SOURCE: Global Medical Education
Guest Commentary by Chittaranjan Andrade, MD
Guest Commentary by Chittaranjan Andrade, MD
GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.
REVIEW INCLUDES:
- Negative Outcome of Charles Bonnet Syndrome
- Rate of Chiari I Malformation in Children of Mothers with Depression With and Without Prenatal SSRI Exposure
- Preventive Effects of Ramelteon on Delirium: A Randomized Placebo-controlled Trial
- Increased Risk of Acute Cardiovascular Events After Partner Bereavement: A Matched Cohort Study
- Preterm Birth and Antidepressant Medication Use During Pregnancy: A Systematic Review and Meta-analysis
Negative Outcome of Charles Bonnet Syndrome
Cox TM, Ffytche DH.
Br J Ophthalmol 2014
Objective
The Charles Bonnet syndrome (CBS) describes the occurrence of visual hallucinations in persons with visual (typically, macular) impairment. It is generally believed that these hallucinations are non-distressing, and that the syndrome is uncommon, transient, and self-limiting. Most studies on CBS are based on small samples. This study described CBS in what is probably the largest study to date.
Conclusion
The Charles Bonnet syndrome may be more common, less benign, and longer lasting than is commonly believed.
Clinical Commentary
Given the low (31%) response rate, it is likely that persons with CBS, especially those with more severe and long-lasting CBS, self-selected themselves into the sample. The percentages reported in this study could therefore be suspect. Furthermore, given that the data were collected through a questionnaire (or a phone call, in some cases) and not through face-to-face clinical assessments, the data could also be suspect. Curiously, the authors did not discuss either limitation.
Cox TM, Ffytche DH.
Br J Ophthalmol 2014
Objective
The Charles Bonnet syndrome (CBS) describes the occurrence of visual hallucinations in persons with visual (typically, macular) impairment. It is generally believed that these hallucinations are non-distressing, and that the syndrome is uncommon, transient, and self-limiting. Most studies on CBS are based on small samples. This study described CBS in what is probably the largest study to date.
Conclusion
The Charles Bonnet syndrome may be more common, less benign, and longer lasting than is commonly believed.
Clinical Commentary
Given the low (31%) response rate, it is likely that persons with CBS, especially those with more severe and long-lasting CBS, self-selected themselves into the sample. The percentages reported in this study could therefore be suspect. Furthermore, given that the data were collected through a questionnaire (or a phone call, in some cases) and not through face-to-face clinical assessments, the data could also be suspect. Curiously, the authors did not discuss either limitation.
Rate of Chiari I Malformation in Children of Mothers with Depression With and Without Prenatal SSRI Exposure
Knickmeyer RC, Meltzer-Brody S, Woolson S, et al
Neuropsychopharmacology 2014
Objective
Selective serotonin reuptake inhibitors (SSRIs) have previously been associated with rare but specific congenital malformations after first trimester exposure during pregnancy. This magnetic resonance imaging (MRI) study suggests that SSRI exposure may also increase the risk of the Chiari I malformation (CIM), a condition in which the cerebellar tonsils extend significantly below the foramen magnum.
Conclusion
Exposure to SSRIs during pregnancy is associated with a marked increase in the risk of MRI-diagnosed Chiari I malformation at 1 and 2 years of age. This risk is increased if SSRI exposure occurs at the time of conception, and if the duration of exposure is greater. This risk does not appear to be mediated by maternal depression.
Clinical Commentary
It is interesting that a maternal family history of depression increased the SSRI-associated risk of CIM. Knickmeyer et al suggested that this may represent a double-hit situation where genetic (family history) and environmental (SSRI exposure) factors may interact to trigger an adverse outcome (CIM). In addition, underdevelopment of the posterior cranial fossa can crowd the developing hindbrain; CIM may be a consequence; the condition develops after birth. Whereas CIM is often asymptomatic, it may be associated with headache, disturbances of hearing or vision, lower cranial nerve disturbances, hydrocephalus, spinal cord syrinx, or other neurological conditions. A follow up of the CIM children in this study would educate readers about the clinical importance of the findings. Knickmeyer et al provided a competent explanation for and a responsible interpretation of their findings.
Knickmeyer RC, Meltzer-Brody S, Woolson S, et al
Neuropsychopharmacology 2014
Objective
Selective serotonin reuptake inhibitors (SSRIs) have previously been associated with rare but specific congenital malformations after first trimester exposure during pregnancy. This magnetic resonance imaging (MRI) study suggests that SSRI exposure may also increase the risk of the Chiari I malformation (CIM), a condition in which the cerebellar tonsils extend significantly below the foramen magnum.
Conclusion
Exposure to SSRIs during pregnancy is associated with a marked increase in the risk of MRI-diagnosed Chiari I malformation at 1 and 2 years of age. This risk is increased if SSRI exposure occurs at the time of conception, and if the duration of exposure is greater. This risk does not appear to be mediated by maternal depression.
Clinical Commentary
It is interesting that a maternal family history of depression increased the SSRI-associated risk of CIM. Knickmeyer et al suggested that this may represent a double-hit situation where genetic (family history) and environmental (SSRI exposure) factors may interact to trigger an adverse outcome (CIM). In addition, underdevelopment of the posterior cranial fossa can crowd the developing hindbrain; CIM may be a consequence; the condition develops after birth. Whereas CIM is often asymptomatic, it may be associated with headache, disturbances of hearing or vision, lower cranial nerve disturbances, hydrocephalus, spinal cord syrinx, or other neurological conditions. A follow up of the CIM children in this study would educate readers about the clinical importance of the findings. Knickmeyer et al provided a competent explanation for and a responsible interpretation of their findings.
Preventive Effects of Ramelteon on Delirium: A Randomized Placebo-controlled Trial
Hatta K, Kishi Y, Wada K, et al
JAMA Psychiatry. 2014;71:397-403.
Objective
Medically ill inpatients, especially those who are elderly and those in intensive care units, are at increased risk of delirium. Medications such as antipsychotics but not cholinesterase inhibitors have been found effective in preventing delirium in elderly patients at risk. Encouraged by reports of benefit with melatonin 0.5 mg/night. This study examined whether the MT1 and MT2 melatonin receptor agonist ramelteon, an approved treatment for sleep-onset insomnia, offers benefits in this regard.
Conclusions
Ramelteon (8 mg/night for 1 week) is associated with a substantial reduction in the risk of delirium in seriously medically ill inpatients. Onset of delirium is also approximately 1 day later in ramelteon-treated patients.
Clinical Commentary
Ramelteon did not improve any sleep outcome; in fact, numerically (but not statistically) more ramelteon patients required emergency medication for insomnia. Therefore, improved sleep or mechanisms related thereto seems an unlikely explanation for the benefits observed with ramelteon. Perhaps modulation of melatonergic neurotransmission, or of hypothalamic activity, reduces the risk of delirium in elderly patients at risk. Melatonin and ramelteon are far better tolerated than antipsychotic drugs and are therefore more important as delirium preventive agents in elderly patients at risk. One wonders whether these drugs would also be effective in delirium prophylaxis in younger patients, post-surgical patients, and patients with alcohol or drug withdrawal states.
Hatta K, Kishi Y, Wada K, et al
JAMA Psychiatry. 2014;71:397-403.
Objective
Medically ill inpatients, especially those who are elderly and those in intensive care units, are at increased risk of delirium. Medications such as antipsychotics but not cholinesterase inhibitors have been found effective in preventing delirium in elderly patients at risk. Encouraged by reports of benefit with melatonin 0.5 mg/night. This study examined whether the MT1 and MT2 melatonin receptor agonist ramelteon, an approved treatment for sleep-onset insomnia, offers benefits in this regard.
Conclusions
Ramelteon (8 mg/night for 1 week) is associated with a substantial reduction in the risk of delirium in seriously medically ill inpatients. Onset of delirium is also approximately 1 day later in ramelteon-treated patients.
Clinical Commentary
Ramelteon did not improve any sleep outcome; in fact, numerically (but not statistically) more ramelteon patients required emergency medication for insomnia. Therefore, improved sleep or mechanisms related thereto seems an unlikely explanation for the benefits observed with ramelteon. Perhaps modulation of melatonergic neurotransmission, or of hypothalamic activity, reduces the risk of delirium in elderly patients at risk. Melatonin and ramelteon are far better tolerated than antipsychotic drugs and are therefore more important as delirium preventive agents in elderly patients at risk. One wonders whether these drugs would also be effective in delirium prophylaxis in younger patients, post-surgical patients, and patients with alcohol or drug withdrawal states.
Increased Risk of Acute Cardiovascular Events After Partner Bereavement: A Matched Cohort Study
Carey IM, Shah SM, DeWilde S, et al.
JAMA Intern Med. 2014; 174: 598-605.
Objective
Death of a spouse is given the highest ranking (100 out of 100) on the Social Readjustment Rating Scale. Can the high emotional turmoil associated with partner bereavement result in adverse cardiovascular and other important health outcomes? If yes, what is the magnitude of the risk? This subject was addressed in this population-based matched cohort study conducted in the UK.
Results
The 30-day risk of fatal or non-fatal myocardial infarction or stroke was significantly higher in the bereaved group than in the nonbereaved group (0.16% vs 0.08%, respectively; IRR, 2.20; 95% CI, 1.52-3.15). This risk remained statistically significant but was substantially attenuated at 90 (0.38% vs 0.27%; IRR, 1.59) and 365 (1.28% vs 1.11%; IRR, 1.14) days. The risk of myocardial infarction and stroke was not significantly modified by age, sex, or preexisting cardiovascular disease at any time point (30, 90, and 365 days). The risk of myocardial infarction and stroke were each significantly elevated at 30 days (IRR, 2.14 and 2.40, respectively) and 90 days (IRR, 1.47 and 1.52, respectively), but not at 365 days (IRR, 1.20 and 1.02, respectively). The risks of non-myocardial infarction acute coronary syndrome and pulmonary embolism could not be assessed at 30 days because there were too few events. However, these risks were significantly increased at 90 but not at 365 days.
Clinical Commentary
The excess risk of fatal or non-fatal myocardial infarction or stroke was 0.08% in the first 30 days after partner bereavement; that is, 1 in 1,250. This statistic may be important at the population level but is perhaps not high at the individual level. The risk of acute myocardial infarction is elevated as early as a day after the experience of bereavement. A meta-analysis suggested that mortality after partner bereavement is higher in men than in women; however, this difference decreased with increasing age. Predictors of the risk of adverse outcomes after partner bereavement need to be identified. Whereas elegant biological mechanisms involving stress, cortisol, autonomic nervous system disturbances, changes in heart rate variability, and others may be validly proposed, it should also be remembered that bereaved persons, especially elderly bereaved persons, may neglect their own health care needs in matters such as compliance to current health instructions and attention to emerging medical symptoms.
Carey IM, Shah SM, DeWilde S, et al.
JAMA Intern Med. 2014; 174: 598-605.
Objective
Death of a spouse is given the highest ranking (100 out of 100) on the Social Readjustment Rating Scale. Can the high emotional turmoil associated with partner bereavement result in adverse cardiovascular and other important health outcomes? If yes, what is the magnitude of the risk? This subject was addressed in this population-based matched cohort study conducted in the UK.
Results
The 30-day risk of fatal or non-fatal myocardial infarction or stroke was significantly higher in the bereaved group than in the nonbereaved group (0.16% vs 0.08%, respectively; IRR, 2.20; 95% CI, 1.52-3.15). This risk remained statistically significant but was substantially attenuated at 90 (0.38% vs 0.27%; IRR, 1.59) and 365 (1.28% vs 1.11%; IRR, 1.14) days. The risk of myocardial infarction and stroke was not significantly modified by age, sex, or preexisting cardiovascular disease at any time point (30, 90, and 365 days). The risk of myocardial infarction and stroke were each significantly elevated at 30 days (IRR, 2.14 and 2.40, respectively) and 90 days (IRR, 1.47 and 1.52, respectively), but not at 365 days (IRR, 1.20 and 1.02, respectively). The risks of non-myocardial infarction acute coronary syndrome and pulmonary embolism could not be assessed at 30 days because there were too few events. However, these risks were significantly increased at 90 but not at 365 days.
Clinical Commentary
The excess risk of fatal or non-fatal myocardial infarction or stroke was 0.08% in the first 30 days after partner bereavement; that is, 1 in 1,250. This statistic may be important at the population level but is perhaps not high at the individual level. The risk of acute myocardial infarction is elevated as early as a day after the experience of bereavement. A meta-analysis suggested that mortality after partner bereavement is higher in men than in women; however, this difference decreased with increasing age. Predictors of the risk of adverse outcomes after partner bereavement need to be identified. Whereas elegant biological mechanisms involving stress, cortisol, autonomic nervous system disturbances, changes in heart rate variability, and others may be validly proposed, it should also be remembered that bereaved persons, especially elderly bereaved persons, may neglect their own health care needs in matters such as compliance to current health instructions and attention to emerging medical symptoms.
Preterm Birth and Antidepressant Medication Use During Pregnancy: A Systematic Review and Meta-analysis
Huybrechts KF, Sanghani RS, Avorn J, et al
PLoS One. 2014; 9: e92778.
Objective
Antidepressant drugs have been associated with an increased risk of preterm birth. However, the risk is small. For example, a recent meta-analysis of 15 studies reported that gestational age was 3.2 (95% CI, 1.8-4.5) days shorter in women who had received an antidepressant during pregnancy relative to controls who had not; there was little difference in analyses that were restricted to different sets of controls. Given that preterm birth is associated with increased neonatal morbidity and mortality, as well as with adverse long-term outcomes, these authors subjected the research in the field to a systematic review and meta-analysis.
Conclusions
Third but not first trimester antidepressant exposure is associated with an increased risk of preterm birth.
Clinical Commentary
Most of the studies in this meta-analysis adjusted risks for various confounding variables. However, no amount of adjustment, or even propensity matching, can alter the fact that illness characteristics are likely to be more severe in depressed women who take an antidepressant during pregnancy relative to depressed women who do not. Therefore, illness behavior, or genetic concomitants thereof (and not necessarily antidepressant use), may explain adverse pregnancy outcomes. This may be why antidepressant use was no longer associated with preterm birth in one study after depression severity was controlled for. Examples of illness behavior that is often not controlled for in such studies include nutrition, smoking, and alcohol and substance use or abuse. If illness behaviors increase adverse pregnancy outcomes, then antidepressant use might actually reduce the adverse pregnancy outcomes to the extent that antidepressants are able to reduce the adverse illness behaviors. This study provided a good discussion on the limitations of the literature in the field. For example, women may fill a prescription for an antidepressant drug but may not take a drug; or, they may take the drug irregularly; or, they may take the drug during part of the pregnancy but not during the whole pregnancy. For these and other reasons, it is hard to correctly classify antidepressant use during pregnancy, and hence interpretation of data becomes difficult.
Huybrechts KF, Sanghani RS, Avorn J, et al
PLoS One. 2014; 9: e92778.
Objective
Antidepressant drugs have been associated with an increased risk of preterm birth. However, the risk is small. For example, a recent meta-analysis of 15 studies reported that gestational age was 3.2 (95% CI, 1.8-4.5) days shorter in women who had received an antidepressant during pregnancy relative to controls who had not; there was little difference in analyses that were restricted to different sets of controls. Given that preterm birth is associated with increased neonatal morbidity and mortality, as well as with adverse long-term outcomes, these authors subjected the research in the field to a systematic review and meta-analysis.
Conclusions
Third but not first trimester antidepressant exposure is associated with an increased risk of preterm birth.
Clinical Commentary
Most of the studies in this meta-analysis adjusted risks for various confounding variables. However, no amount of adjustment, or even propensity matching, can alter the fact that illness characteristics are likely to be more severe in depressed women who take an antidepressant during pregnancy relative to depressed women who do not. Therefore, illness behavior, or genetic concomitants thereof (and not necessarily antidepressant use), may explain adverse pregnancy outcomes. This may be why antidepressant use was no longer associated with preterm birth in one study after depression severity was controlled for. Examples of illness behavior that is often not controlled for in such studies include nutrition, smoking, and alcohol and substance use or abuse. If illness behaviors increase adverse pregnancy outcomes, then antidepressant use might actually reduce the adverse pregnancy outcomes to the extent that antidepressants are able to reduce the adverse illness behaviors. This study provided a good discussion on the limitations of the literature in the field. For example, women may fill a prescription for an antidepressant drug but may not take a drug; or, they may take the drug irregularly; or, they may take the drug during part of the pregnancy but not during the whole pregnancy. For these and other reasons, it is hard to correctly classify antidepressant use during pregnancy, and hence interpretation of data becomes difficult.
