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You might have seen the recent headlines. The Sun: The Mirror: Millions taking antidepressants ‘must be warned of dangerous side effects’ The Times: Antidepressants are effective but their use needs to be rationed and monitored The Guardian: I know antidepressant withdrawal symptoms are real. Why didn’t doctors? This news reflects a recently published document from the UK Royal College of Psychiatrists, the professional body responsible for education, for training, and for setting and raising standards in psychiatry. This Position Statement on Antidepressants and Depression describes a range of actions to promote optimal use and management of antidepressants, including, most notably, an updated appraisal of the risk of antidepressants ‘addiction’, i.e., the difficulty that some people have in stopping antidepressants because of ‘withdrawal’ symptoms experienced when they stop these drugs. The document is 29-pages long and you can read it here. Or you can read this blog: an enriched summary — enriched with my personal experience as a psychiatrist and extracts from other clinical guidelines, such as the 2018 Maudsley Prescribing Guidelines. Are antidepressants addictive? If you have ever had problems with tobacco, alcohol, opioids or other street drugs, you will know that taking such substance gives immediate pleasure, gratification and reward. Addictive substances are ‘mood-changing’. This is why people seek them out. Now, if you have ever taken an antidepressant, you know that there is no immediate pleasure. In fact, the only immediate effects of antidepressants are usually the adverse effects, such nausea, diarrhoea or increased agitation. In this sense, antidepressants are not addictive. Moreover, people can become ‘dependent’ on tobacco, alcohol, opioids or other street drugs, as they develop a compulsive desire to take the substances, and have difficulty controlling their use, despite evidence of harm. Again, people do not experience such a compulsive desire to take antidepressants. However, addictive substances have one important characteristic that can also be present with antidepressants. After you have taken the substance regularly, you suffer when you stop it, not only because you are missing the pleasurable effects, but because your body and brain now ‘require’ the substance, and you feel unwell if you do not take it. When you stop, you suffer from withdrawal symptoms. You go ‘cold turkey’. And antidepressants can do this. Not all antidepressants. Not in all patients. But some antidepressants can be very difficult to stop, for some patients. As the statement says, ‘Whilst the withdrawal symptoms which arise on and after stopping antidepressants are often mild and self-limiting, there can be substantial variation in people’s experience, with symptoms lasting much longer and being more severe for some patients.” This is what this blog is about. What do antidepressants withdrawal symptoms feel like? There are many types of symptoms, and not all patients experience all of them. Typical symptoms are: flu-like symptoms (shivering, excessive sweating, headache, nausea, vomiting); ‘shock-like’ sensations (brain zapping, as described by patients); insomnia and vivid dreams; irritability and crying spells; dizziness; and occasionally, movement problems and decreased concentration and memory. They usually start abruptly and within a few days of stopping the antidepressants. Thus, they are different from a return of the original anxiety and depression for which the antidepressants were prescribed in the first place, which is more gradual and can take weeks or months to reappear. The percentage of patients reporting withdrawal symptoms varies a lot in between studies, also because different antidepressants have different risk of withdrawal symptoms. An analysis of many studies, some including patients’ surveys– which may not be representative of the entire population of people taking antidepressants — find that more than half of patients who stop or reduce antidepressants experience withdrawal symptoms, with almost all of them reporting severe symptoms, and a significant proportion experiencing symptoms for several weeks, months, or longer. A stricter analysis only of studies that have a ‘placebo’ comparison– believe it or not, people can have withdrawal symptoms even when stopping an inert, dummy pill — brings the proportion of people who experience withdrawal symptoms at around 40%, with various levels of severity, from mild and self-limiting to prolonged and severe. In any case, it is a relevant proportion of people taking antidepressants. It is more than we used to think. And it is a good thing that new scientific evidence and patients’ voices have prompted the statement from the Royal College. And this blog. So, how can you minimise the risk of antidepressant withdrawal symptoms? First, do not take antidepressants unless you really need to take them. Most people who go through a difficult time in their lives should not be prescribed antidepressants. They should rely on the support of friends, family and the wider social support when going through a crisis. And, if they need professional help for coping, they should access psychological therapies first. In many countries, psychological therapies are rarely available in the public health services, but in the UK they are– another jewel in our NHS crown. Antidepressants should only be prescribed for people who suffer from clinical depression of significant intensity. These are people who have been suffering from sadness, tiredness, lack of hope and motivation, and thoughts about death, every day, for weeks or months. And who have a reduced quality of life because of their depression: they have stopped working; they no longer have social relationships; they have used more alcohol than before; they have been thinking about, or planning how, taking their own lives. Second, you should only take the antidepressants for as long as you need them, and not longer. Accepted clinical guidelines indicate that, for people who take an antidepressant for the first time, or only sporadically throughout their life, these drugs should be taken for a maximum of 6 to 9 months after people have started to be well again. Longer treatments, for 1–2 years or more, are only appropriate if there have been multiple, frequent and severe phases of depression. The decision to continue on an antidepressant should be regularly reviewed in discussion with the doctor. Third, if you decide to stop, do so slowly, and with the support of your doctor. People should never stop an antidepressant abruptly and without consulting their doctor. The dose should be reduced gradually, and the current advice of reducing and stopping over four weeks should be considered the minimum time, provided it is tolerable for the patient, but not the rule for everybody. For some people, it may be necessary to reduce over several months, especially if they have taken the antidepressants for years. The slower reduction should be toward the end, because this is when the proportional reduction of the dose is bigger. Of course, not everybody will experience the withdrawal symptoms in their more severe form. Longer duration of treatment, as mentioned above, and higher doses, increase the risk of severe withdrawal symptoms. Some antidepressants increase the risk more than others (for example, paroxetine, venlafaxine, amitriptyline, imipramine, all MOAIs). Children and adolescents are at a higher risk of severe withdrawal symptoms (and they should only receive antidepressants under the care of a specialist psychiatrist). People who are taking other medications affecting the brain (antihypertensive, antihistamine, antipsychotics) are a higher risk. People who experience a worsening of anxiety symptoms at the start of an antidepressant are a higher risk. And if you have experienced withdrawals symptoms when stopping an antidepressant before, you are likely to experience them again. If the symptoms do develop and cannot be tolerated, or do not improve spontaneously over 1–2 weeks, then there are steps that can be taken. The doctor should re-start the same antidepressant (or another antidepressant that is less likely to induce withdrawal symptoms) at the last dose before the withdrawal symptoms occurred, and the reduction should be slowed down. Slowed right down. What does the future hold? As the College statement says, ‘Depression is a condition that can affect people differently and cause a wide variety of distressing symptoms. It can lead to relationship and family breakdown, increase the likelihood of drug or alcohol addiction, reduce the ability to overcome serious illness and increase mortality rates — not just from the risk of suicide.’ Antidepressants are a recommended therapeutic option. And they do work — in fact they are more effective than many medications used for physical health problems (for example, than some drugs routinely prescribed for hypertension and chronic heart failure). But of course, we do need to understand more about these drugs. About ‘personalizing’ antidepressant treatment, in order to choose the antidepressant which is more likely to work best for an individual patient, or least likely to induce side effects. And, of course, as discussed here, we need to understand the best antidepressants to minimize the severity and duration of withdrawal symptoms. But we should not dismiss this important therapeutic tool, nor judge it more harshly than we judge other medications for physical disorders. Otherwise, we are simply perpetuating the stigma about mental health problems: not needing medications because they are ‘not real’ and are ‘all in the mind’. Disclaimer: My research work, and the work of our research group, is funded mostly by the UK National Health Service, and other governmental and charitable organisations. We also receive some research funding from pharmaceutical companies interested in the development of medications for depression; however, this blog, and similar blogs we post on these topics, are completely independent, and only based on the best scientific and clinical evidence.

The latest edition of the Diagnostic and Statistical Manual (DSM), a handbook used by healthcare professionals to diagnose mental illnesses, featured several new disorders. One was Gambling Disorder, the first and only behavioural addiction currently included in the manual. It was included on the basis that gambling activates the same parts of the brain as drugs like cocaine (specifically, parts of the brain related to reward and motivation). However, calls from the scientific community to recognise overeating as an addictive disorder were not applied, sparking controversy and debate amongst researchers. The idea of food being addictive is not a new one. In 1890, the word “addiction” was first used scientifically in one of the earliest medical journals on this topic (The Journal of Inebriety), in reference to chocolate. The term “food addiction” was later coined by Theron Randolph in 1956 but remained fairly unexplored in the following years. However, driven by rising rates of obesity and concern over the associated health and economic costs, the last decade has seen a rapid increase in interest in food addiction amongst scientists, the media and the public. As a relatively young field of research, many questions about food addiction remain unanswered: Can overeating become an uncontrollable medical condition? Is there enough evidence to include it as a mental disorder in the DSM? And if so, what are the potential consequences of such an important decision? What is the evidence for Food Addiction? Addiction? “My drug of choice is food. I use food for the same reasons an addict uses drugs: to comfort, to soothe, to ease stress.” — Oprah Winfrey To be diagnosed with an addictive disorder you must meet the following criteria: i) impaired control — difficulty controlling your use of the substance, ii) social impairment — experiencing social problems due to the addiction, iii) risky use — continuing to use the substance despite physical or mental health problems (or both),and iv) pharmacological criteria — such as withdrawal symptoms (symptoms like sweating or shaking as a result of stopping opioids suddenly). These have been shown in animal models in relation to foods high in fat or sugar. One study found that rats were willing to tolerate painful foot shocks to acquire a supply of Oreo cookies, which was interpreted as evidence of risky use. Other studies have documented intense withdrawal symptoms, such as teeth chattering, head shaking, anxiety and aggression shortly after a diet high in sugar was removed. In humans, the evidence is less clear. There is plenty of evidence from online forums and clinical case studies showing signs of craving, lack of control and withdrawal in people trying to cut down on processed food such as bread, sweets and crisps. But this type of evidence can be subjective and is often based on small numbers of participants. Scientists need much more than this to prove that food addiction exists. “Over the years, I needed to consume more calories for longer periods to achieve the same sense of control, emotional numbness, and euphoria” — Hansen (2016) More recently, scientists have shown that the same brain areas are activated by drugs like alcohol, cocaine, heroin and by processed foods. These are brain areas involved in reward, motivation, stress and self-control. Of course, we expect some overlap in brain areas relevant to both food and pleasure, but there is more and more evidence suggesting that they share brain processes which, when hijacked, result in binging and loss of control. One such brain imaging study found that individuals who tend to score higher on a specific scale that measures “food addiction” (for example, that eat to the point of feeling physical ill or that avoid professional or social situations where certain foods are available for fear of overeating) have increased activity in reward and motivation parts of the brain when they were told to expect a chocolate milkshake, and decreased activity in self-control parts of the brain when actually given the chocolate milkshake to drink. Interestingly, this can be found in both people of normal weight and with obesity. So if evidence shows that processed food activates the same reward and motivational parts of the brain as drugs and gambling do, why has food addiction not been officially recognised yet? Critics of food addiction argue that food is necessary for survival and therefore cannot be addictive. But think for a moment about water, a substance that is essential for survival. Water can become addictive when certain ingredients are added. Beer, for example, can be up to 97% water but becomes an addictive substance when ethanol is added. Supporters of the notion that food addiction does exist are not arguing that foods such as vegetables are addictive. It is the refined ingredients such as sugar and fats, specifically added to processed food, that make the food addictive. A recent BBC documentary “Why are we getting so fat?” featuring Dr Giles Yeo, a geneticist from Cambridge University, emphasises the importance of studying combinations of nutrients that do not occur naturally, but when combined can “pack a punch” to brain motivation circuits and change our normal eating behaviour. Yeo quotes a study where food items that containedbothfat and carbohydrate were valued more highly than food items high in just fat or carbohydrate alone. These “double-whammy” food items also had a greater effect on brain reward areas than the food items that were high in just fat or carbohydrate alone. It might seem obvious to some people that foods high in carbohydrates and fat would be more addictive, but as a recent Guardian article noted there is a certain hysteria surrounding food in today’s mainstream media. On a daily basis, we are bombarded with contradictory advice about what to eat and what not to eat. It is no wonder than many of us feel alienated and confused. A task for future research will be to work out exactly which combinations of nutrients have the potential to become addictive and to communicate this in a clear way to the public. What would be the potential repercussions of including food addiction in the DSM? Classifying overeating as an addiction would have far-reaching effects. It will undoubtedly impact public health, healthcare provision, economics, public opinion and governmental policy. Valuable lessons can be learned from looking back at the history of the tobacco industry. For many years the tobacco industry framed smoking addiction as a problem of self-control, blaming individuals rather than the companies supplying the cigarettes. Person-centered treatments, where the individual addicted to smoking was helped in finding their way of reducing or stopping, were the only accepted approach for a long time. This was before any effective policy interventions were considered due to lobbying from smoking companies. Luckily, things have changed now. Smoking rates in the UK are at an all-time low because of population-level changes to taxation, shop displays and laws on smoking indoors. Currently, much of society blames individuals with obesity for their excess weight, with common misunderstandings that individuals with obesity are entirely responsible for their condition. This mirrors what happened to smokers 50 years ago. These views are prevalent and exist even in those making critical decisions for the health of the UK. In a recent speech Health Secretary, Matt Hancock, said the following: “Prevention is about ensuring that people take greater responsibility for managing their own health. It’s about people choosing to look after themselves better…making better choices by limiting alcohol, sugar, salt and fat.” However, if the concept of food addiction is given support, we may see a shift towards more balanced, society-wide approaches to tackling the population’s diet. We have to make it easier for people to make healthy choices, across all social classes. Ideally, the price of processed foods should increase, the price of fresh, healthy produce should be subsidised, and advertising should be regulated more. Moreover, we could hope to see a reduction in weight-related discrimination targeted at individuals who are overweight or living with obesity, which would actually have positive consequences not only for their mental health, but also for their weight loss and maintenance of weight loss over time. However, not everybody shares this view. Opposing researchers theorise that it could offer individuals an excuse for unhealthy eating patterns and worsen the problem of obesity. Also, we could see the food industry try to contest research or block policy reforms, as has already occurred in the US with regard to menu labeling and restriction of junk food in schools. The food industry may also begin more aggressive marketing in developing countries, where laws are more relaxed (a trend we are already beginning to see). This issue will continue to be debated. As the field of food addiction moves into unknown territory, it important to truly understand if advocating a diagnosis of “food addiction” will have a more harmful or more beneficial net impact on health. Research, and more evidence, are urgently needed. The decision about this important question should not be left to the strongest lobbiers, it should be based on the populations’ health and wellbeing. We will need to work with the government and food producers to achieve this.

An overview of the biological link between cancer and depression (and how to win the chess match against them both). There is a silent but brutal accomplice to cancer, which dramatically affects the lives of those who are affected. Depression frequently co-occurs in cancer cases. But it is not just due to the emotional distress of having a life-threatening disease. A common biological mechanism seems to underpin this comorbidity. A recent article by our group reviewed the scientific literature on the link between cancer and depression, highlighting the effect of this common biological mechanism: inflammation, and a specific aspect of inflammation called the ‘kynurenine pathway’. Here I will take cues from our paper to explore the reasons behind this comorbidity and the clinical implications of this intricate chess match between us — patients, clinicians, and researchers — and the combined force of cancer and depression. Cancer and Depression Cancer patients are a population at high-risk for the development of depression, with overall higher prevalence rates than those observed in the general population. Cancer, with all its more than 100 subtypes, could affect almost every part of the body, with different symptoms and prognoses. It is often unpredictable, sometimes rapidly lethal, and the therapies are highly invasive and not always effective. Its potential to invade the whole body, along with the visible signs of the illness and the challenging treatments, contribute to the ever-lasting fears about it. It’s quite clear to everyone that receiving a diagnosis of cancer could be enough to feel down and to lower your mood. However, not every person diagnosed with cancer is clinically depressed, that is, has a clinical condition that is more than being sad and worried about one’s health status. The detrimental effects of these two diseases — cancer and depression — do add up, especially when they occur together, impacting the life of those who are affected, and of their relatives. The role of inflammation and implications for treatment In the last few decades, we have understood more about the role of inflammation in the pathophysiology of both cancer and depression. Inflammation is, on a basic level, a response of our body to potential threats (such as illnesses), that involves the activation of the immune system. Cancer is associated with immune abnormalities, and inflammation is pivotal in cancer development. Inflammation is also caused by cancer therapies, especially chemotherapy, in an often-unfavourable alliance between cancer and its treatment. Depression is also linked to inflammation: depressive symptoms are frequent when the immune system is activated, and many depressed patients have high inflammation. It is therefore particularly intriguing to look at depression in illnesses that are also characterized by high inflammation — like, indeed, cancer. If the high prevalence rates of depression in cancer is due to the immune activation, fighting inflammation could also prevent the development of depression. Depression is not an easy-to-treat disorder and the limits of the current antidepressant therapies are well known to clinical practitioners. About one third of depressed patients have inadequate responses to treatment. This reveals an urgent need for new approaches in treating depressive disorders. If inflammation is elevated in at least some depressed patients — for example, patients with cancer — than anti-inflammatory treatments could be helpful. But which anti-inflammatories? Which bits of inflammation are important in causing depression? One inflammation-related pathway that appears to be dysregulated in both cancer and depression, is the kynurenine pathway. This is a metabolic process in which the essential amino acid tryptophan is converted into substances that are toxic for the brain and can induce depression. The activation of the kynurenine pathway during cancer may therefore be crucial to the development of depression, even though further research is needed to disentangle its exact role. Is this going to deliver new antidepressant drugs? It is probably too early to say, although drugs exist that inhibit the key enzyme of kynurenine pathway, indoleamine 2,3-dioxygenase (IDO). Many trials have been performed on IDO inhibitors in cancer, although with conflicting results, and some IDO inhibitors have shown promising results in association with classical anticancer therapies. Nevertheless, at this stage of research, the potential efficacy of IDO inhibitors in treating depression during cancer is still only a hypothesis. However, one thing is clear: to win the chess match against cancer, we really will need to fight against both cancer and depression. Targeting inflammation might be just such a strategy to win the match — especially if we can develop a more precision medicine approach in this field, identifying those patients who will benefit from anti-inflammatory interventions.

The Postpartum, and Why She Became Depressed I met Lynn Lu, a visual artist from Singapore, in November 2015. Lynn was working on an interactive performance/installation art project inspired by her own recent experience of depression during pregnancy and the postpartum. Whilst helping Lynn prepare for the project and reflecting on her own experience, we identified many concepts and notions that she did not know at that time, and that could have helped her. She has allowed me to share these with you. 1. Miscarriage increase the risk of depression in a subsequent pregnancy. Lynn was devastated after suffering from miscarriages in 2011 and 2012. And then she planned for another pregnancy. She did not know that women who have suffered a miscarriage are at increased risk of developing anxiety and depression in a subsequent pregnancy, especially if the interval is less than six months. She became pregnant again in late 2012. 2. Depression and anxiety in pregnancy increase the risk of postpartum depression. Lynn cried often throughout her pregnancy, and felt anxious about the future. She did not know that, like her, around 8–12% of pregnant women suffer from significant symptoms of depression and anxiety. Indeed, depression in pregnancy is probably more common than its much more famous relative, “postpartum depression”. She also did not know that depressive and anxiety symptoms in pregnancy are the most powerful risk factor for postpartum depression, and thus should be treated early. 3. Many pregnant women worry and ruminate. Lynn was trapped in constantly ruminating about her pregnancy, and because of this she felt desperate and disappointed in herself. For example, she was worried that her baby was not normal and was not growing inside her, or that she would not be a good mother, able to take care of her child. She did not know that these so called “pregnancy-related” anxiety symptoms are very common, occurring in up to 12% of pregnant women, and that specific scales have been developed to detect and measure their intensity. 4. For many women, labour is excruciatingly painful. Lynn thought she could avoid pain during labour by reading abut orgasmic birth, practicing hypnobirthing training, and engaging a doula. So many of her friends told her that they had a successful delivery at home without medications. However, she eventually “begged for an epidural” during her labour. And then she felt disappointed in herself for experiencing pain. She did not know that more than half of women receive epidural analgesia or powerful opioids painkillers during labour. Indeed, labour rates higher than many other pain conditions, such as back pain, cancer pain, toothache, or arthritic pain; only amputation of a digit and nerve lesions are rated higher. A quarter of women early in labour, and half of women late in labour, describe their pain as “horrible or excruciating”. However, some women later recall their experience of paid during labour with a positive emphasis on coping strategies and increased confidence. This does not make labour less painful. 5. Difficult breastfeeding can lead to depression. Lynn successfully breastfed her daughter for a whole year, but she struggled with a slow flow of milk, horrendously sore breasts, continuous use of a breast pump, painful bleeding nipples, and a terror of mastitis. She did not know that difficult breastfeeding increases the risk of postpartum depression. Breastfeeding may protect mothers from cancers and diabetes, and confer children lower infectious morbidity and higher intelligence; however, postpartum depression, with the emotional suffering and the disruption of mother-infant bond, can also negatively affect offspring development, and perhaps more so than formula feeding. 6. It is ok to seek respite from a relentless, inconsolable baby. Lynn suffered from the relentlessness of caring for an inconsolable baby. She felt lonely, isolated, sad, guilt, helpless and, occasionally, angry. She did not know that up to 10% of crying bouts are inconsolable, with babies appearing to be in pain even if perfectly healthy; that 25% of babies cry more than 3.5 hours per day; and that the longest crying bouts last up to two hours. She also did not know that all parents feel guilty and helpless and angry when dealing with an inconsolable baby, so much so that guidelines recommend alternating with a second caregiver and using coping strategies, such as leaving the baby in the cot or another safe place for a few minutes and taking a hot shower with the radio playing. 7. Sometimes you just need help from specialists in perinatal mental health. Lynn’s depression was not recognised in pregnancy, and then she was prescribed “low intensity” talking therapies for her postpartum depression, based on education and counselling. While these strategies are effective for minor mental health ailments, they did not help Lynn, who remained depressed at 18 months postpartum. She did not know that more intense psychological therapies, such as individual cognitive-behavioural therapy or psychological therapy focussed on the relationship between the mother and baby, are effective for depression both in pregnancy and in the postpartum; and that nutritional interventions, such as fish oil, can also be effective. She also did not know that antidepressants are an available clinical choice both in pregnancy and in the postpartum, albeit with a higher prescribing threshold than outside these periods. Editor's Note: It was amazing to work with Lynn and experiencing how performance art could address an issue that I had only considered as a medical problem until then. And it is a testimony to her strength-and perhaps to the healing power of art-that Lynn improved with little outside help. However, from the time she developed depression in pregnancy it took almost three years to get better. Lynn felt that her daughter became fun, interacting and able to reciprocate her love, when she turned two. She now finds that it is “a profound pleasure and privilege” to be a mother. However, I wonder if this could have happened sooner, if she had known then what she knows now; if she had asked sooner for the help she needed.