In many cases, a single form of therapy does not relieve symptoms of depression or anxiety. For every person, I recommend a range of healthy lifestyle changes, and I usually would encourage psychotherapy. For many, I encourage trials of antidepressant medication as well. For a significant number of people, a single medication does not relieve symptoms. In these cases of treatment-resistance, it can help to search for an effective combination of several medications. In this post, I will discuss the evidence-based foundation for combining antidepressants.
I find that several different antidepressant combos are worth trying, including an SSRI + mirtazapine, venlafaxine + mirtazapine, or an SSRI + bupropion. Adding trazodone to another antidepressant can be helpful for sleep, although I am less convinced of this combination substantially improving depressive symptoms. Combining newer antidepressants with older tricyclics is another area of interest, which I think we should be open-minded about, but I don't tend to prescribe tricyclics very often, mainly due to concerns about safety and side-effects. There are far fewer careful studies of antidepressant combinations compared to studies looking at single medication treatments, so the level of evidence in this area is not very strong yet. But here are a few references to existing articles from the research literature (I will try to expand my list over time):
http://www.ncbi.nlm.nih.gov/pubmed/19345072
This is a 2009 article from a Montreal group (Blier et al.) showing that a combination of mirtazapine + SSRI (paroxetine) led to significantly more improvement in depressive symptoms over 6 weeks, compared to groups taking either medication alone. The combination was well-tolerated for the most part-- in particular there was little difference in side effects experienced by the combination group compared to the group taking mirtazapine alone. Unfortunately, there are conflict-of-interest problems here: the study was funded by Organon, the mirtazapine manufacturer. And several authors of the study were "consultants" paid by the drug manufacturers for speaking engagements. The continued behaviour of psychiatrists accepting corporate money to give "educational lectures" is unfortunate. Usually large sums of money are involved. Please see my posts on industry-sponsored research: http://garthkroeker.blogspot.com/2008/11/biases-associated-with-industry-funded.html and http://garthkroeker.blogspot.com/2009/05/my-experiences-with-industry.html
Here's another recent article (2010) by Blier et al, again making a strong case for using combination antidepressants right from treatment initiation: http://www.ncbi.nlm.nih.gov/pubmed/20008946
http://www.ncbi.nlm.nih.gov/pubmed/18832958
This is an open study looking at combining escitalopram (Cipralex) with bupropion in chronic depression. There was no placebo or comparison group, so the study has a weak design. But it shows the combination was quite well-tolerated, and led to 50-60% of patients experiencing a remission of symptoms after 12 weeks, which in general is a better result than most single-agent trials, especially in chronic depression. The study was funded by NIMH, which reduces the likelihood of bias.
http://www.ncbi.nlm.nih.gov/pubmed/16165100
This is a 2006 review from Biological Psychiatry looking at combinations of bupropion with SSRIs. It is a good paper, but really most of the evidence presented is of mediocre quality. It does support the idea of using bupropion-SSRI combos, to improve treatment response in depression, and also to reduce SSRI-induced sexual side-effects such as delayed or inhibited orgasm.
http://www.ncbi.nlm.nih.gov/pubmed/15539864
This interesting 2004 paper is looking at the treatment of patients with depression plus chronic headache, using citalopram alone, or amitriptyline (a tricyclic antidepressant) alone, for 16 weeks. Then, a combination of the two medications was given to non-responders, for a further 16 weeks. The combination group showed substantial improvement in both headache and depression.
http://www.ncbi.nlm.nih.gov/pubmed/14744472
This is an important 2004 study from Biological Psychiatry showing that 6 weeks of a fluoxetine (SSRI) + desipramine (tricyclic) combination was more effective than either drug alone, in treating depressed patients admitted to hospital. While similar proportions (about 35-50%) of patients failed to respond to any of the three treatments, those patients who did respond improved much more with the combination. That is, the combination treatment led to a significantly higher chance of total remission compared to either single antidepressant treatment. The study was funded by NIMH.
http://www.ncbi.nlm.nih.gov/pubmed/12172337
This 2002 study looked at several options to treat non-responding depressed patients taking fluoxetine: the first group took a higher dose of fluoxetine (40-60 mg/d), the second group took a combination of regular-dose fluoxetine + desipramine, and the third group took fluoxetine + lithium. The results favoured the first strategy, of maximizing the dose of fluoxetine, instead of combining with something else. However, this result is not very useful, since normally we would maximize the dose of a single agent first anyway, before resorting to a combination. Yet the study does show that combining is not necessarily the best first step in addressing treatment-resistance. It was funded by NIMH.
http://www.ncbi.nlm.nih.gov/pubmed/8988452
This is one of the few studies looking at trazodone combinations: in this case, trazodone+fluoxetine showed some promise in treating resistant depression.
http://www.ncbi.nlm.nih.gov/pubmed/1548249
A weak old study from 1992 showing that trazodone can sometimes help as a combination with an SSRI (in this case, fluoxetine). 3 out of 8 depressed patients in this study improved with the combination (of course, this means that 5 out of 8 did not improve).
http://www.ncbi.nlm.nih.gov/pubmed/19415584
This is a 2009 review article on combining antidepressants. It is in German, which makes it hard for me to read!
Tuesday, May 26, 2009
MDMA (ecstasy): risks and benefits
"Ecstasy" is a common recreational drug. Chemically, it is known as MDMA, or 3,4-methylenedioxymethamphetamine. It is a type of chemically modified amphetamine compound which causes a release of serotonin and other transmitters from brain cells. It probably has a variety of other pharmacological effects.
MDMA has been shown in many studies to be neurotoxic, particularly causing harm to the cells in the brain which produce serotonin. There is evidence that MDMA can cause permanent harm or cell death. These studies have been done using rodents, monkeys, and using laboratory cell cultures. The neurotoxicity seems to be associated with, or magnified by, the increase in body temperature caused by ecstasy ingestion. Here are a few of the many references about this:
http://www.ncbi.nlm.nih.gov/pubmed/1379014
http://www.ncbi.nlm.nih.gov/pubmed/18991870
http://www.ncbi.nlm.nih.gov/pubmed/16884865
http://www.ncbi.nlm.nih.gov/pubmed/12464456
But here is a paper describing long-term MDMA exposure in monkeys, which did not lead to chemical evidence of neurotoxicity:
http://www.ncbi.nlm.nih.gov/pubmed/15039771
An important body of research is the Netherlands XTC Toxicity (NeXT) study. This 2008 paper from the NeXT study describes a prospective follow-up of new low-dose ecstasy users, and found evidence through functional brain imaging of neurotoxicity in the ecstasy-using group:
http://www.ncbi.nlm.nih.gov/pubmed/18842607
Here is another similar 2007 paper published in Archives of General Psychiatry describing a slight reduction in verbal memory performance in individuals who had used even just a few doses of ecstasy, compared to individuals who had not used any:
http://www.ncbi.nlm.nih.gov/pubmed/17548754
However, this paper gave rise to a good debate in subsequent issues of this journal. Basically, neither group in the study declined in memory performance, it's just that the non-ecstasy group improved more than the ecstasy group on re-testing. The ecstasy group included some people who had used much more than others. Also, the ecstasy-using group may have been more anxious about negative memory effects, since they had been warned about this possibility in advance. Such anxiety can impare test performance. The ecstasy-using group may have taken drugs tainted with impurities. A very important point I would add is that most people who use ecstasy recreationally do so in a chaotic, loud environment such as a rave--the drug may act as an emotional or interpersonal "amplifier", which in the case of a rave, could give rise to an amplification of social chaos. Also such an environment might lead to a higher degree of hyperthermia, which is associated with worse neurotoxicity. Use of ecstasy in a controlled, gentle, intimate environment might be much safer.
Here's a reference to a 2009 British Journal of Psychiatry study showing no difference in serotonin transporter binding between groups of former MDMA users, other drug users, and controls with no history of street drug use:
http://www.ncbi.nlm.nih.gov/pubmed/19336788?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
This is a randomized, double-blind study looking at physical and emotional effects of acute MDMA ingestion, at low (1 mg/kg) and high (1.6 mg/kg) doses. It did not demonstrate hyperthermia as an effect of the drug, rather it implies that hyperthermia is caused by the environmental situation in conjunction with the drug (e.g. vigorous activity dancing indoors in a crowd).
http://www.ncbi.nlm.nih.gov/pubmed/18626271
There may be therapeutic applications for MDMA. The subjective effects of the drug can be to dramatically increase a feeling of openness, empathy or connectedness with other people, both on an emotional level and also sensually or physically.
Here are some references about this:
http://www.ncbi.nlm.nih.gov/pubmed/19273493
{this is a brief 2009 review of the subject of possible psychotherapeutic uses of MDMA, such as in anxiety disorders and PTSD}
http://www.ncbi.nlm.nih.gov/pubmed/19004414
{this 2008 study from Madrid showed that 50-75 mg doses of MDMA used in conjunction with psychotherapy for PTSD appeared to be physiologically and emotionally safe for 6 subjects. The study apparently had to be ended due to political pressures, before more subjects could be treated. Clearly, this is a controversial issue}
A psychiatrist by the name of Michael Mithoefer is trying to do research about using MDMA for treating PTSD. Here are some related sites:
http://scienceblogs.com/neurophilosophy/2007/11/mdma_for_ptsd.php
http://www.maps.org/mdma/protocol/
http://www.maps.org/mdma/
I think it is important to be open-minded about things outside the mainstream, and to recognize that mainstream research may sometimes dismiss ideas considered too controversial. Yet I recognize that the above sites have a biased agenda of their own which may undervalue important risk analyses published in the mainstream literature.
Answering questions relating to controversial issues, such as the potential use of MDMA as a therapeutic agent, requires a very neutral, unbiased research environment.
Aside from therapeutic possibilities in PTSD, it seems to me that MDMA might be worth investigating as an adjunct for couples' therapy, particularly for couples who feel inhibited or disconnected with each other. MDMA can foster a sense of connectedness, sensuality, and empathy. These three domains are often major weaknesses in troubled relationships. Apparently MDMA has been used in relationship therapy in the past, but the results have been poorly documented.
I have seen patients for whom MDMA use appears to have been part of a destructive long-term drug abuse pattern, which has most likely exacerbated mood, anxiety, and interpersonal problems. I have also seen a few patients for whom isolated experiences with MDMA have led to strong, memorable experiences of openness and intimacy with friends or partners.
In conclusion, I emphasize that MDMA is clearly a dangerous drug. It is most definitely neurotoxic. The risk of neurotoxicity is most likely higher with frequent, regular, or long-term use. Most "ecstasy" obtained on the street is tainted with numerous impurities--both deliberately, to reduce production costs, and as by-products of crude synthetic techniques; the impurities are likely to add to potential toxicity. I think that the setting in which MDMA is used most frequently (e.g. as a "dance drug") is likely to magnify its toxicity, in that hyperthermia is more likely, and any intimate emotional benefit is less likely. Many MDMA users are taking this drug frequently, over a period of years--I think this pattern has a very high risk of causing permanent neuropsychiatric harm.
We do not know yet if MDMA could have a positive therapeutic role for some people, but if it did, it would most likely have to be used only a very small number of times, in a carefully controlled, socially supported, comfortable, quiet, cool setting, by individuals who are already in a state of relative emotional calm. I suspect that a history of psychotic or bipolar illness, or a history of other street drug use or dependence, would greatly magnify the psychiatric risks of MDMA use. In the meantime, the existing research shows that any possible benefits would have to be weighed against very substantial risks. It remains an illegal drug in most jurisdictions.
MDMA has been shown in many studies to be neurotoxic, particularly causing harm to the cells in the brain which produce serotonin. There is evidence that MDMA can cause permanent harm or cell death. These studies have been done using rodents, monkeys, and using laboratory cell cultures. The neurotoxicity seems to be associated with, or magnified by, the increase in body temperature caused by ecstasy ingestion. Here are a few of the many references about this:
http://www.ncbi.nlm.nih.gov/pubmed/1379014
http://www.ncbi.nlm.nih.gov/pubmed/18991870
http://www.ncbi.nlm.nih.gov/pubmed/16884865
http://www.ncbi.nlm.nih.gov/pubmed/12464456
But here is a paper describing long-term MDMA exposure in monkeys, which did not lead to chemical evidence of neurotoxicity:
http://www.ncbi.nlm.nih.gov/pubmed/15039771
An important body of research is the Netherlands XTC Toxicity (NeXT) study. This 2008 paper from the NeXT study describes a prospective follow-up of new low-dose ecstasy users, and found evidence through functional brain imaging of neurotoxicity in the ecstasy-using group:
http://www.ncbi.nlm.nih.gov/pubmed/18842607
Here is another similar 2007 paper published in Archives of General Psychiatry describing a slight reduction in verbal memory performance in individuals who had used even just a few doses of ecstasy, compared to individuals who had not used any:
http://www.ncbi.nlm.nih.gov/pubmed/17548754
However, this paper gave rise to a good debate in subsequent issues of this journal. Basically, neither group in the study declined in memory performance, it's just that the non-ecstasy group improved more than the ecstasy group on re-testing. The ecstasy group included some people who had used much more than others. Also, the ecstasy-using group may have been more anxious about negative memory effects, since they had been warned about this possibility in advance. Such anxiety can impare test performance. The ecstasy-using group may have taken drugs tainted with impurities. A very important point I would add is that most people who use ecstasy recreationally do so in a chaotic, loud environment such as a rave--the drug may act as an emotional or interpersonal "amplifier", which in the case of a rave, could give rise to an amplification of social chaos. Also such an environment might lead to a higher degree of hyperthermia, which is associated with worse neurotoxicity. Use of ecstasy in a controlled, gentle, intimate environment might be much safer.
Here's a reference to a 2009 British Journal of Psychiatry study showing no difference in serotonin transporter binding between groups of former MDMA users, other drug users, and controls with no history of street drug use:
http://www.ncbi.nlm.nih.gov/pubmed/19336788?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
This is a randomized, double-blind study looking at physical and emotional effects of acute MDMA ingestion, at low (1 mg/kg) and high (1.6 mg/kg) doses. It did not demonstrate hyperthermia as an effect of the drug, rather it implies that hyperthermia is caused by the environmental situation in conjunction with the drug (e.g. vigorous activity dancing indoors in a crowd).
http://www.ncbi.nlm.nih.gov/pubmed/18626271
There may be therapeutic applications for MDMA. The subjective effects of the drug can be to dramatically increase a feeling of openness, empathy or connectedness with other people, both on an emotional level and also sensually or physically.
Here are some references about this:
http://www.ncbi.nlm.nih.gov/pubmed/19273493
{this is a brief 2009 review of the subject of possible psychotherapeutic uses of MDMA, such as in anxiety disorders and PTSD}
http://www.ncbi.nlm.nih.gov/pubmed/19004414
{this 2008 study from Madrid showed that 50-75 mg doses of MDMA used in conjunction with psychotherapy for PTSD appeared to be physiologically and emotionally safe for 6 subjects. The study apparently had to be ended due to political pressures, before more subjects could be treated. Clearly, this is a controversial issue}
A psychiatrist by the name of Michael Mithoefer is trying to do research about using MDMA for treating PTSD. Here are some related sites:
http://scienceblogs.com/neurophilosophy/2007/11/mdma_for_ptsd.php
http://www.maps.org/mdma/protocol/
http://www.maps.org/mdma/
I think it is important to be open-minded about things outside the mainstream, and to recognize that mainstream research may sometimes dismiss ideas considered too controversial. Yet I recognize that the above sites have a biased agenda of their own which may undervalue important risk analyses published in the mainstream literature.
Answering questions relating to controversial issues, such as the potential use of MDMA as a therapeutic agent, requires a very neutral, unbiased research environment.
Aside from therapeutic possibilities in PTSD, it seems to me that MDMA might be worth investigating as an adjunct for couples' therapy, particularly for couples who feel inhibited or disconnected with each other. MDMA can foster a sense of connectedness, sensuality, and empathy. These three domains are often major weaknesses in troubled relationships. Apparently MDMA has been used in relationship therapy in the past, but the results have been poorly documented.
I have seen patients for whom MDMA use appears to have been part of a destructive long-term drug abuse pattern, which has most likely exacerbated mood, anxiety, and interpersonal problems. I have also seen a few patients for whom isolated experiences with MDMA have led to strong, memorable experiences of openness and intimacy with friends or partners.
In conclusion, I emphasize that MDMA is clearly a dangerous drug. It is most definitely neurotoxic. The risk of neurotoxicity is most likely higher with frequent, regular, or long-term use. Most "ecstasy" obtained on the street is tainted with numerous impurities--both deliberately, to reduce production costs, and as by-products of crude synthetic techniques; the impurities are likely to add to potential toxicity. I think that the setting in which MDMA is used most frequently (e.g. as a "dance drug") is likely to magnify its toxicity, in that hyperthermia is more likely, and any intimate emotional benefit is less likely. Many MDMA users are taking this drug frequently, over a period of years--I think this pattern has a very high risk of causing permanent neuropsychiatric harm.
We do not know yet if MDMA could have a positive therapeutic role for some people, but if it did, it would most likely have to be used only a very small number of times, in a carefully controlled, socially supported, comfortable, quiet, cool setting, by individuals who are already in a state of relative emotional calm. I suspect that a history of psychotic or bipolar illness, or a history of other street drug use or dependence, would greatly magnify the psychiatric risks of MDMA use. In the meantime, the existing research shows that any possible benefits would have to be weighed against very substantial risks. It remains an illegal drug in most jurisdictions.
Thursday, May 21, 2009
Eating Disorders
Disordered eating is a complex problem which takes a variety of forms.
Anorexia nervosa is characterized by restrictive eating behaviours and excessive exercise which lead to medically dangerous weight loss.
Bulimia nervosa is characterized by binge-eating, and by purging (most commonly, self-induced vomiting). During binges, people often feel out of control, unable to stop.
In many cases, individuals have a mixture of anorexic and bulimic symptoms, without having a full syndrome of anorexia or bulimia.
In most cases of any eating disorder, there is a prominent disturbance of body image. Individuals may feel disgusted with their physical appearance. There may be an extremely strong preoccupation with fat. Fat (the word itself, as well as everything it represents) becomes something to be feared, avoided, and reviled. Any perception of normal subcutaneous fat is met with self-criticism or loathing. A perception of becoming thinner can be met with a feeling of satisfaction or addictive euphoria. Dietary fat, and dietary calories, often become subjects of intense preoccupation. Planning meals, or thinking about past meals, can lead to a great deal of anxiety. Eating socially with others can be extremely difficult. Situations in which people are more physically exposed (e.g. swimming pools, or the outdoors on a hot summer day) can cause increased self-consciousness and consequent self-loathing. Therefore, these situations are often avoided. Physical comparisons with other people can intensify symptoms. Many eating disorder behaviours (such as binges and purges) occur in secret.
Eating disorders can be medically dangerous: severe anorexia nervosa can be fatal. Other metabolic abnormalities from starvation or purging can cause weakness, cognitive impairments, bone demineralization, and abnormal heart rhythms. Repeated vomiting can cause damage to the esophagus. Overall poor nutrition makes it hard to treat other mental health problems, such as anxiety or depression.
In the treatment of eating disorders, sometimes a hospital stay is needed if weight is dangerously low.
Effective long-term resolution of severe symptoms can begin with an intensive multi-disciplinary day program, and may require lifelong treatment.
But here are a few basic ideas that I think can help in a less intensive outpatient setting:
1) It is important to be well-educated about basic nutrition -- to know what your body needs in a day, in terms of calories, fat, protein, vitamins, etc -- and to have a good sense of what foods might contain this balance of nutrients in a typical day. A consult with a dietician can be helpful.
2) Regular meals are important. Having regular meals can reduce the tendency to binge, since hunger will not build up as intensely. Experiencing meals is a component of behavioural therapy: planning the meal, obtaining & preparing the food, consuming the food, and then allowing the food to stay inside and be digested without purging. Each of these aspects may carry a lot of anxiety and stress. Having interpersonal support during these times can be powerfully helpful. Cognitive-behavioural techniques could also be helpful to manage the anxiety.
3)It can be important to recognize familiar patterns of thinking (e.g. having to do with fat or caloric calculations, dieting, weight loss plans, etc.) and practicing ways of directing attention away from these themes. It is also unhelpful to be bombarded with these themes in your social or cultural life, so I encourage a practice of redirecting social, cultural, or conversational energy away from subjects such as dieting, weight loss, etc.
4) Antidepressants such as SSRIs can help with bulimia (reference: http://www.ncbi.nlm.nih.gov/pubmed/14583971). The anticonvulsant topiramate can help reduce binge eating (references: http://www.ncbi.nlm.nih.gov/pubmed/18774432; http://www.ncbi.nlm.nih.gov/pubmed/14728106). Pharmacologic treatments for anorexia have not yet been very successful.
5) I think a very important element to work on is the confrontation and challenge of negative body image, its associated language, and its associated impairment in sensuality. Steps may need to be taken to stop or challenge "negative self-talk" and criticism about your body--about the way your body looks in a mirror, or the way your body feels to touch. This negative self-talk, and the ensuing negative emotions, need to be replaced by affirmations and by enjoyment. I think this type of work needs to be done every day. It can sometimes require work to gain pleasure from something, or to learn how to experience pleasure: this is a theme strongly present in the treatment of depression as well. Actually, I think it is a theme present in life generally -- we need to learn and practice something, to be with it consistently, in order for love or enjoyment to grow.
6) Similarly, I think it is important to reclaim the sensuality of food: the process of planning, preparing, consuming, and digesting food needs to be transformed from a source of dread or anxiety to a set of simple life pleasures. I think this type of sensuality should be emphasized in behavioural therapeutic techniques. Mindfulness meditation techniques can be helpful along these lines.
Anorexia nervosa is characterized by restrictive eating behaviours and excessive exercise which lead to medically dangerous weight loss.
Bulimia nervosa is characterized by binge-eating, and by purging (most commonly, self-induced vomiting). During binges, people often feel out of control, unable to stop.
In many cases, individuals have a mixture of anorexic and bulimic symptoms, without having a full syndrome of anorexia or bulimia.
In most cases of any eating disorder, there is a prominent disturbance of body image. Individuals may feel disgusted with their physical appearance. There may be an extremely strong preoccupation with fat. Fat (the word itself, as well as everything it represents) becomes something to be feared, avoided, and reviled. Any perception of normal subcutaneous fat is met with self-criticism or loathing. A perception of becoming thinner can be met with a feeling of satisfaction or addictive euphoria. Dietary fat, and dietary calories, often become subjects of intense preoccupation. Planning meals, or thinking about past meals, can lead to a great deal of anxiety. Eating socially with others can be extremely difficult. Situations in which people are more physically exposed (e.g. swimming pools, or the outdoors on a hot summer day) can cause increased self-consciousness and consequent self-loathing. Therefore, these situations are often avoided. Physical comparisons with other people can intensify symptoms. Many eating disorder behaviours (such as binges and purges) occur in secret.
Eating disorders can be medically dangerous: severe anorexia nervosa can be fatal. Other metabolic abnormalities from starvation or purging can cause weakness, cognitive impairments, bone demineralization, and abnormal heart rhythms. Repeated vomiting can cause damage to the esophagus. Overall poor nutrition makes it hard to treat other mental health problems, such as anxiety or depression.
In the treatment of eating disorders, sometimes a hospital stay is needed if weight is dangerously low.
Effective long-term resolution of severe symptoms can begin with an intensive multi-disciplinary day program, and may require lifelong treatment.
But here are a few basic ideas that I think can help in a less intensive outpatient setting:
1) It is important to be well-educated about basic nutrition -- to know what your body needs in a day, in terms of calories, fat, protein, vitamins, etc -- and to have a good sense of what foods might contain this balance of nutrients in a typical day. A consult with a dietician can be helpful.
2) Regular meals are important. Having regular meals can reduce the tendency to binge, since hunger will not build up as intensely. Experiencing meals is a component of behavioural therapy: planning the meal, obtaining & preparing the food, consuming the food, and then allowing the food to stay inside and be digested without purging. Each of these aspects may carry a lot of anxiety and stress. Having interpersonal support during these times can be powerfully helpful. Cognitive-behavioural techniques could also be helpful to manage the anxiety.
3)It can be important to recognize familiar patterns of thinking (e.g. having to do with fat or caloric calculations, dieting, weight loss plans, etc.) and practicing ways of directing attention away from these themes. It is also unhelpful to be bombarded with these themes in your social or cultural life, so I encourage a practice of redirecting social, cultural, or conversational energy away from subjects such as dieting, weight loss, etc.
4) Antidepressants such as SSRIs can help with bulimia (reference: http://www.ncbi.nlm.nih.gov/pubmed/14583971). The anticonvulsant topiramate can help reduce binge eating (references: http://www.ncbi.nlm.nih.gov/pubmed/18774432; http://www.ncbi.nlm.nih.gov/pubmed/14728106). Pharmacologic treatments for anorexia have not yet been very successful.
5) I think a very important element to work on is the confrontation and challenge of negative body image, its associated language, and its associated impairment in sensuality. Steps may need to be taken to stop or challenge "negative self-talk" and criticism about your body--about the way your body looks in a mirror, or the way your body feels to touch. This negative self-talk, and the ensuing negative emotions, need to be replaced by affirmations and by enjoyment. I think this type of work needs to be done every day. It can sometimes require work to gain pleasure from something, or to learn how to experience pleasure: this is a theme strongly present in the treatment of depression as well. Actually, I think it is a theme present in life generally -- we need to learn and practice something, to be with it consistently, in order for love or enjoyment to grow.
6) Similarly, I think it is important to reclaim the sensuality of food: the process of planning, preparing, consuming, and digesting food needs to be transformed from a source of dread or anxiety to a set of simple life pleasures. I think this type of sensuality should be emphasized in behavioural therapeutic techniques. Mindfulness meditation techniques can be helpful along these lines.
Antidepressants and Bone
There is some evidence that antidepressants, particularly the serotonin reuptake inhibitors, can reduce bone density, and increase the risk of fractures. This risk would be most pertinent in an elderly population.
Serotonin is a relevant factor in bone metabolism, so it is important to consider the potential impact of serotonergic antidepressants on bone health.
Here's a study showing an association between depression and reduced bone mineral density. Depression itself is an understandable cause for bone mineral loss, since it is associated with fatigue, therefore less exercise, worse nutrition, and increased stress hormones such as corticosteroids. In this study, antidepressant use was independently associated with bone mineral density loss in women. It is a retrospective analysis from a large catchment area study involving over 1000 people, who were followed since 1981.
http://www.ncbi.nlm.nih.gov/pubmed/19126857
There are some other studies showing an association between antidepressant use (especially SSRIs) and fractures due to fragile bone. One of the better such studies was published in 2008, looking at the incidence of fractures in a large population-based cohort involving 7983 people aged 55 and over. Importantly, the authors attempted to control for the impact of depression itself on fracture incidence, and basically showed that current SSRI use approximately doubles the risk of fractures:
http://www.ncbi.nlm.nih.gov/pubmed/18626268
There is one important prospective animal study, which shows a small effect of SSRI treatment on bone quality over a 6-month period:
http://www.ncbi.nlm.nih.gov/pubmed/17163489
In conclusion, it is important to know that antidepressants could possibly reduce bone density, and therefore contribute to an increased risk of fractures in the elderly. If antidepressant therapy is needed, it is especially important to encourage activities which protect bone health, such as regular exercise, and good nutrition (including ample calcium and vitamin D in the diet). Non-SSRI antidepressants such as tricyclics may have a smaller effect than the SSRIs. Bone density testing could be indicated, as could medication treatments to protect bone mineralization. These issues should be discussed with your family physician and your psychiatrist.
Serotonin is a relevant factor in bone metabolism, so it is important to consider the potential impact of serotonergic antidepressants on bone health.
Here's a study showing an association between depression and reduced bone mineral density. Depression itself is an understandable cause for bone mineral loss, since it is associated with fatigue, therefore less exercise, worse nutrition, and increased stress hormones such as corticosteroids. In this study, antidepressant use was independently associated with bone mineral density loss in women. It is a retrospective analysis from a large catchment area study involving over 1000 people, who were followed since 1981.
http://www.ncbi.nlm.nih.gov/pubmed/19126857
There are some other studies showing an association between antidepressant use (especially SSRIs) and fractures due to fragile bone. One of the better such studies was published in 2008, looking at the incidence of fractures in a large population-based cohort involving 7983 people aged 55 and over. Importantly, the authors attempted to control for the impact of depression itself on fracture incidence, and basically showed that current SSRI use approximately doubles the risk of fractures:
http://www.ncbi.nlm.nih.gov/pubmed/18626268
There is one important prospective animal study, which shows a small effect of SSRI treatment on bone quality over a 6-month period:
http://www.ncbi.nlm.nih.gov/pubmed/17163489
In conclusion, it is important to know that antidepressants could possibly reduce bone density, and therefore contribute to an increased risk of fractures in the elderly. If antidepressant therapy is needed, it is especially important to encourage activities which protect bone health, such as regular exercise, and good nutrition (including ample calcium and vitamin D in the diet). Non-SSRI antidepressants such as tricyclics may have a smaller effect than the SSRIs. Bone density testing could be indicated, as could medication treatments to protect bone mineralization. These issues should be discussed with your family physician and your psychiatrist.
Thursday, May 7, 2009
Long-term stimulants & ADHD
The long-term use of stimulants such as methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and mixed amphetamine salts (Adderall), in the treatment of attention or behaviour problems in children and adults, has been a controversial issue.
Symptoms of so-called ADHD include inability to sustain attention while doing academic, social, domestic, or work activities; restlessness, and inability to sit quietly or wait patiently. Of course, everyone has difficulties in these domains at times. The diagnosis of ADHD is intended to apply to individuals whose symptoms are so severe in these areas that it causes serious, ongoing problems functioning socially, academically, and with other life tasks. Those with an ADHD diagnosis are much more likely to drop out of school, to be unable to maintain jobs, to have difficulty maintaining friendships, and to have conduct problems ultimately leading to problems with the law, etc.
It is abundantly clear, from careful research, that stimulants improve symptoms of ADHD, and associated problems with social behaviour and disordered conduct.
I do not see good evidence that stimulants adversely affect personality traits or sense of self. Rather, in many cases, the experience of having severe untreated ADHD symptoms adversely affects personality traits and sense of self.
I will add to this post later, to discuss potential adverse effects from stimulant therapy. But stimulants are generally well-tolerated, with a low risk of serious adverse effects for most people.
Existing psychosocial treatments can help ADHD symptoms as well, but they do not work as well as stimulants, and--surprisingly--combining psychosocial treatments with stimulant therapy does not work much better than stimulants alone, except possibly for some individual cases. Here is some evidence, from a 2008 meta-analysis, for this finding:
http://www.ncbi.nlm.nih.gov/pubmed/18068284
Here are a few other important studies pertaining to long-term stimulant use:
This 5 year prospective study shows that stimulant therapy substantially reduces the rate of smoking and substance use disorders in adolescents with ADHD:
http://www.ncbi.nlm.nih.gov/pubmed/18838643
About 20% of ADHD adolescents treated with stimulants over 5 years developed a substance use disorder, compared to 55% of ADHD adolescents not treated with stimulants.
Stimulant-treated adolescents also had much lower rates of smoking. This is a very strong and compelling study, showing profound reductions in addictive disorders as a result of long-term stimulant treatment.
This 2008 study looked at a group of 169 children with ADHD, and followed up on them 9 years later:
http://www.ncbi.nlm.nih.gov/pubmed/18928410
The children who had taken stimulant treatment for their ADHD fared better than those with ADHD who had not taken stimulants, in terms of academic performance (as measured in several different ways). Neither ADHD group performed as well as a comparison group without ADHD.
This 2007 study from the Journal of Developmental and Behavioral Pediatrics is particularly strong, in that it looks at an entire birth cohort (all 5718 children born in Rochester between 1976-1982, of whom 370 with ADHD were identified):
http://www.ncbi.nlm.nih.gov/pubmed/17700079
It looked at long-term outcomes, over an average of 18 years. The study shows reduced absenteeism, reduced likelihood of being held back a grade, and slightly higher reading test scores, for ADHD children receiving long-term stimulant therapy.
Reading scores were particularly higher in the children who had received high doses of stimulants for longer periods of time.
The stimulant group did not differ from the non-stimulant group with respect to sociodemographic variables or duration of follow-up. The study was retrospective and was not randomized, yet it remains a very strong piece of evidence about long-term effects of stimulant treatment for ADHD.
I think these findings emphasize a number of things:
1) stimulants work very well for ADHD symptoms
2) stimulants unfortunately only have a slight effect on long-term academic outcomes
3) existing psychosocial treatments work modestly well on their own, but for most people do not add to the benefits of stimulants. The psychosocial treatments did not improve long-term academic outcomes. The duration of psychosocial treatment did not correlate with better improvement in symptoms, so the weakness of existing psychosocial treatments is not likely due to inadequate length of treatment.
4) long-term stimulant therapy may substantially reduce the risk of ADHD kids getting into alcohol use, substance use, or smoking problems. This finding is strong evidence against the idea that stimulant use increases the risk for subsequent addictive disorders.
I do think we need to keep working on better psychosocial treatments. I suspect that intensive, long-term, individualized treatment, with a style which suits the personality and strengths of each person, will be most effective. And I suspect that such treatments would need to be combined with positive, supportive milieux at home, school, work, and in peer relationships.
I will add to this post, or write a sequel post, to discuss other treatments for ADHD, such as atomoxetine, antidepressants, EEG biofeedback, dietary modification, and some newer psychosocial treatment ideas.
Symptoms of so-called ADHD include inability to sustain attention while doing academic, social, domestic, or work activities; restlessness, and inability to sit quietly or wait patiently. Of course, everyone has difficulties in these domains at times. The diagnosis of ADHD is intended to apply to individuals whose symptoms are so severe in these areas that it causes serious, ongoing problems functioning socially, academically, and with other life tasks. Those with an ADHD diagnosis are much more likely to drop out of school, to be unable to maintain jobs, to have difficulty maintaining friendships, and to have conduct problems ultimately leading to problems with the law, etc.
It is abundantly clear, from careful research, that stimulants improve symptoms of ADHD, and associated problems with social behaviour and disordered conduct.
I do not see good evidence that stimulants adversely affect personality traits or sense of self. Rather, in many cases, the experience of having severe untreated ADHD symptoms adversely affects personality traits and sense of self.
I will add to this post later, to discuss potential adverse effects from stimulant therapy. But stimulants are generally well-tolerated, with a low risk of serious adverse effects for most people.
Existing psychosocial treatments can help ADHD symptoms as well, but they do not work as well as stimulants, and--surprisingly--combining psychosocial treatments with stimulant therapy does not work much better than stimulants alone, except possibly for some individual cases. Here is some evidence, from a 2008 meta-analysis, for this finding:
http://www.ncbi.nlm.nih.gov/pubmed/18068284
Here are a few other important studies pertaining to long-term stimulant use:
This 5 year prospective study shows that stimulant therapy substantially reduces the rate of smoking and substance use disorders in adolescents with ADHD:
http://www.ncbi.nlm.nih.gov/pubmed/18838643
About 20% of ADHD adolescents treated with stimulants over 5 years developed a substance use disorder, compared to 55% of ADHD adolescents not treated with stimulants.
Stimulant-treated adolescents also had much lower rates of smoking. This is a very strong and compelling study, showing profound reductions in addictive disorders as a result of long-term stimulant treatment.
This 2008 study looked at a group of 169 children with ADHD, and followed up on them 9 years later:
http://www.ncbi.nlm.nih.gov/pubmed/18928410
The children who had taken stimulant treatment for their ADHD fared better than those with ADHD who had not taken stimulants, in terms of academic performance (as measured in several different ways). Neither ADHD group performed as well as a comparison group without ADHD.
This 2007 study from the Journal of Developmental and Behavioral Pediatrics is particularly strong, in that it looks at an entire birth cohort (all 5718 children born in Rochester between 1976-1982, of whom 370 with ADHD were identified):
http://www.ncbi.nlm.nih.gov/pubmed/17700079
It looked at long-term outcomes, over an average of 18 years. The study shows reduced absenteeism, reduced likelihood of being held back a grade, and slightly higher reading test scores, for ADHD children receiving long-term stimulant therapy.
Reading scores were particularly higher in the children who had received high doses of stimulants for longer periods of time.
The stimulant group did not differ from the non-stimulant group with respect to sociodemographic variables or duration of follow-up. The study was retrospective and was not randomized, yet it remains a very strong piece of evidence about long-term effects of stimulant treatment for ADHD.
I think these findings emphasize a number of things:
1) stimulants work very well for ADHD symptoms
2) stimulants unfortunately only have a slight effect on long-term academic outcomes
3) existing psychosocial treatments work modestly well on their own, but for most people do not add to the benefits of stimulants. The psychosocial treatments did not improve long-term academic outcomes. The duration of psychosocial treatment did not correlate with better improvement in symptoms, so the weakness of existing psychosocial treatments is not likely due to inadequate length of treatment.
4) long-term stimulant therapy may substantially reduce the risk of ADHD kids getting into alcohol use, substance use, or smoking problems. This finding is strong evidence against the idea that stimulant use increases the risk for subsequent addictive disorders.
I do think we need to keep working on better psychosocial treatments. I suspect that intensive, long-term, individualized treatment, with a style which suits the personality and strengths of each person, will be most effective. And I suspect that such treatments would need to be combined with positive, supportive milieux at home, school, work, and in peer relationships.
I will add to this post, or write a sequel post, to discuss other treatments for ADHD, such as atomoxetine, antidepressants, EEG biofeedback, dietary modification, and some newer psychosocial treatment ideas.
Monday, May 4, 2009
Direct personal requests for help
I encourage all of you who might be searching for help, waiting for help, or struggling with existing help, to be patient, to be brave, to hold onto hope.
At times I have had some direct personal requests for help from individuals who are not currently my patients. I feel that I have to stick to a policy of not being able to respond directly to such requests, as I feel that a direct response would, for me, cause me to feel a professional duty to maintain ongoing care.
But, once again, I do encourage all those who are struggling to hold on, to be patient, to be brave, to be open-minded about your options for new things to try, to hold onto hope.
For those in the Vancouver area, I remind you of some of the local resources:
http://garthkroeker.blogspot.com/2008/12/finding-help.html
If local resources are failing to keep you afloat, please keep an open mind about using emergency services, such as the local hospital emergency rooms.
At times I have had some direct personal requests for help from individuals who are not currently my patients. I feel that I have to stick to a policy of not being able to respond directly to such requests, as I feel that a direct response would, for me, cause me to feel a professional duty to maintain ongoing care.
But, once again, I do encourage all those who are struggling to hold on, to be patient, to be brave, to be open-minded about your options for new things to try, to hold onto hope.
For those in the Vancouver area, I remind you of some of the local resources:
http://garthkroeker.blogspot.com/2008/12/finding-help.html
If local resources are failing to keep you afloat, please keep an open mind about using emergency services, such as the local hospital emergency rooms.
Friday, May 1, 2009
My Experiences with Industry Sponsorship
Around 2001, when I was a mood disorders fellow, I was asked to do an educational lecture by Organon, the manufacturer of the antidepressant mirtazapine. The company clearly wanted one of the more prominent mood disorders research psychiatrists to do the lecture--but since no one else was available, they settled for me. It was common practice for research psychiatrists or other perceived "leaders in the field" to be paid by drug companies for "educational lectures" attended by family physicians or other psychiatrists, usually at expensive restaurants or lavishly-catered hotel conference rooms (the drug company footing the bill, of course); I think this common practice remains. To be fair, I think everyone assumed that this was all fine, even a useful educational service. Probably many of those involved in this practice still believe that. And perhaps many of these lectures are useful educational services to some degree, it's just that both the lecturers and the recipients may be unaware of the biases involved. Anyway, my lecture was supposed to be about treating resistant depression. I was provided by the company rep with numerous powerpoint slides about mirtazapine to include in my lecture. I did the lecture, and was paid generously for it. I included a few of the slides about mirtazapine, but I truly tried to give a lecture broadly about treating resistant depression, and discussed mirtazapine for only about 20% of the talk. Clearly the company rep was not impressed with my performance, and I was never again asked to do a lecture for them. I'm glad of that, since the more one does these things, the more one can be convinced that it is professionally appropriate, despite the obvious biases involved.
Around 2000-2001 I was involved in a clinical study of a new drug. The drug company sponsored the study, flew everyone business-class to Monaco (on the French Riviera), and put us up in a lavish 5-star hotel, to attend an introductory meeting regarding the study. Such meetings, in my opinion, are utterly needless expenses. Introductions and instructions about a study can be done without transcontinental travel. Training for rating scales, etc., could be done in some other simple, standardized way, without any need for travel. I did enjoy the trip, and I wouldn't doubt that it contributed to my having a more favourable view of that company's products in the following years.
Also around 2000-2001 I was involved in another clinical study. The drug company, also sponsoring the study, flew everyone business-class to Miami, Florida, and put us up in a famous 5-star hotel. By this time I was starting to have more questions about the neutrality of the research, under these circumstances. Something that struck me during that trip was my observations of the company reps meticulously preparing their video presentation for us -- they were preparing a show; it was basically a slick info-mercial, sound-effects and all. I was also struck by the fact that no one around me seemed to notice this or have a critical view of it. I felt like, on the one hand, we were being treated like royalty, but on the other hand we were simply being bought. I realize that it is good for companies to make participation in research projects attractive to everyone involved. It can be frustrating work to recruit patients for clinical studies, and many psychiatrists would rather not take time away from other aspects of work to participate in research. Research is important, and maybe travel & adventure could be fair aspects to enjoying the life of a researcher. BUT -- the travel is really not necessary at all. It is an extravagance. Information and training about a research protocol can happen locally. Other communication can happen over the phone, over the net, or over a video link. The other expensive extravagances just reduce the neutrality of the study, and also bias all participants (many of whom are "leaders in the field" who often influence other practitioners) to have and convey a more favourable view of the company's products, irrespective of the results of the particular study.
I think it would be interesting to have disclosures in research papers not only about the authors' affiliations with, or income received from, the drug companies, but also about the travel expenses paid by the companies for meetings pertaining to the study in question.
A more mundane aspect of industry sponsorship, during my residency between 1995-2000, was the weekly phenomenon of the "drug lunch." Basically, during almost every group meeting or rounds, food would be provided by a drug rep--usually quite a tasty lunch.
A continuing aspect of industry sponsorship is the distribution of free samples. At times I find this quite useful, to help someone get started on something right away, without the time or expense of a pharmacy visit. At other times, people have not been able to afford medication (the most common psychiatric medications are available for free in BC, through a government plan, but many more exotic medications are not covered by this plan): in some cases, the drug companies have provided a free "compassionate release" supply of medication for extended periods of time. Yet, I recognize that these phenomena lead to bias. The presence of a particular sample can influence the choice of which particular medication to recommend, particularly when the different choices are all similarly effective.
I realize this post may come off sounding like some kind of anti-corporate rant. I don't want to slam corporations too much though -- thanks to large companies, we have many more treatments which can profoundly improve quality of life, and which can save many lives. Profit-oriented motivations can drive productivity, competition, and better research. It's just that we can't be swept into the current of advertising and other biased persuasive tactics which companies use to sell more of their products. We can sympathize with the reality that companies behave this way, but as health care professionals, or as individuals contemplating whether or not to take a particular medication or other treatment, we need to have information which is clear, unbiased, as objective as possible.
Around 2000-2001 I was involved in a clinical study of a new drug. The drug company sponsored the study, flew everyone business-class to Monaco (on the French Riviera), and put us up in a lavish 5-star hotel, to attend an introductory meeting regarding the study. Such meetings, in my opinion, are utterly needless expenses. Introductions and instructions about a study can be done without transcontinental travel. Training for rating scales, etc., could be done in some other simple, standardized way, without any need for travel. I did enjoy the trip, and I wouldn't doubt that it contributed to my having a more favourable view of that company's products in the following years.
Also around 2000-2001 I was involved in another clinical study. The drug company, also sponsoring the study, flew everyone business-class to Miami, Florida, and put us up in a famous 5-star hotel. By this time I was starting to have more questions about the neutrality of the research, under these circumstances. Something that struck me during that trip was my observations of the company reps meticulously preparing their video presentation for us -- they were preparing a show; it was basically a slick info-mercial, sound-effects and all. I was also struck by the fact that no one around me seemed to notice this or have a critical view of it. I felt like, on the one hand, we were being treated like royalty, but on the other hand we were simply being bought. I realize that it is good for companies to make participation in research projects attractive to everyone involved. It can be frustrating work to recruit patients for clinical studies, and many psychiatrists would rather not take time away from other aspects of work to participate in research. Research is important, and maybe travel & adventure could be fair aspects to enjoying the life of a researcher. BUT -- the travel is really not necessary at all. It is an extravagance. Information and training about a research protocol can happen locally. Other communication can happen over the phone, over the net, or over a video link. The other expensive extravagances just reduce the neutrality of the study, and also bias all participants (many of whom are "leaders in the field" who often influence other practitioners) to have and convey a more favourable view of the company's products, irrespective of the results of the particular study.
I think it would be interesting to have disclosures in research papers not only about the authors' affiliations with, or income received from, the drug companies, but also about the travel expenses paid by the companies for meetings pertaining to the study in question.
A more mundane aspect of industry sponsorship, during my residency between 1995-2000, was the weekly phenomenon of the "drug lunch." Basically, during almost every group meeting or rounds, food would be provided by a drug rep--usually quite a tasty lunch.
A continuing aspect of industry sponsorship is the distribution of free samples. At times I find this quite useful, to help someone get started on something right away, without the time or expense of a pharmacy visit. At other times, people have not been able to afford medication (the most common psychiatric medications are available for free in BC, through a government plan, but many more exotic medications are not covered by this plan): in some cases, the drug companies have provided a free "compassionate release" supply of medication for extended periods of time. Yet, I recognize that these phenomena lead to bias. The presence of a particular sample can influence the choice of which particular medication to recommend, particularly when the different choices are all similarly effective.
I realize this post may come off sounding like some kind of anti-corporate rant. I don't want to slam corporations too much though -- thanks to large companies, we have many more treatments which can profoundly improve quality of life, and which can save many lives. Profit-oriented motivations can drive productivity, competition, and better research. It's just that we can't be swept into the current of advertising and other biased persuasive tactics which companies use to sell more of their products. We can sympathize with the reality that companies behave this way, but as health care professionals, or as individuals contemplating whether or not to take a particular medication or other treatment, we need to have information which is clear, unbiased, as objective as possible.
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