Pain Affects Clinical Patterns and Treatment Outcomes for Patients With Major Depressive Disorder Taking Fluoxetine

Although pain is not listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) as a symptom of major depressive disorder (MDD), previous studies have shown that a large proportion of patients with depressive report symptoms of pain. In addition, research has shown that pain and depression may share common pathways in the body. They may be connected through stress and the hypothalamic-pituitary-adrenal axis.

This study aimed to see how baseline levels of pain affect outcomes in patients treated for MDD with fluoxetine. Specifically, the study hypothesized that severity of baseline would be associated with poorer outcomes and a distinct clinical profile. For 6 weeks in an in-patient hospital, 119 MDD patients were given 20 mg fluoxetine daily doses and monitored for various outcomes. Outcomes included adherence, pain severity and pain interference (measured by the body pain index of the Medical Outcomes Study Short-Form), symptom severity (measured by the Hamilton Rating Scale for Depression), social functioning (measured by the Work and Social Adjustment Scale), and adverse event severity (Utvalg for Kliniske Undersogelser Side Effect Rating Scale).

Results from this study showed that pain and multiple aspects of MDD were associated and that patients with higher baseline levels of pain experienced more severe depressive symptoms. Specifically, subjects with higher levels of pain had greater risk of suicide and stressful life events. They also had less improvement in depressive symptoms despite receiving the same fluoxetine treatment as well as more functional impairment.

This study reminds me of the pain lecture from Dr. Pruskowski as she also explained the connection between depression and pain. Being cognizant of this connection can help us better understand our patients as pharmacists. Perhaps we can inquire about MDD patients’ pain levels during medication therapy management. I would be curious to see if there is evidence supporting the use of pain treatments to help improve depressive symptoms in those with both severe pain and depression. If so, many patients may have a drug therapy problem of needing additional therapy.

Lin H, Wang F, Lin C. Pain affects clinical patterns and treatment outcomes for patients with major depressive disorder taking fluoxetine. J Clin Psychopharmacol. 2015; 35(6):661-6

Polymorphism Associated with the Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Response in Depression

Are pharmacogenetics-based strategies the key to effective depression treatment? This study set out to dig deeper into this questions by researching additional polymorphisms affecting the efficacy of SSRIs. Previously, a polymorphism in the serotonin transporter linked promoter region was found to be associated with a difference in SSRI efficacy. This polymorphism, however, only explained a small amount of the differences in efficacy seen in the treatment of those with depression. So this study intended to find additional polymorphisms in the gene coding for the serotonin transporter (SLC6A4) accounting for different responses in SSRI/SNRI treatment. (Remember that the serotonin transporter is the target of serotonin uptake inhibitors)

A 6-week randomized controlled trial of 201 patients with major depressive disorder was performed. Subjects were given paroxetine 20-40 mg/d (SSRI), fluvoxamine 50-150 mg/d (SSRI), or milnacipran 50-75 mg/d (SNRI). Efficacy of the therapy was measured by comparing baseline Hamilton Depression Rating Scale (HAM-D) values with those from the end of the 6 week treatment period. Genomic DNA was gathered from each patient and sequenced so that SLC6A4 mutations could be analyzed. 32 variants were found, and 17 of these were new polymorphisms. One of the polymorphisms, rs3813034, resulted in significantly altered HAM-D scores for each medication administered, suggesting it has an effect on SSRI/SNRI response.

Considering all the treatment hurdles those with depression face (medications take a lot of time for effects to be realized and they may not be effective for many people), I think it is important to research the pharmacogenetics involved with SSRIs. This can help create more individualized treatments for patients who do not have months to spend time putting their well-being on hold while they try numerous antidepressants before finding one that works. Do you think it would be practical and possible to someday have a genotype-based protocol for antidepressant treatments?

Nonen, S et al. Polymorphism of rs3813034 in Serotonin Transporter Gene SLC6A4 Is Associated With the Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Response in Depressive Disorder: Sequencing Analysis of SLC6A4. J. Clin. Psychopharmacol. 2016; 36(1):27-3.

Depression in Childhood and the association of Cortical Grey Matter Development

In early childhood the volume of cortical grey matter in the brain increases significantly, and then begins to decrease again after puberty. The decrease in thickness is a very selective elimination and demyelination. This period “U-shaped trajectory” is very important and has been found to be associated with cognition and emotional function. Luby and colleagues decided to study the effects that early childhood depression has on the cortical grey matter development in adolescence.

The trail design included 193 children from St Louis, Missouri, aged 3 to 6. They were studied in a longitudinal study for 11 years (Sep. 2003 to Dec. 2014). The data collected was behavioral and neuroimaging and trajectory was measured based on volume, thickness, and surface area. These were analyzed to study the association between depression symptoms and previously diagnosed major depressive disorder with the trajectory of cortical grey matter. The study found that there was an association between an episode of major depressive disorder in childhood with grey matter volume loss (slope of -0.93cm^3) and thinning (slope of -0.0044mm). Both were found to be significant findings. On the other hand there was no association found with family history of major depressive disorder or a traumatic life experience.

This study was shown to really highlight the significance of childhood depression and neural development. I think its really interesting that children so young are experiencing major depressive disorder. A study should be done, if not already, in order to determine if depression rates have increased in children over the past few decades. I do not think that medications are always the answer for children, but I do believe that we need to find the root of the problem and begin there. If this depression is making such an impact on the development, then it could be associated with many problems down the road for individuals. This study shows that if major depressive disorder can be prevented in children, problems down the road with cognitive and emotional abilities.

Jama Psychiatry. 2016;73(1):31-38.

Antidepressant Use and Risk of Recurrent Stroke: A Population-Based Nested Case-Control Study

Approximately 30% of individuals that have had a stroke are also diagnosed with depression, and although antidepressant therapy is recommended in patients with post-stroke depression, there are no guidelines for choosing therapy options. For this reason, a study was conducted to determine the relationship between the use of various classes of antidepressant medications and the recurrence of stokes. This longitudinal study analyzed health insurance database information of adults over the age of 18 who had a stroke and were readmitted with this condition. Around 10,000 patient cases were included in the study results (6,679 controls; 3,536 cases).  The study found that there was not an increased risk of stroke recurrence in patients taking SSRIs for depression; however, a correlation was found in patients being treated with TCAs (1.41 times increase). The risk for stroke recurrence in patients taking TCAs did not show much differentiation when analyzing dose and treatment duration variations. As a result, the study highly recommends using alternative methods of treatment for depression symptoms in patients who have experienced a stroke.

I believe this article is important to the understanding of pharmaceutical care due to the fact that antidepressants are one of the most commonly prescribed classes of medications. As healthcare professional that prioritize on the safety of treatment methods, we should be aware of medication contraindications so that we can provide the best patient care. Although all healthcare professionals look out for the best interests of the patient, pharmacists specialize on medications and thus will have the best knowledge on the potential dangers associated with treatment methods. This study makes me want to learn more about specific medication contraindications so that I will no how to protect patients health after graduation from pharmacy school.

 

 

Antidepressants Taken by Pregnant Woman and the Risk of Autism in her Child

Autism spectrum disorder has no known single cause for its occurrence, but it is known to result from some sort of abnormality in the brain. Some studies suggest that it is genetic, however, a gene has not been identified to cause autism. It is also thought that babies may be born susceptible to autism, but there is no trigger that has been identified. One theory of autism is mothers using harmful substances while pregnant.

This study aims to uncover if antidepressants in pregnant mothers constitutes a harmful substance to the baby and therefore causes autism. This is a controversial topic, because the mother is put in a tough spot. The study was register-based of an ongoing population-based cohort in Quebec from January 1, 1998 to December 31, 2009. 145, 456 babies were born during this time. The study classified the different antidepressants into class as well as what trimesters they were used in. The average age of the children studied was 6.24 years old. About 1,054 of these children had a diagnosis of autism, which is about 0.7%. There were 4 boys to every 1 girl diagnosed. 31 infants were exposed to antidepressants during the second or third trimester, and the hazard ratio was 1.87. Specifically, 22 infants were exposed to SSRIs, and this caused the health ratio to be 2.17. It was concluded that antidepressants, especially SSRIs, do increase the risk of having an autistic child if the medication is taken during the second or third trimester. More research is needed to figure out why.

I think this is such a hard decision for a mother that suffers from depression, because she needs to decide if she can handle her mental health without medication for the sake of her child. Relapse into depression may also be harmful for her baby though. The percentage of babies born with autism was relatively small, however, I would not want to take that risk with my baby. Would you choose to suffer depression or take your chances with your baby? Are there other treatment options for depression that would not harm the baby?

Boukhris T, Sheehy O, Mottron L, Bérard A. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr. 2016;170(2):117-124. doi:10.1001/jamapediatrics.2015.3356.

Cognitive Based Therapy versus Pharmacologic Treatment of Adult Patients with Major Depressive Disorder. A Clinical Guideline

Major depressive disorder (MDD) is characterized by a depressed mood, loss of pleasure and interest, significant changes in weight or appetite, trouble sleeping or sleeping too much, fatigue and loss of energy, inability to concentrate, feelings of worthlessness, or thoughts of death or suicide that last for at least two weeks and affect the normal functioning of the individual. Major depression disorder effects 16% of American people and the healthcare costs surrounding it totaled around 83.1 billion dollars in the year 2000, and is probably higher today. Various treatment options exist for MDD, including cognitive behavior therapy such as psychotherapy, exercise, alternative medicine, and pharmacotherapy. This study sought to create a clinical guideline that compared the effectiveness and safety of nonpharmacologic treatments, such as cognitive behavioral therapy (CBT) and pharmacotherapy, alone and in combination for the treatment of MDD. The American College of Physicians recommends that the clinician select between either cognitive behavior therapy or second-generation antidepressants to treat individuals diagnosed with MDD. Using them in combination did not prove to be more effective in the treatment of MDD.

Question: As a pharmacist, how do you feel about individuals that forgo prescription medication and choose to go an alternative route such as cognitive behavior therapy. Do you think pharmacist should be able to recognize when prescription medication is unneeded and when behavior therapy would work better for the patient, or should that be up to the MD to recognize?

PDF

Qaseem A, Barry MJ, Kansagara D. Nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. Epub ahead of print 9 February 2016.

Depression: An Increased Need for Screenings in Primary Care Settings

Depression is found to be one of the leading causes of disability for people in the United States that are 15 and older. Depression is also commonly seen in primary care settings, and is very common in older adults and in women that are pregnant or that just gave birth. In pregnant and post-partum women in particular, it is a large concern because it not only affects the mother, but the child as well. The USPSTF has found that screening adults for depression has greatly improved the identification of adults suffering from depression that came into the primary care setting. Some common screening techniques to use are the Patient Health Questionnaire, the Geriatric Depression Scale in older adults, and the Edinburgh Postnatal Depression Scale in pregnant or postpartum women. After screening, appropriate and common treatments of depression include antidepressants or psychotherapy, either alone or combined. The study also found that treating adults with depression that was identified through screening has lead to decreased morbidity in these patients, and the USPSTF recommends screening for the general adult population, which is all patients over the age of 18, with particular emphasis on pregnant and postpartum women.

JAMA. 2016;315(4):380-387

I chose this article because depression is becoming more and more prevalent in our country. We see this firsthand in the pharmacy with all of the depression and anxiety medications that we dispense, and have even seen proof in our Professions of Pharmacy class with the depression medications that have made it to the Top Drugs list. However, with all of the depression and associated medications that we do see, it is scary to me to hear that there are still so many cases of depression that go un-diagnosed. I believe that having greater screenings for patients that are known to be more prone to depression is important because it will prevent their illness from spiraling out of control while no one knows it is happening. I do not believe that medications should be used in every instance of depression or anxiety, and think that therapy is also a valid option to try, but whatever a patient needs is what they should receive because the primary goal of all health care professionals is to help patient get better, and the first step to that is knowing that there is a problem present.

New study on effects of mirtazapine on tumor necrosis factor-α and serum BDNF could change the way we treat depression.

In a study conducted by Gupta et.al at Guru Teg Bahadur Hospital, New Delhi, they found that mirtazapine could work as a treatment for patients with clinically diagnosed severe depression. According to the drug label for mirtazapine found on Dailymed, it is indicated to treat major depressive disorder as defined by DSM III. Based on DSM IV, episodes of depression can be categorized as mild moderate and severe. According to this paper, mirtazapine has only been proven to be effective in moderate to severe depression, so they intended to test its effect strictly with patients who had severe depression.

 

This study looked at 30 severely depressed patients who were receiving services from the outpatient psychiatric clinic at Guru Teg Bahadur Hospital. They were each given 30 mg of mirtazapine per day and monitored for up to 12 weeks. Their levels of tumor necrosis factor-α and serum BDNF were also monitored, as there are new hypotheses that link high and low amounts respectively of these compounds to depression. The results of the study showed that mirtazapine not only significantly reduced patients’ depression, but also significantly increased mean levels of serum BDNF and significantly decreased mean levels of tumor necrosis factor-α.

 

While this study is exciting and could raise questions about whether the current monoamine theory of depression should be reconsidered, it also has some flaws. For starters, there was a small sample size of just thirty participants. Additionally, the mirtazapine wasn’t tested against a placebo or a positive control such as fluoxetine to determine if it was more or less effective. While the results point in a positive direction, there is still a lot of research to be done to determine if mirtazapine should be considered a first line therapy in the treatment of severe depression.

Link to Article

References

 

Gupta R, Gupta K, Tripathi A, K, Bhatia M, S, Gupta L, K, Effect of Mirtazapine Treatment on Serum Levels of Brain-Derived Neurotrophic Factor and Tumor Necrosis Factor-α in Patients of Major Depressive Disorder with Severe Depression. Pharmacology 2016;97:184-188

 

Remeron (mirtazapine) indications and usage. Hatfield, Hertfordshire: Mylan; 2007 May.

 

American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.).

Use of Ketamine for the Treatment of Severe Depression

Traditional antidepressants and mood stabilizers available on the market often take weeks or months to work. Thus, since 2006 researchers have been studying how ketamine can reverse the type of severe depression that traditional antidepressants are unable to treat. Ketamine is a staple anesthetic in the emergency rooms that are regularly used for children with broken bones or dislocated shoulders. This drug is also used in burn centers and veterinary medicine. In popular culture, ketamine known as a date-rape drug that can quickly numb and render someone immobile.

There are several uses of ketamine, and researchers are finding that it produces a rapid and robust antidepressant effect that can be a quick end to suicidal thinking. For this reason, experts are calling this discovery the “most significant advance in mental health in more than half a century”. A study in the Journal of American Medical Association reported that drugs in a leading class of antidepressants were no better than placebos for most depression. However, with ketamine, one physician reported a 75% effective response rate for treating patients with depression. Ketamine has worked for patients who have spent years switching between antidepressants, mood stabilizers, and other therapies. A significant number of people who do not respond to antidepressants may try cognitive behavior therapy, electroshock therapy, and transcranial stimulation. Instead of going through with these alternative treatments, researchers are hoping that use of ketamine will benefit these patients more.

Currently, patients who seek out ketamine treatment go through six IV drips over a two week period. The dose is about a 10th of the amount used in anesthesia, and the drug takes effect within minutes or hours. So far, there are no signs of addiction involved with this treatment. However, there are several concerns involved with the use of ketamine for the treatment of depression. The relief involved with ketamine is only temporary. Studies have shown that relapse usually occurs a week after an infusion, which is causing patients to seek booster infusions. Low doses of ketamine have also been reported to cause intense hallucinations. Researchers are also concerned about the many unknowns, such as the effect on heart rate and blood pressure and the long-term benefits of the usage of ketamine. In addition there is currently no registry for tracking the number of patients being treated with ketamine for depression, the frequency of treatments, dosage levels, follow up care, and adverse effects. Thus, more standardization is needed for this treatment. Finally, patients who are currently receiving ketamine treatment usually go to anesthesiologists, who are not primarily responsible for treating mental health, which is the field of expertise of psychiatrists. If ketamine treatment becomes more widespread, the relationship between anesthesiologists and psychiatrists may change.

I believe that researching the use of ketamine treatment will be beneficial in the future, because the effectiveness of current treatments for depression are not as effective. However, based on the current information, I agree that there needs to be more research done on ketamine use for depression, especially since the relief is only temporary with ketamine. If Ketamine is becoming more well known as a treatment for depression, there must be more standardization involved. Do you think there any other possible risks of the usage of ketamine for severe depression? Furthermore, if IV administration for ketamine will still continue in the future, how do you think this will affect the role and relationship of anesthesiologists and psychiatrists?

Way, M. L. Ketamine Infusion for the Treatment of Depression. Am J Psychiatry. 2015;10:6-8. 

Cognitive behavioural therapy as an adjunct to pharmacotherapy for depression

Depression can affect individuals for an acute or chronic period, but there has been little research done to examine the efficacy of antidepressants for over 1 year[1]. This recent article by Wiles et al.[2] examines the efficacy of cognitive behavioural therapy (CBT) in conjunction with pharmacotherapy for improving depression in treatment-resistant patients over a 3-5 year period. Depression is a mood disorder characterized by symptoms like decreased energy, difficulty sleeping, concentrating, or eating, loss of interest in activities, and suicidal thoughts. There are several classes of antidepressants such as SSRIs, SNRIs, and tricyclics available that function by affecting receptors of specific neurotransmitters. Cognitive behavioural therapy is a technique to change thinking and behavior patterns to assist the patient in taking action to solve problems.

248 individuals aged 18-75 year olds with substantial depression who had taken antidepressants for at least 6 weeks participated in this UK study from 2008-2010. Individuals were randomly assigned either normal care or CBT in conjunction with normal care. Severity of depression was scored based on the Beck Depression Inventory, where a lower score indicates less severe depression. The median follow-up period during treatment was 45 months. The group that received both pharmacotherapy and CBT had a mean score of 19 whereas the group that received only pharmacotherapy had a mean score of 23. After therapy ended the average follow-up period was 40 months. Cost-analysis showed that using both therapies in conjunction was cost-effective for the quality-adjusted life year (QALY) gain.

Since CBT in conjunction with pharmacotherapy has been shown to be effective in the long-term, how do you think pharmacists can increase the amount of patients who receive CBT?

  1. Uher R, Pavlova B. Long-term effects of depression treatment. The Lancet Psychiatry. 2016;3(2):95-96.
  2. Wiles, Nicola J et al. Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised control trial. The Lancet Psychiatry. 2016;3(2):137-144.