much like cardiac pacemakers. They are connected to the electrodes in the brain by wires tunneled beneath the skin.</p>
<p>We researchers do not yet have a precise understanding of exactly how deep brain stimulation works, but we do know that it <a href="https://doi.org/10.1038/nn.3344">normalizes the communication</a> between parts of the brain responsible for taking in information and those responsible for acting on this information. These areas are hyperconnected in people with OCD, leading to a reduced ability to make thoughtful, value-driven decisions and an over-reliance on <a href="https://doi.org/10.1038/s41380-020-01007-8">reflexive or habitual behaviors</a>. And the changes induced by deep brain stimulation correlate with a reduction in OCD symptoms.</p>
<p>This type of neurostimulation is most commonly used to manage symptoms of <a href="https://www.nia.nih.gov/health/parkinsons-disease">Parkinson’s disease</a>, a movement disorder that leads to tremors and body rigidity. OCD is the only psychiatric disorder that currently has approval from the Food and Drug Administration for deep brain stimulation treatment. But deep brain stimulation <a href="https://doi.org/10.3171/2015.3.FOCUS1546">has been investigated</a> in <a href="https://doi.org/10.1016/j.neuroimage.2020.117515">other conditions, including major depression</a>, Tourette syndrome, schizophrenia, substance use disorders, post-traumatic stress disorder and eating disorders. </p>
<p>Deep brain stimulation is a procedure of last resort for patients with OCD. Because of the invasive nature of brain surgery and the potential for <a href="https://doi.org/10.1016/j.neubiorev.2020.01.007">serious adverse effects</a> such as infection or hemorrhage, individuals need to try standard, less invasive treatments first and meet the <a href="https://doi.org/10.3389/fpsyt.2021.706181">criteria for severe and persistent OCD</a>, which have been established based on OCD and brain stimulation research. </p>
<p>But for those who do undergo the procedure for OCD treatment and receive ongoing stimulation, <a href="https://doi.org/10.1038/mp.2008.55">up to 70%</a> have a <a href="http://dx.doi.org/10.5498/wjp.v11.i9.659">good long-term response</a>. “Good” is considered to be a 35% reduction in OCD symptoms based on a <a href="https://doi.org/10.1001/archpsyc.1989.01810110048007">standardized scale for obsessive-compulsive behavior</a> that experts in our field rely on. </p>
<p>This, for example, could mean that someone goes from spending more than eight hours per day on OCD behaviors and not leaving the house at all to spending four hours per day and being able to go to school with significant support. Such progress is remarkable, given how ill these individuals are.</p>
<h2>Barriers and stigma</h2>
<p>There aren’t very many treatment centers anywhere in the world, so patients who need this procedure may have trouble getting to one. Additionally, as our team has described in published research, getting insurance coverage for the procedure is <a href="https://doi.org/10.1038/s41591-022-01879-z">often time-consuming</a> and <a href="https://doi.org/10.3389/fsurg.2021.642503">sometimes prohibitive</a>. </p>
<p>Another barrier is the stigma associated with brain surgery for psychiatric illness. The reasons behind this stigma are complicated, and some factors have historical roots. In the early to mid-1900s, destructive, dangerous and <a href="https://nihrecord.nih.gov/2019/11/01/when-faces-made-case-lobotomy">not very effective brain surgeries such as lobotomies</a> were performed routinely for mental illness without regulation, ethical guidelines or regulatory oversight.</p>
<h2>A way forward</h2>
<p>After I worked with Patel for about a year, including trials of six additional medications and ongoing exposure and response prevention therapy, his symptoms remained severe. I recommended he begin the extensive evaluation process for deep brain stimulation surgery.</p>
<p>Three weeks after his surgery, I turned on electrical stimulation, and we began the intensive programming procedure to determine the optimal settings. This process takes several hours a day over the course of several days, with fine-tuning in the following weeks and months. </p>
<p>Patel recalls that early on, during programming, he experienced a roller coaster of feelings, shifting between “giddiness and sadness.” Most individuals experience gradual improvement over the course of six to 12 months. At first, they feel happier and less anxious, and weeks to months later they experience a decrease in OCD symptoms. </p>
<p>Most commonly, stimulation is constant, 24 hours a day. But the treating psychiatrist may give the patient the ability to turn it off, such as at night if the stimulation causes problems with sleep.</p>
<p>Since surgery, Patel has continued weekly therapy sessions. Research shows that <a href="https://doi.org/10.1017/s0033291714000956">deep brain stimulation is most effective</a> when people continue to engage in exposure and response prevention therapy. Electricity alone will not break years of hard-wired habits, but it can be the catalyst that allows for new neural pathways to be established and new behaviors to be learned. Likewise, most individuals need to continue medication. Though the effects of deep brain stimulation can be remarkable, it is not a cure. </p>
<p>Patel has experienced a 54% reduction in his OCD, according to the <a href="https://doi.org/10.1001/archpsyc.1989.01810110048007">standardized scale</a>. This means that his symptoms decreased from the “extreme OCD” to the “moderate” range. </p>
<p>He can now eat and drink at work and use public restrooms. He has more social connections, seeks less reassurance and spends less time decontaminating himself and his belongings. While sleep was previously his only respite, Patel is now intentional about finding meaningful activities to fill the hours that are no longer occupied by rituals. </p>
<p>Most importantly, he is beginning to feel hopeful that it just might be possible to build a life driven by purpose and intention, rather than by fear.</p><img src="https://counter.theconversation.com/content/186109/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rachel Davis consults for Medtronic, Inc. She receives funding from the NIH . </span></em></p>This rare procedure is offered by only a handful of centers in the US and around the world and should be used only when less invasive treatment options for OCD have been tried.Rachel A. Davis, Associate Professor of Psychiatry and Neurosurgery, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1256332019-11-21T13:59:01Z2019-11-21T13:59:01ZTurning to turkey’s tryptophan to boost mood? Not so fast<figure><img src="https://images.theconversation.com/files/302740/original/file-20191120-467-1r1k6iy.jpg?ixlib=rb-1.1.0&rect=69%2C333%2C5036%2C2793&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Those smiles probably aren’t thanks to tryptophan.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/multi-generation-family-celebrating-christmas-meal-121428664">Monkey Business Images/Shutterstock.com</a></span></figcaption></figure><p>Every Thanksgiving, myths of the quasi-magical powers of tryptophan rise again.</p>
<p>There’s the turkey/drowsiness myth: Eating lots of juicy turkey meat supposedly makes people feel tired because it contains an amino acid called tryptophan. This molecule travels into the brain, where it’s converted into a neurotransmitter called serotonin, which in turn is converted into a hormone called melatonin. Voila! Sleepiness.</p>
<p><a href="https://doi.org/10.1136/bmj.39420.420370.25">But science</a> and <a href="https://www.google.com/search?q=turkey+and+sleepiness">the internet</a> agree: It’s not the turkey’s tryptophan to blame for your post-feast nap. All protein sources, and even vegetables, contain some tryptophan; turkey isn’t at all special in this regard.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=900&fit=crop&dpr=1 600w, https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=900&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=900&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1131&fit=crop&dpr=1 754w, https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1131&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/302741/original/file-20191120-554-1ehsxrr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1131&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">What could eating more tryptophan, or taking it in pill form, mean for your brain?</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/5htp-bottle-l5hydroxytryptophan-precursor-serotonin-1052268893?src=9701ca16-33c4-4a4d-91d7-f45bafa7eed1-1-0">Evan Lorne/Shutterstock.com</a></span>
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</figure>
<p>So the sleepiness myth of turkey may be fading, but other legends around tryptophan’s effects in the brain are taking hold. Some people are eyeing tryptophan supplements as an <a href="https://doi.org/10.3390/nu8010056">unconventional treatment for depression</a>. Others are curious whether <a href="https://doi.org/10.1111/j.1601-5215.2010.00508.x">eating foods that are high or low in tryptophan</a> could be useful for influencing mood. Recently, some scientists have even proposed that <a href="https://doi.org/10.1016/j.bbr.2014.07.027">gut bacteria are driving changes in emotion</a> by producing or breaking down tryptophan.</p>
<p>This tryptophan/mood connection is an area of ongoing research. And while some are captivated by tryptophan’s potential, it’s not clear whether the excitement is warranted.</p>
<h2>Looking for a tryptophan link to mood</h2>
<p>There is some scientific evidence that eating tryptophan can alter your mood.</p>
<p>For example, back in 2000, researchers found that when people ate an isolated protein that was very high in tryptophan, they <a href="https://doi.org/10.1093/ajcn/71.6.1536">felt less stress while doing math problems</a>.</p>
<p>However, placebo-controlled clinical trials haven’t, in general, shown much of a connection. A few studies have found that <a href="https://doi.org/10.1016/j.jad.2013.05.042">supplementing with pure tryptophan</a> provided little to no benefit for people with depression. Some studies have even looked at what happens when you <a href="https://doi.org/10.1038/sj.mp.4001949">remove tryptophan from people’s diets</a>, but also found little to no effect.</p>
<p>So what explains the mixed results? </p>
<h2>Serotonin itself still holds mysteries</h2>
<p>Alongside human studies, the biology of tryptophan has been well studied in rodents. Research in the early 1970s showed that taking <a href="https://doi.org/10.1126/science.178.4059.414">tryptophan supplements can boost serotonin</a>, a neurotransmitter that was historically associated with feelings of well-being and happiness.</p>
<p>Since then, scientists have learned lots of interesting facts <a href="https://www.serotoninclub.org/">about serotonin</a>. For example, there are <a href="https://doi.org/10.1523/JNEUROSCI.2830-16.2016">14 separate receptors for serotonin</a>, and they’re found all over the brain.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1005&fit=crop&dpr=1 600w, https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1005&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1005&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1263&fit=crop&dpr=1 754w, https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1263&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/302742/original/file-20191120-467-ff7ud6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1263&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">SSRIs block neurons’ abilities to reabsorb serotonin, leaving more of the neurotransmitter in the brain to affect other receptors.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/drawing-synapse-showing-serotonin-reuptake-action-309901151">Blamb/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Researchers have learned how to affect this system with drugs, but not with much precision. For example, drugs like the antidepressant selective serotonin reuptake inhibitors – more widely known as SSRIs – don’t target individual receptors and they don’t restrict themselves to particular brain regions. Instead, SSRIs, the <a href="https://www.medicalnewstoday.com/kc/prozac-fluoxetine-side-effects-263773">best-known of which is Prozac</a>, bluntly boost serotonin everywhere.</p>
<p>This non-specificity is why, in my mind, it’s hard to believe that SSRIs work at all. Here’s an analogy: Say you’re Jeff Bezos and you want to increase Amazon’s revenue by speeding up your deliveries. So you decide to crank up the speed on all delivery vehicles. From now on, every truck will boost its speed by 5%. It may be a stroke of logistical genius, or it may, perhaps more likely, end up in chaos. Like ramping up serotonin all over the brain, this blunt approach might not be ideal.</p>
<p>Analogies aside, whether SSRIs affect people’s moods is an experimental question, and some research has supported the idea that these drugs work. However, especially lately, their effectiveness has <a href="https://www.newscientist.com/article/mg23931980-100-nobody-can-agree-about-antidepressants-heres-what-you-need-to-know/">come under intense scrutiny</a>. Some recent analyses cite 30 years’ worth of studies and <a href="https://doi.org/10.1186/s12888-016-1173-2">question the clinical value of SSRIs</a>, while others maintain that these drugs <a href="https://doi.org/10.1016/S0140-6736(17)32802-7">improve the symptoms of depression</a>.</p>
<p>It’s complicated, and there’s still some disagreement, but most psychiatrists agree that SSRIs are <a href="https://doi.org/10.1016/S0140-6736(17)32802-7">not effective for everyone</a>. These drugs are not psychiatric-cure-alls.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=372&fit=crop&dpr=1 600w, https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=372&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=372&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=468&fit=crop&dpr=1 754w, https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=468&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/302753/original/file-20191120-547-1so7x8d.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=468&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Tryptophan’s role in any gut-brain connection still isn’t clear.</span>
<span class="attribution"><span class="source">Andrew Neff</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>More chemical fine-tuning for mood</h2>
<p>In light of all this, I’ve often found myself asking whether psychiatric researchers needed <a href="https://doi.org/10.1038/sj.mp.4001949">73 studies</a> looking at whether tryptophan depletion has an impact on mood. </p>
<p>When it comes to understanding connections between gut bacteria and the brain, or the bigger challenge of understanding and treating mental illness, should researchers really still be thinking about tryptophan?</p>
<p>It’s seems true that, similar to SSRIs, boosting tryptophan <a href="https://doi.org/10.1371/journal.pone.0035916">has a broad impact on serotonin</a>. It’s definitely possible that cranking up serotonin can influence mood, and that therefore boosting tryptophan could do the same. But it’s also possible that to manipulate something as complicated as human emotion requires a little more nuance.</p>
<p>Psychiatric research has long been moving away from the idea that <a href="https://www.ted.com/talks/david_anderson_your_brain_is_more_than_a_bag_of_chemicals?language=en">your brain is a bag of chemicals</a>; modern neuroscientists are asking for a little more specificity. From this perspective, I’m skeptical of the notion that tryptophan is the depression remedy psychiatry needs. Not only has experimental research found fairly weak results, but the theory itself isn’t very compelling.</p>
<p>Serotonin, seemingly full of psychiatric possibility, has long fascinated psychiatric researchers. But what the past half century seems to have demonstrated is that the neuroscience of human emotion is not simple. To promote lasting changes in mental health, scientists may need a little more reverence for the complex emotional beings that we all are.</p>
<p>So no, a big turkey dinner, as filled with delicious tryptophans as it might be, will likely not be the neurochemical driver for your mood on Thanksgiving.</p>
<p>[ <em>You’re smart and curious about the world. So are The Conversation’s authors and editors.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=youresmart">You can read us daily by subscribing to our newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/125633/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Neff does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Tryptophan, found in food, is an important ingredient in the neurotransmitter serotonin. But is that enough to support it as a possible mood booster? The research is decidedly mixed.Andrew Neff, Adjunct Faculty in Psychology, Rochester UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/486652016-04-29T03:22:27Z2016-04-29T03:22:27ZExplainer: how do drugs work?<figure><img src="https://images.theconversation.com/files/116857/original/image-20160331-28445-kns6qy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Ever wondered how the small, white ibuprofen pill turns off your headache?</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>Whether a drug is prescribed by the doctor, bought over the counter or obtained illegally, we mostly take their mechanism of action for granted and trust they will do what they’re supposed to.</p>
<p>But how does the ibuprofen pill turn off your headache? And what does the antidepressant do to help balance your brain chemistry?</p>
<p>For something that seems so incredible, drug mechanics are wonderfully simple. It’s mostly about receptors and the molecules that activate them.</p>
<h2>Receptors</h2>
<p>Receptors are large protein molecules embedded in the cell wall, or membrane. They receive (hence “receptors”) chemical information from other molecules – such as drugs, hormones or neurotransmitters – outside the cell.</p>
<p>These outside molecules bind to receptors on the cell, activating the receptor and generating a biochemical or electric signal inside the cell. This signal then makes the cell do certain things such as making us feel pain.</p>
<h2>Agonist drugs</h2>
<p>Those molecules that bind to specific receptors and cause a process in the cell to become more active are called agonists. An agonist is something that causes a specific physiological response in the cell. They can be natural or artificial.</p>
<p>For instance, endorphins are natural agonists of opioid receptors. But morphine – or heroin that turns into morphine in the body – is an artificial agonist of the main opioid receptor.</p>
<p>An artificial agonist is so structurally similar to a receptor’s natural agonist that it can have the same effect on the receptor. Many drugs are made to mimic natural agonists so they can bind to their receptors and elicit the same – or much stronger – reaction.</p>
<p>Simply put, an agonist is like the key that fits in the lock (the receptor) and turns it to open the door (or send a biochemical or electrical signal to exert an effect). The natural agonist is the master key but it is possible to design other keys (agonist drugs) that do the same job.</p>
<p>Morphine, for instance, wasn’t designed by the body but can be found naturally in opium poppies. By luck it mimics the shape of the natural opioid agonists, the endorphins, that are natural pain relievers responsible for the “endorphin high”.</p>
<p>Specific effects such as pain relief or euphoria happen because opioid receptors are only present in some parts of the brain and body that affect those functions. </p>
<p>The main active ingredient in cannabis, THC, is an agonist of the cannabinoid receptor, and hallucinogenic drug LSD is a synthetic molecule mimicking the agonist actions of the neurotransmitter serotonin at one of its many receptors – the 5HT2A receptor.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/116912/original/image-20160331-6126-4srdso.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/116912/original/image-20160331-6126-4srdso.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=796&fit=crop&dpr=1 600w, https://images.theconversation.com/files/116912/original/image-20160331-6126-4srdso.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=796&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/116912/original/image-20160331-6126-4srdso.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=796&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/116912/original/image-20160331-6126-4srdso.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1000&fit=crop&dpr=1 754w, https://images.theconversation.com/files/116912/original/image-20160331-6126-4srdso.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1000&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/116912/original/image-20160331-6126-4srdso.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1000&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
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<span class="attribution"><a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
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</figure>
<h2>Antagonist drugs</h2>
<p>An antagonist is a drug designed to directly oppose the actions of an agonist.</p>
<p>Again, using the lock and key analogy, an antagonist is like a key that fits nicely into the lock but doesn’t have the right shape to turn the lock. When this key (antagonist) is inserted in the lock, the proper key (agonist) can’t go into the same lock. </p>
<p>So the actions of the agonist are blocked by the presence of the antagonist in the receptor molecule. </p>
<p>Again, let’s think of morphine as an agonist for the opioid receptor. If someone is experiencing a potentially lethal morphine overdose, the opioid receptor antagonist naloxone can reverse the effects.</p>
<p>This is because naloxone (marketed as Narcan) quickly occupies all the opioid receptors in the body and prevents morphine from binding to and activating them. </p>
<p>Morphine bounces in and out of the receptor in seconds. When it’s not bound to the receptor, the antagonist can get in and block it. Because the receptor can’t be activated once an antagonist is occupying the receptor, there is no reaction.</p>
<p>The effects of Narcan can be dramatic. Even if the overdose victim is unconscious or near death, they can become fully conscious and alert within seconds of injection.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/117443/original/image-20160405-13561-1f23yyw.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/117443/original/image-20160405-13561-1f23yyw.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=742&fit=crop&dpr=1 600w, https://images.theconversation.com/files/117443/original/image-20160405-13561-1f23yyw.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=742&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/117443/original/image-20160405-13561-1f23yyw.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=742&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/117443/original/image-20160405-13561-1f23yyw.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=933&fit=crop&dpr=1 754w, https://images.theconversation.com/files/117443/original/image-20160405-13561-1f23yyw.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=933&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/117443/original/image-20160405-13561-1f23yyw.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=933&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="attribution"><a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
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<h2>Membrane transport inhibitors</h2>
<p>Membrane transporters are large proteins embedded in a cell’s membrane that shuttle smaller molecules – such as neurotransmitters – from outside of the cell that releases them, back to the inside. Some drugs act to inhibit their action.</p>
<p>Selective serotonin reuptake inhibitors (SSRIs) – such as the antidepressant fluoxetine (Prozac) – work like this. </p>
<p>Serotonin is a brain neurotransmitter that regulates mood, sleep and other functions such as body temperature. It’s released from nerve terminals, binding to serotonin receptors on nearby cells in the brain.</p>
<p>For the process to work smoothly, the brain must quickly turn off the signals coming from the serotonin soon after the chemicals are released from the terminals. Otherwise moment-to-moment control of brain and body function would be impossible.</p>
<p>The brain does so with the help of serotonin transporters in the nerve terminal membrane. Like a vacuum cleaner, the transporters scoop serotonin molecules that haven’t bound to receptors and transport them back to the inside of the terminal for later use.</p>
<p><iframe id="tc-infographic-208" class="tc-infographic" height="400px" src="https://cdn.theconversation.com/infographics/208/c9155b6de068ee8db5f479e346142000b4e92dd2/site/index.html" width="100%" style="border: none" frameborder="0"></iframe></p>
<p>SSRI drugs work by getting stuck inside the vacuum hose so unbound serotonin molecules can’t be transported back into the terminal. </p>
<p>Because more serotonin molecules are then hanging around receptors for longer, they continue to stimulate them. </p>
<p>We can crudely say the extra serotonin moderately turns up the volume of the signal to enhance positive mood. But the actual way this has an effect on depression and anxiety is far more complicated.</p>
<p>Around 40% of all medicinal drugs target just one superfamily of receptors – the <a href="https://theconversation.com/the-2012-nobel-prize-in-chemistry-what-are-g-protein-coupled-receptors-10101">G-protein coupled receptors</a>. There are variations on these drug mechanisms, including partial agonists and ones that act like antagonists but slightly differently. Overall though, a lot of drugs actions fall into the categories described above.</p><img src="https://counter.theconversation.com/content/48665/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>MacDonald Christie receives funding from the National Health and Medical Research Council of Australia</span></em></p>Have you ever wondered how the small white ibuprofen pill turns off your headache? Or how a regular antidepressant keeps your brain chemistry in balance?MacDonald Christie, Professor of Pharmacology, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/443582015-07-09T00:09:55Z2015-07-09T00:09:55ZPregnant women taking antidepressants shouldn’t panic about birth defect claims<figure><img src="https://images.theconversation.com/files/87722/original/image-20150708-31567-bgtl8s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Women planning a family who abruptly stop using antidepressants may be putting themselves in harm's way.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/lastyearsgirl_/3775445831/in/photolist-6KC9vD">Lis Ferla/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>No one in the world has greater proscriptions on her behaviour than a pregnant woman in the developed world. And <a href="http://www.bmj.com/lookup/doi/10.1136/bmj.h3190">research published today in the BMJ</a> – and the mass of media coverage it will inevitably inspire – will add a new and potentially dangerous rule to the list.</p>
<p>The commotion I’m expecting is based on a study that suggests a link between a common class of antidepressants, known as selective serotonin re-uptake inhibitors (SSRIs), and birth defects. These findings are not new. </p>
<p>For almost a decade now, we’ve known about <a href="http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152062.htm">the potential association between paroxetine</a>, a member of this drug class, and a slightly increased risk of minor heart defects in children when mothers in first trimester use this drug. But women suffering depression and hoping to start a family may face a <a href="http://www.ncbi.nlm.nih.gov/pubmed/15811496">greater harm if they abruptly stop taking their antidepressants</a>. </p>
<h2>A difficult test</h2>
<p>The potential for congenital effects from drug exposure in pregnancy has concerned the general public <a href="http://www.sciencedirect.com/science/article/pii/S0140673661909278">since the early 1960s</a>, when <a href="http://www.abc.net.au/radionational/programs/drawingroom/the-shocking-thalidomide-cover-up/6569442">thalidomide was found to cause limb defects</a>. We now tend to look for <a href="http://www.ncbi.nlm.nih.gov/pubmed/2228814">a causal drug</a> every time a woman bears a child with some form of congenital anomaly, and forget that there’s actually a background rate of children who will be born with a defect of some kind. In fact, between <a href="https://npesu.unsw.edu.au/sites/default/files/npesu/surveillances/Congenital%20anomalies%20in%20Australia%202002-2003.pdf">two and four Australian women for every 100</a> will bear a child with a minor or major birth defect. </p>
<p>This BMJ paper, no doubt unintentionally, plays to the fears raised by the thalidomide case. If you just read the abstract or try to work through its elegant statistical analysis, it’s tempting to accept the results from a paper published in a highly regarded journal at face value. And its central claim is clearly sensational enough for the media to cover the research in good faith, even though the story may promote fear in a relatively vulnerable group of women. </p>
<p>But there are not only key flaws in this study. Similar birth registry studies that suggest a causal association between this class of antidepressants and birth defects are also problematic. Let me explain why.</p>
<p>The best way to scientifically determine a causal association between a drug and an adverse outcome is to run a controlled randomised trial with one group receiving the drug and a similar group not receiving it. But it’s ethically not appropriate to do this with pregnant women. </p>
<p>Instead, we have to rely on research where we observe outcomes of people with a common characteristic – pregnant women taking antidepressants, for instance – over time (cohort studies). Or studies that identify two existing groups of people with a differing outcome, and compare them on the basis of some supposed causal attribute (case control studies). Such studies examine data to find possible “red flags”. </p>
<p>But research like this is open to misinterpretation because it’s impossible to account for all the causes of an effect. If I said there was an association between “number of churches” in a city and its “crime rate”, for instance, you would rightly be sceptical. But if I swapped “number of churches” to “city size”, and could still draw the same graph, only one of these associations is likely to be true. The problem with epidemiological research like this is that there could be any number of causes contributing to an observed effect. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=465&fit=crop&dpr=1 600w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=465&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=465&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=584&fit=crop&dpr=1 754w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=584&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=584&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
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</figcaption>
</figure>
<p>A number of maternal diseases, such as diabetes and epilepsy, may increase birth defect rates, as can untreated depression. Indeed, babies born to women with untreated depression are at <a href="http://aje.oxfordjournals.org/content/157/1/14.full.pdf+html">risk of prematurity</a>, low birth weights and <a href="http://www.ncbi.nlm.nih.gov/pubmed/11573032">cognitive or behavioural difficulties</a>. Untreated depression also has other <a href="http://www.ncbi.nlm.nih.gov/pubmed/15633850">adverse maternal outcomes</a>, such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/15339755">developing postpartum depression and suicidality</a>, increased <a href="http://www.ncbi.nlm.nih.gov/pubmed/15339755">risk of hospital admission and pregnancy complications</a>, including <a href="http://www.ncbi.nlm.nih.gov/pubmed/10725477">pre-eclampsia</a>.</p>
<p>Importantly, in the BMJ study, pregnant women with depression taking SSRIs in early pregnancy were not compared with untreated pregnant women with depression in early pregnancy. In fact, women with depression, anxiety, bipolar disorder or obsessive compulsive disorder but not reporting any antidepressant use were excluded from the study. This means that we don’t have a true baseline risk from which we can compare a possible increased risk from SSRI use in pregnancy. </p>
<h2>True testing</h2>
<p>For a drug to be a “proven” cause of birth defects, <a href="http://trove.nla.gov.au/work/21362667?selectedversion=NBD193939">several criteria must be met</a>. It must:</p>
<ol>
<li> Produce deformities in more than 2% to 4% of mothers exposed (that is, the incidence rate must be higher than baseline); </li>
<li> Produce a consistent pattern of deformities; </li>
<li> Be given in sufficient dosage (as this adverse effect is dose-related effect); </li>
<li> Be given at the precise moment the vulnerable fetal body organ is forming. Once the organ has formed, the fetus is at no greater risk from the drug than a child or an adult.</li>
</ol>
<p>Much of this information is not accessible in data collected from pregnancy registries, which is what most studies rely on.</p>
<p>Where does this leave our now anxious woman who is taking an antidepressant and planning a pregnancy or already pregnant? She needs to have a frank and open discussion with her prescriber about the true benefits and risks of her antidepressant medication in pregnancy. Together, they can make a shared decision on how best to proceed.</p>
<p>The BMJ study, together with many other registry studies, suggest that of the various drugs known as SSRIs, sertraline appears to have a reasonable safety track record for pregnancy outcomes. In fact, it’s fairly similar to that of mothers not taking an antidepressant. This would be a good first option for women of reproductive age and first-time users of antidepressants.</p>
<p>But it may not work for every woman. An alternative SSRI or an antidepressant from another class may be needed to control moderate to severe depression in non-responders. </p>
<p>Reputable publications have a duty of care to provide a lay explanation of how research that may invoke unnecessary anxiety or controversy should be interpreted by the general public. They need to clearly explain the limitations of such research in terms that can be easily understood by everyone. </p>
<p>If this had been done when the <a href="https://www.nhlbi.nih.gov/whi/">Women’s Health Initiative study</a>, which suggested hormone replacement therapy caused breast cancer, was first published in JAMA, we would not have had <a href="http://www.ncbi.nlm.nih.gov/pubmed/22612615">millions of women suffering</a> recurrence of their menopausal symptoms by unnecessarily abrupt withdrawal of their medication before seeking medical advice.</p>
<p>We don’t want this to happen too with SSRI antidepressants. Women should remember that the risk of having uncontrolled depression is greater for baby and her than the small absolute increased risk of birth defect that may be associated with specific antidepressants.</p><img src="https://counter.theconversation.com/content/44358/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Treasure McGuire 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>Research published today has found an association between commonly used antidepressants and birth defects. But pregnant women face greater harms from stopping their medication abruptly.Treasure McGuire, Senior Lecturer in Pharmacy, The University of QueenslandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/352942014-12-22T06:31:23Z2014-12-22T06:31:23ZProzac and PMS – how antidepressants could help with that painful time of the month<figure><img src="https://images.theconversation.com/files/67642/original/image-20141218-31021-5grmti.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">It's as much about what's happening in your brain. </span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-69017146/stock-photo-woman-holding-a-human-brain-model-against-white-background.html?src=kY5sajh9bsZ1IR08zwVXLw-1-30">Brain by Shutterstock</a></span></figcaption></figure><p>Already widely prescribed as antidepressants, SSRIs such as fluoxetine (the non-brand name for Prozac) have gained increasing acceptance over the past 20 years in the <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001396.pub3/abstract">treatment of premenstrual syndrome</a> (PMS). </p>
<p>Recent research has given us an idea of the way these drugs do this, which should pave the way to improved treatment.</p>
<p>SSRIs, short for selective serotonin re-uptake inhibitors, are thought to work <a href="http://www.nhs.uk/conditions/ssris-%28selective-serotonin-reuptake-inhibitors%29/Pages/Introduction.aspx">by increasing levels of serotonin</a>, a neurotransmitter that relays information between nerve cells in the brain. Once a message has been sent, serotonin is reabsorbed but SSRIs stop this from happening, leaving more of the chemical in the brain. As serotonin is linked to good mood it is extensively used to treat depressive and anxiety disorders.</p>
<p>In treating PMS, however, these drugs appear to do something else instead, <a href="http://onlinelibrary.wiley.com/doi/10.1111/bph.12891/abstract;jsessionid=846B7B910C5C2575A0AFFFB9518F511F.f04t01">inhibiting an enzyme</a> involved in the metabolism of the ovarian steroid hormone progesterone.</p>
<h2>Premenstrual disorders</h2>
<p>Most women have experienced some of the <a href="http://www.pms.org.uk/">symptoms of PMS</a>, which include irritability, anxiety, fatigue, sleep disturbance and an increased sensitivity to pain, as a normal part of their menstrual cycle. While about a quarter seek treatment for the more loosely defined <a href="http://www.ncbi.nlm.nih.gov/pubmed/12665391">premenstrual syndrome</a>, an estimated 5% of women experience <a href="http://www.sciencedirect.com/science/article/pii/S001502820900867X">a severe and debilitating form</a> called premenstrual dysphoric disorder (PMDD) during their reproductive years. </p>
<p>We know that PMS is caused by changes in ovarian hormone production during the menstrual cycle, in particular the approximately ten-fold rise in progesterone after ovulation, followed by a sharp fall in its secretion in the week before menstruation. Importantly, this rapid fall in ovarian progesterone secretion is accompanied by a <a href="http://www.ncbi.nlm.nih.gov/pubmed/12665391">decline in its metabolite allopregnanolone</a>, a steroid which acts as a potent sedative and tranquilising agent. </p>
<p>In other words, premenstrual women are undergoing withdrawal from the internal tranquiliser allopregnanolone. This is a major contributory factor in PMS.</p>
<h2>So how to treat it?</h2>
<p>If PMS is caused by cyclic ovarian activity, then one potential cure is to stop ovulation. Of course, this is what happens in pregnancy and one interesting idea is that <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211719/">PMS evolved to drive women away</a> from an infertile pair bond. </p>
<p>There are drugs which will also prevent ovulation but, if used over the long-term, they require additional therapy with synthetic hormones to replace the missing ovarian oestrogens and progesterone. Then there are contraceptive steroids that can suppress ovulation and cause <a href="http://www.ncbi.nlm.nih.gov/pubmed/12665391">some relief from PMS</a>, but symptoms can recur during the withdrawal bleed period. </p>
<p>Replacement therapy with progesterone is also problematic as this can <a href="http://www.sciencedirect.com/science/article/pii/S0301008213000671">worsen the symptoms</a> and <a href="http://www.ncbi.nlm.nih.gov/pubmed/7904330">make some patients drowsy</a>, probably because of the metabolism of progesterone into excessive amounts of the sedative allopregnanolone. </p>
<h2>The use of fluoxetine</h2>
<p>An ideal treatment for PMS would be a drug which slows the fall in allopregnanolone towards the end of the menstrual cycle. This appears to be how fluoxetine works. Treatment with fluoxetine and other SSRIs can increase the concentration of allopregnanolone <a href="http://www.pnas.org/content/93/22/12599.long">in rat</a> and <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670606/">mouse brains</a>, a response which can be seen within an hour and at doses lower than those required to inhibit the re-uptake of serotonin. Low doses of SSRIs can also increase allopregnanolone <a href="http://www.pnas.org/content/95/6/3239.long">in human brains</a>. </p>
<p>A recent study in <a href="http://www.sciencedirect.com/science/article/pii/S0924977X14003289">female rats</a> showed that low doses of fluoxetine which didn’t block the re-uptake of serotonin but did increase allopregnanolone in the brain, also prevented the development of PMS-like symptoms. Interestingly, they also blocked the increase in excitability of brain circuits mediating responses to fear.</p>
<h2>Fluoxetine acts on a biochemical switch</h2>
<p>The ovary and brain convert progesterone to allopregnanolone in two steps, both controlled by enzymes. In the first step, progesterone is converted into a steroid called 5α-dihydroprogesterone – an inactive precursor. The second step is regulated by a pair of enzymes, one of which transforms this precursor into allopregnanolone, while the other converts allopregnanolone back into the inactive precursor. So the level of allopregnanolone is controlled by the balance of these opposing activities – essentially, <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104102/">a biochemical switch</a>.</p>
<p>In rat brains, <a href="http://onlinelibrary.wiley.com/doi/10.1111/bph.12891/abstract;jsessionid=846B7B910C5C2575A0AFFFB9518F511F.f04t01">fluoxetine blocks the enzyme</a> that converts allopregnanolone back into the inactive precursor. It also has the same effect on the <a href="http://onlinelibrary.wiley.com/doi/10.1111/bph.12891/abstract;jsessionid=846B7B910C5C2575A0AFFFB9518F511F.f04t01">human enzyme</a>. So, fluoxetine should blunt the premenstrual fall in allopregnanolone.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/67130/original/image-20141212-6027-p301rx.JPG?ixlib=rb-1.1.0&rect=0%2C51%2C5733%2C3887&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/67130/original/image-20141212-6027-p301rx.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/67130/original/image-20141212-6027-p301rx.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/67130/original/image-20141212-6027-p301rx.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/67130/original/image-20141212-6027-p301rx.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/67130/original/image-20141212-6027-p301rx.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/67130/original/image-20141212-6027-p301rx.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Not seeing red.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-138992249/stock-photo-pms-premenstrual-syndrome-on-red-button-humorous-warning.html?src=6S8-Ob7K2GM8m7wjuMfPVg-1-1">PMS by Shutterstock</a></span>
</figcaption>
</figure>
<h2>Sex and age differences</h2>
<p>If fluoxetine elevates allopregnanolone in the brain in this way then we can understand why younger women of reproductive age, with regular fluctuations of allopregnanolone, <a href="http://www.ncbi.nlm.nih.gov/pubmed/10964861">are more</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/16012273">sensitive</a> to SSRIs than men, who produce continuous low levels of this steroid. </p>
<p><a href="http://onlinelibrary.wiley.com/doi/10.1111/bph.12891/abstract;jsessionid=846B7B910C5C2575A0AFFFB9518F511F.f04t01">This sex difference can be observed in rats</a>. Indeed, there is growing evidence from <a href="http://www.sciencedirect.com/science/article/pii/S0301008213000968">animal studies</a> that elevation of brain allopregnanolone may be an important part of the antidepressant response to SSRIs.</p>
<p>The elevation of allopregnanolone in the brain from only low doses of fluoxetine also explains why women with PMS respond so quickly – <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442940/">within two days</a> – to this drug. By contrast, full antidepressant responses to larger doses of fluoxetine which alter brain serotonin function <a href="http://www.oxfordmhf.org.uk/blog/2012/03/why-do-antidepressants-take-so-long-to-work/">can take up to two months</a>. </p>
<p>There is therefore a basis here for the treatment of PMS with low doses of SSRIs, given intermittently to reduce the side effects of these drugs, which include nausea, diarrhoea, anorexia, insomnia, tiredness and sexual dysfunction. The discovery of an <a href="http://onlinelibrary.wiley.com/doi/10.1111/bph.12891/abstract;jsessionid=846B7B910C5C2575A0AFFFB9518F511F.f04t01">allopregnanolone metabolising enzyme as a target</a> means that we can also hope for the development of more specific drugs for the treatment of PMS.</p><img src="https://counter.theconversation.com/content/35294/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Work in Jonathan Fry's laboratory was supported by UCL and the MRC.</span></em></p>Already widely prescribed as antidepressants, SSRIs such as fluoxetine (the non-brand name for Prozac) have gained increasing acceptance over the past 20 years in the treatment of premenstrual syndrome…Jonathan Fry, Senior Lecturer in Physiology, UCLLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/253452014-04-09T05:09:50Z2014-04-09T05:09:50ZProzac alters prawns’ behaviour, reproduction and even their colour<figure><img src="https://images.theconversation.com/files/45885/original/8gsqrqmb-1396981323.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Amphipods on anti-depressants found their lives brightened, right up until they were eaten.</span> <span class="attribution"><a class="source" href="http://commons.wikimedia.org/wiki/File:Talitrus_saltator_2c.jpg">Arnold Paul</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>The idea that tiny amounts of antidepressants present in our rivers and estuaries may be affecting aquatic life is generally met with surprise, sometimes scepticism, or even a degree of humour. </p>
<p>The public were first alerted to pharmaceuticals in the environment in the 1990s through <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1518861/">studies</a> which showed that synthetic oestrogens, such as in the contraceptive pill, could feminise male fish, even in incredibly low concentrations of nanograms per litre (ng/L). This led to concerns of a similar effect on <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1519860/">male human fertility</a>, although it’s been hard to draw any conclusions. </p>
<p>The idea that even tiny amounts of chemicals might dramatically alter the physiology of fish and other aquatic organisms isn’t that new. Back in the 1980s scientists were aware that concentrations even below 10ng/L of <a href="http://www.abc.net.au/environment/articles/2014/01/13/3916477.htm">tributyltin or TBT</a>, a compound used in anti-fouling paints for ships’ hulls, would cause female dog whelks (a sort of sea snail) to <a href="http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=4390216">grow a penis</a>. This resulted in catastrophic reproductive failure in females which wiped out snail populations along the world’s coasts, which had knock-on effects on organisms further up and down the food chain.</p>
<p>A more recent example is diclofenac, a non-steroidal anti-inflammatory drug given to lame cattle in India and Pakistan. While considered harmless to mammals, what was not predicted was that vultures preying on dead cattle would <a href="http://rspb.royalsocietypublishing.org/content/271/Suppl_6/S458">suffer catastrophic renal failure</a>, resulting in their populations <a href="http://www.nature.com/nature/journal/v427/n6975/full/nature02317.html">plunging by 90%</a>.</p>
<p>Some scientists have suggested that reduced vulture populations led to a boom in feral dog populations and an increase in rabies among the human population. <a href="http://www.theguardian.com/world/2004/apr/22/outlook.development1">Highly publicised</a>, this focused people’s attention on the toxicological impact of human and veterinary drugs on wildlife. </p>
<h2>Amphipods on anti-depressants</h2>
<p>So what’s the evidence that anti-depressants, now quite commonly prescribed medicines, are affecting aquatic wildlife? After all, studies have found that sewage effluent entering rivers can carry anti-depressants at concentrations up to around 1µg/l (one microgram, equal to 1000ng/L), although in most rivers the concentrations recorded are considerably less at around 10-20ng/L. There is growing evidence that even at these low concentrations of under 100ng/L medicines can cause changes in a wide range of biological functions and behaviours. </p>
<p>For example, many anti-depressants were designed to modulate serotonin. Serotonin is a hormone that is found throughout the animal kingdom and is known to play a role in controlling <a href="http://www.ncbi.nlm.nih.gov/pubmed/24374179">behaviour, growth, metabolism, reproduction, colour, and the immune system</a>.</p>
<p>At the <a href="http://www.port.ac.uk/school-of-biological-sciences/facilities/institute-of-marine-sciences/">Institute of Marine Sciences</a> in the University of Portsmouth we <a href="http://dx.doi.org/10.1016/j.aquatox.2010.05.019">published an article</a> in 2010 that demonstrated that serotonin in amphipods, a crustacean rather like a tiny prawn, was responsible for controlling their preference to seek light or dark areas. </p>
<p>As amphipods high in serotonin preferred light areas, would anti-depressants such as fluoxetine (Prozac) have the same effect? We found that a few weeks’ exposure to 10-100ng/L of fluoxetine – about the level found in rivers around urban areas – resulted in a five times greater preference for light.</p>
<h2>Many effects on many creatures</h2>
<p>A <a href="http://www.sciencedirect.com/science/article/pii/S0166445X14000551">special edition</a> of the journal Aquatic Toxicology has pooled together studies of antidepressants in the aquatic environment. The most striking results suggest that many species, including fish, snails, bivalves, cuttlefish and crustaceans, are affected by anti-depressants even in low concentrations. The observed effects include altered swimming and behaviour patterns, locomotion, immune function, reproduction, feeding and predator behaviour through to gene expression – even a physical change of colour. There appears to be considerable variability between the species affected.</p>
<p>Despite these findings however, there is no evidence that these particular pharmaceuticals have the same effects in the wild as all studies to date have been laboratory studies. While it’s relatively easy to determine whether a fish has had past exposure to, for example, an oestrogenic chemical, it’s currently very difficult to determine abnormal behaviour from exposure to antidepressants. Others have <a href="http://dx.doi.org/10.1016/j.aquatox.2013.11.021">expressed caution</a>, suggesting that these studies must be repeated at other laboratories and rigorous measurements must be taken on the exposure concentrations used in the laboratory experiments. </p>
<p>There are other factors to consider too: while the crustaceans exposed to serotonin showed a preference for light, some of the species studied also carry parasites which have evolved to alter their host’s serotonin precisely so that they swim in open areas. This makes them more vulnerable to being eaten – the ultimate goal of the parasite, for whom the crustacean is merely an intermediate step towards entering the predator’s body where it completes its lifecycle.</p>
<h2>Medicines, medicines, everywhere</h2>
<p>This isn’t just about anti-depressants. We consume hundreds of different types of medication every day and they all appear to some extent in sewage effluent. Even the most modern, most costly sewage treatment processes still aren’t able to filter out all chemical contaminants.</p>
<p>The question of “greener” pharmaceuticals that break down more readily into harmless chemicals has been suggested, but this may prove incredibly difficult to achieve given they are formulated specifically to work optimally in the human (or animal) body. Some countries are strongly debating the need for national <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866706/">take-back programs</a> whereby unused medication is collected and appropriately disposed.</p>
<p>I expect the next few years will strengthen the evidence that anti-depressants and other biologically active compounds are pollutants of concern, in which case they will join a long list of chemicals, including industrial pollutants such as sulphur and lead, whose effects on health were scientifically established and regulations passed to protect human and environmental health.</p><img src="https://counter.theconversation.com/content/25345/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Alex Ford receives funding from the Natural Environment Research Council (NERC) & EU Interreg program (PeReNE) to study reproductive and neuro-endocrine disruption in crustaceans.</span></em></p>The idea that tiny amounts of antidepressants present in our rivers and estuaries may be affecting aquatic life is generally met with surprise, sometimes scepticism, or even a degree of humour. The public…Alex Ford, Reader in Biology, University of PortsmouthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/117882013-01-24T19:57:55Z2013-01-24T19:57:55ZAre antidepressants over-prescribed in Australia?<figure><img src="https://images.theconversation.com/files/19592/original/w6txmc29-1358999171.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Antidepressant prescribing has been increasing in most developed countries since the the late 1980s and early 1990s.</span> <span class="attribution"><span class="source">PrettyPills/Flickr</span></span></figcaption></figure><p>The British Medical Journal (BMJ) has just published two opposing views on the vexed question of whether antidepressants are being over-prescribed. The issues raised by debate are by no means unique to the United Kingdom; increasing rates of antidepressant prescribing are apparent in most developed countries, including Australia.</p>
<p>The BMJ discussion was precipitated by <a href="https://catalogue.ic.nhs.uk/publications/prescribing/primary/pres-disp-com-eng-2001-11/pres-disp-com-eng-2001-11-rep.pdf">recent UK prescribing data</a>, which reported a 9.6% increase in antidepressant prescriptions in 2011 – the largest increase in prescriptions of all medication classes for that year.</p>
<p>Arguing that the figures indicated over-prescribing, general practitioner <a href="http://www.bmj.com/content/346/bmj.f191">Des Spence writes</a>, “I think that we use antidepressants too easily, for too long, and that they are effective for few people (if at all).” </p>
<p>In the opposing camp, professor of psychiatry <a href="http://www.bmj.com/content/346/bmj.f190">Ian Reid contends</a>, “Given recent demonstrations that depression is still under-recognised and under-treated, the claim that antidepressants are over-prescribed needs careful consideration.”</p>
<h2>Situation in Australia</h2>
<p>A <a href="http://www.ncbi.nlm.nih.gov/pubmed/23144164">recent report</a> on prescribing patterns of antidepressants and other psychotropic medications (drugs for mental illnesses) has aroused similar controversy in the local media. The study’s authors reported a 58.2% increase in the dispensing of psychotropic drugs over the period from 2000 to 2011, including a 95.3% increase in antidepressants. </p>
<p>Echoing the argument that antidepressants are being over-prescribed, the authors raised concern about “ … the dramatic increase in antidepressant prescriptions despite questions about the efficacy of these drugs in mild to moderate depression.”</p>
<p>These recent UK and Australian data are not surprising; they are consistent with the major increase in antidepressant prescribing that’s been occurring in most developed countries since the introduction of the SSRI (selective serotonin reuptake inhibitor) antidepressants in the late 1980s and early 1990s.</p>
<h2>An international trend</h2>
<p>In 2000, <a href="http://www.ncbi.nlm.nih.gov/pubmed/11149300">my colleagues and I wrote</a> one of the first major reports of this global trend. We found an approximately threefold increase in antidepressant prescribing in Australia from 1990 to 1998. The increase reflected what was occurring in most major Western countries and coincided with the widespread introduction of SSRI antidepressants such as Prozac, Zoloft, Aropax and Cipramil during that period. </p>
<p>In a <a href="http://www.ncbi.nlm.nih.gov/pubmed/15462638">another paper</a>, we examined a longer timeframe (1975 to 2002) finding a 1.1% annual increase in antidepressant prescribing from 1975 to 1990, an acceleration to 29% in 1995, then a slowing down to 6.6% in 2002. </p>
<p>There’s no doubt there’s a continuing increase in the use of antidepressants in developed countries such as Australia and the UK, in the range of between 6% and 9% annually. The critical question, though, is whether this substantial increase in prescribing is justified at both a national public health and the individual clinical level.</p>
<h2>Benefit or harm?</h2>
<p>In Australia, we are able to look at the question of benefit or harm by examining national epidemiological and suicide data. </p>
<p>In terms of <a href="http://www.ncbi.nlm.nih.gov/pubmed/19530018">adequacy of depression treatment</a>, a 2007 national survey found that 6.2% of individuals had experienced a mood disorder (mainly depression) over the prior 12 months, but over half (51.2%) did not access any services for mental health problems in that time. This indicates a substantial unmet treatment need for depression, rather than over-treatment. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/19596/original/2yfvpgwb-1359000758.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/19596/original/2yfvpgwb-1359000758.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/19596/original/2yfvpgwb-1359000758.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/19596/original/2yfvpgwb-1359000758.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/19596/original/2yfvpgwb-1359000758.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/19596/original/2yfvpgwb-1359000758.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/19596/original/2yfvpgwb-1359000758.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">
<figcaption>
<span class="caption">It’s important to consider whether the increase in prescribing is justified at both a national public health and the individual clinical level.</span>
<span class="attribution"><span class="source">Erin DeMay</span></span>
</figcaption>
</figure>
<p>While it’s not possible to identify rates of antidepressant prescribing, as such, from the survey, the <a href="http://www.ncbi.nlm.nih.gov/pubmed/19530016">rate of use</a> for psychological services was 23.2% for those with a mood disorder. This is a substantial increase from the 11.8% in an analogous 1997 survey, suggesting that doctors were readily utilising psychological services via Commonwealth-funded schemes such as <a href="http://www.health.gov.au/internet/main/publishing.nsf/content/mental-ba">Better Access</a>. </p>
<p>Overall, these data do not indicate that there’s over-prescribing of antidepressants in Australia.</p>
<h2>Antidepressants and suicide</h2>
<p>A second potential measure of the value or otherwise of this increase in antidepressant use is its impact on suicide rates. </p>
<p>We <a href="http://www.ncbi.nlm.nih.gov/pubmed?term=mant%20mitchell%20suicide%20antidepressant%20bmj">examined this question</a> in 2003, and found there was a significant correlation between changes in antidepressant prescribing rates from 1991 to 2000 and the rates of suicide. We also found that people in age and gender groups with increased rates of prescribing demonstrating lower suicide rates. </p>
<p>This same finding has also been reported in the United States and Scandinavia, indicating that greater rates of effective treatment for depression in a population have a significant impact on suicide. </p>
<p>We interpreted our findings broadly – that effective treatment of depression, whether by medication or psychological treatment can lead to a measurable benefit (here a fall in suicide rates), even at a whole population level.</p>
<h2>Issues around effectiveness</h2>
<p>Another issue raised in the BMJ debate is the current state of knowledge about the effectiveness of antidepressants for those with mild depression – the most common form in the community. Unfortunately, current evidence is inconsistent and dependent on the methodology used by researchers. </p>
<p>A highly publicised <a href="http://www.ncbi.nlm.nih.gov/pubmed/18303940">2008 meta-analysis</a> of published and unpublished antidepressant trials found that only those with severe levels of depression benefited more from antidepressants than a placebo. </p>
<p>But a <a href="http://www.ncbi.nlm.nih.gov/pubmed/22393205">recent report</a> examining longitudinal data from individual patients in a series of large antidepressant trials found no relationship between likelihood of benefit from antidepressants and the initial severity of depression. In other words, patients benefited at similar rates independently of how severely depressed they were. </p>
<p>These inconsistent findings indicate the jury is still out on whether those with mild depression benefit from antidepressants.</p>
<h2>What to make of it all?</h2>
<p>So, where does this leave us in determining whether current rates of antidepressant prescribing are excessive? While rates of prescribing are undoubtedly increasing, data from national surveys suggest continuing high rates of untreated depression as well as increased use of psychological services. And, as discussed above, findings from a number of developed countries, including Australia, indicate the public health benefit of reduced suicide rates.</p>
<p>Still, we must remain vigilant in monitoring such prescribing and avoid mindless use of antidepressants, particularly for milder levels of depression where psychological treatments are probably more appropriate.</p>
<p><em>If you think you may be experiencing depression or another mental health problem, please contact your general practitioner or in Australia, contact <a href="http://www.lifeline.org.au/">Lifeline</a> 13 11 14 for support, <a href="http://beyondblue.org.au/index.aspx?">beyondblue</a> 1300 22 4636 or <a href="http://www.sane.org/">SANE Australia</a> for information.</em></p>
<p><strong>This is the sixth and final article in our short series on depression. Click on the links below to read the other articles:</strong></p>
<p><strong>Part one –</strong> <a href="https://theconversation.com/explainer-what-is-depression-11447">Explainer: what is depression?</a> </p>
<p><strong>Part two –</strong> <a href="https://theconversation.com/treating-depression-ethically-requires-more-than-drugs-8997">Treating depression ethically requires more than drugs</a></p>
<p><strong>Part three –</strong> <a href="https://theconversation.com/predicting-the-risk-of-depressive-disorder-promises-and-pitfalls-1097">Predicting the risk of depressive disorder – promises and pitfalls</a></p>
<p><strong>Part four -</strong> <a href="https://theconversation.com/the-science-of-interpreting-common-symbols-in-dreams-10732">The science of interpreting common symbols in dreams</a></p>
<p><strong>Part five –</strong> <a href="https://theconversation.com/genetic-testing-for-depression-creates-an-ethical-minefield-7644">Genetic testing for depression creates an ethical minefield</a></p><img src="https://counter.theconversation.com/content/11788/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Philip Mitchell receives funding from the Australian National Health and Medical Research Council.</span></em></p>The British Medical Journal (BMJ) has just published two opposing views on the vexed question of whether antidepressants are being over-prescribed. The issues raised by debate are by no means unique to…Philip Mitchell, Scientia Professor & Head of the School of Psychiatry, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.