SOURCE: Global Medical Education
Guest Commentary by Rajnish Mago, M.D
Guest Commentary by Rajnish Mago, M.D
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:
- Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis
- Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study
- A double-blind randomized controlled trial of augmentation and switch strategies for refractory social anxiety disorder
- Prescribing thiamine to inpatients with alcohol use disorders: how well are we doing?
- Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial
Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis.
Grigoriadis et al.
BMJ. 2014 Jan 14;348:f6932.
Objective
To systematically review all relevant papers on the risk for persistent pulmonary hypertension of the newborn (PPHN) in neonates who were exposed to antidepressants in utero.
Results
• Only for selective serotonin reuptake inhibitors (SSRIs) was there enough data for quantitative analyses to be possible
• Persistent pulmonary hypertension of the newborn was not statistically significantly associated with exposure to an SSRI in early pregnancy (odds ratio 1.23 but p=0.58).
• However, PPHN was statistically significantly associated with exposure to an SSRI in late pregnancy (odds ratio 2.50, p=0.005).
• The authors then tried to see how some other variables might affect this finding, but study design, congenital malformations, and meconium aspiration were not found to be statistically significantly affect the main finding of the study. Possible effect of some other variables (caesarean section, body mass index, or preterm delivery) could not be assessed.
• Lastly, while there is clearly an association between persistent pulmonary hypertension of the newborn and use of an SSRI in late pregnancy, an important question is how rare is this problem. The increase in risk was estimated to be somewhere between 2.9 to 3.5 per 1000 infants. This means that it is estimated that about if about 300 women were treated with an SSRI in late pregnancy, one additional neonate would be born with persistent pulmonary hypertension of the newborn.
Conclusions
• Persistent pulmonary hypertension of the newborn is associated with exposure to an SSRI in late pregnancy, but not to exposure in early pregnancy.
• The absolute risk is, however, low
Clinical Commentary
• A lot of interest has been generated in this topic. Thus, this article does us a service by bringing together the most important studies on the topic. We must conclude that a number of studies have now shown the association between persistent pulmonary hypertension of the newborn and exposure to an SSRI in late pregnancy.
• Clinicians should not be falsely reassured by studies that followed a few hundred or a few thousand mothers who took an SSRI in late pregnancy and did not find such an association. Rare adverse events are hard to detect in such cohort studies unless tens of thousands of exposed individuals are followed. It is precisely in such situations that a case control design (starting with neonates with or without PPHN and working backwards) is more informative.
• In my opinion, it is now unacceptable to not discuss the risk of PPHN with women prescribed an SSRI in late pregnancy.
• In thinking about this matter, it should be remembered that even though the risk is small, PPHN is a very serious condition and is often fatal
Grigoriadis et al.
BMJ. 2014 Jan 14;348:f6932.
Objective
To systematically review all relevant papers on the risk for persistent pulmonary hypertension of the newborn (PPHN) in neonates who were exposed to antidepressants in utero.
Results
• Only for selective serotonin reuptake inhibitors (SSRIs) was there enough data for quantitative analyses to be possible
• Persistent pulmonary hypertension of the newborn was not statistically significantly associated with exposure to an SSRI in early pregnancy (odds ratio 1.23 but p=0.58).
• However, PPHN was statistically significantly associated with exposure to an SSRI in late pregnancy (odds ratio 2.50, p=0.005).
• The authors then tried to see how some other variables might affect this finding, but study design, congenital malformations, and meconium aspiration were not found to be statistically significantly affect the main finding of the study. Possible effect of some other variables (caesarean section, body mass index, or preterm delivery) could not be assessed.
• Lastly, while there is clearly an association between persistent pulmonary hypertension of the newborn and use of an SSRI in late pregnancy, an important question is how rare is this problem. The increase in risk was estimated to be somewhere between 2.9 to 3.5 per 1000 infants. This means that it is estimated that about if about 300 women were treated with an SSRI in late pregnancy, one additional neonate would be born with persistent pulmonary hypertension of the newborn.
Conclusions
• Persistent pulmonary hypertension of the newborn is associated with exposure to an SSRI in late pregnancy, but not to exposure in early pregnancy.
• The absolute risk is, however, low
Clinical Commentary
• A lot of interest has been generated in this topic. Thus, this article does us a service by bringing together the most important studies on the topic. We must conclude that a number of studies have now shown the association between persistent pulmonary hypertension of the newborn and exposure to an SSRI in late pregnancy.
• Clinicians should not be falsely reassured by studies that followed a few hundred or a few thousand mothers who took an SSRI in late pregnancy and did not find such an association. Rare adverse events are hard to detect in such cohort studies unless tens of thousands of exposed individuals are followed. It is precisely in such situations that a case control design (starting with neonates with or without PPHN and working backwards) is more informative.
• In my opinion, it is now unacceptable to not discuss the risk of PPHN with women prescribed an SSRI in late pregnancy.
• In thinking about this matter, it should be remembered that even though the risk is small, PPHN is a very serious condition and is often fatal
Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study.
Stamm et al.
J Clin Psychiatry. 2014;75(2):162-8. PMID: 24345793
Objective
To test the whether adding supraphysiologic doses of levothyroxine to other medications in patients with bipolar depression is efficacious.
Methods
• A multicenter, double-blind, randomized, placebo-controlled trial was conducted.
• Patients with either bipolar I or bipolar II disorder who were currently depressed were recruited.
• Patients had to have normal TSH levels, no history of either thyroid disease, and no rapid cycling.
• Patients were required to have not responded to treatment with a mood stabilizer and/or an antidepressant taken for at least 6 weeks.
• Levothyroxine was given in a fixed-dose of 300 mcg/day and was compared to a placebo.
• Patients were also continued on previous medications: either a mood stabilizer and/or an antidepressant
• The primary efficacy variable was reduction in severity of depression. This was measured as the mean change in total score on the Hamilton Depression Rating Scale (HDRS).
Results
• 62 patients were randomized
• 35 of these patients had bipolar I disorder
• The mean change in HDRS score from randomization to end of 6 weeks of treatment was larger in the levothyroxine group compared to the placebo group and the change in severity of depression was greater with levothyroxine after 4 weeks of treatment. However, on the primary outcome measure, which was reduction in severity of depression over 6 weeks of treatment, addition of levothyroxine was not statistically significantly superior to addition of placebo (p= .198).
• A secondary analysis of female patients only (n = 32) was also done. This showed that reduction in severity of depression with addition of levothyroxine (- 42.4%) was statistically significantly greater than reduction in depression with addition of placebo (-16.6%; p= .018 ).
• High thyroid-stimulating hormone (TSH) levels, which indicate lower levels of thyroid hormones, predicted for good response to addition of levothyroxine.
Conclusions
• The study did not find a statistically significant difference overall between addition of levothyroxine or placebo. The authors attributed this to a high placebo response rate.
• However, the study did confirm what has been found in previous studies; that women with bipolar disorder benefit more from addition of thyroid hormone than men.
Clinical Commentary
• Bipolar depression is a difficult-to-treat illness, especially when the patient has already not responded to initial treatment. Thus this study and other treatment studies about bipolar depression are particularly welcome.
• It should not be missed that these patients had normal TSH at baseline and no history of thyroid disease.
• Similarly, it is relevant that the patients did not have rapid cycling since thyroid hormone has been used as a treatment for patients with rapid cycling bipolar disorder.
• Also to be noted is the high dose of levothyroxine used (300 mcg/day); patients with hypothyroidism are commonly treated with 50 to 100 mcg/day.
Stamm et al.
J Clin Psychiatry. 2014;75(2):162-8. PMID: 24345793
Objective
To test the whether adding supraphysiologic doses of levothyroxine to other medications in patients with bipolar depression is efficacious.
Methods
• A multicenter, double-blind, randomized, placebo-controlled trial was conducted.
• Patients with either bipolar I or bipolar II disorder who were currently depressed were recruited.
• Patients had to have normal TSH levels, no history of either thyroid disease, and no rapid cycling.
• Patients were required to have not responded to treatment with a mood stabilizer and/or an antidepressant taken for at least 6 weeks.
• Levothyroxine was given in a fixed-dose of 300 mcg/day and was compared to a placebo.
• Patients were also continued on previous medications: either a mood stabilizer and/or an antidepressant
• The primary efficacy variable was reduction in severity of depression. This was measured as the mean change in total score on the Hamilton Depression Rating Scale (HDRS).
Results
• 62 patients were randomized
• 35 of these patients had bipolar I disorder
• The mean change in HDRS score from randomization to end of 6 weeks of treatment was larger in the levothyroxine group compared to the placebo group and the change in severity of depression was greater with levothyroxine after 4 weeks of treatment. However, on the primary outcome measure, which was reduction in severity of depression over 6 weeks of treatment, addition of levothyroxine was not statistically significantly superior to addition of placebo (p= .198).
• A secondary analysis of female patients only (n = 32) was also done. This showed that reduction in severity of depression with addition of levothyroxine (- 42.4%) was statistically significantly greater than reduction in depression with addition of placebo (-16.6%; p= .018 ).
• High thyroid-stimulating hormone (TSH) levels, which indicate lower levels of thyroid hormones, predicted for good response to addition of levothyroxine.
Conclusions
• The study did not find a statistically significant difference overall between addition of levothyroxine or placebo. The authors attributed this to a high placebo response rate.
• However, the study did confirm what has been found in previous studies; that women with bipolar disorder benefit more from addition of thyroid hormone than men.
Clinical Commentary
• Bipolar depression is a difficult-to-treat illness, especially when the patient has already not responded to initial treatment. Thus this study and other treatment studies about bipolar depression are particularly welcome.
• It should not be missed that these patients had normal TSH at baseline and no history of thyroid disease.
• Similarly, it is relevant that the patients did not have rapid cycling since thyroid hormone has been used as a treatment for patients with rapid cycling bipolar disorder.
• Also to be noted is the high dose of levothyroxine used (300 mcg/day); patients with hypothyroidism are commonly treated with 50 to 100 mcg/day.
A double-blind randomized controlled trial of augmentation and switch strategies for refractory social anxiety disorder.
Pollack et al.
Am J Psychiatry. 2014;171(1):44-53. PMID: 24399428
Objective
• Despite initial treatment for generalized social anxiety disorder, most patients continue to have symptoms.
• This study assessed next-step medications for these patients
Methods
• A three site, 12-week, double-blind randomized controlled trial was conducted
• Patients were first treated for 10 weeks with sertraline alone
• Patients who had a Liebowitz Social Anxiety Scale score of > 50 after 10 weeks of treatment with sertraline were enrolled in the next phase of the study
• These patients were randomly allocated to receive one of the following three treatment options:
1) 3 mg/day of clonazepam added to the sertraline
2) Switch to venlafaxine (up to 225 mg/day)
3) Continuation of sertraline treatment with addition of placebo
Results
• 397 were patients treated with sertraline
• Of these, 181 nonresponders at week 10 were randomly assigned to one of the three treatment options
• Patients achieving remission (LSAS score ≤30) at the end of the study were as follows:
- Sertraline plus clonazepam 27%
- Venlafaxine 19%
- Sertraline plus placebo 17%
• However, these proportions were not statistically significantly different.
• Sertraline plus clonazepam was associated with a significantly greater drop in LSAS severity (p=0.020) and disability (p=0.0028) compared with sertraline plus placebo
• When looking at response rather than remission, a significantly greater proportion of patients in the sertraline plus clonazepam group (56%) compared with the sertraline plus placebo group (36%) showed a response to the treatment (p=.027).
• There was no statistically significant difference when venlafaxine was compared to the either of the other two groups on either remission or response
Conclusions
• For patients who do not show a response to sertraline alone for generalized social anxiety disorders, addition of clonazepam seems to be efficacious, while switching to venlafaxine does not.
Clinical Commentary
• Social anxiety disorder or social phobia is a relatively common and disabling condition. Its 12- month prevalence (6.8% of the population) is exactly the same as that of major depressive disorder (6.7%; Kessler et al., 2005).
• As noted in the accompanying Editorial (Roy-Byrne, 2014), second-step treatment studies are almost non-existent for anxiety disorders. Thus, this study is very welcome.
• While remission is a laudable goal, in short-term studies like this one, there may be benefit to focusing on response, i.e., significant but not near-complete improvement. Here, adding clonazepam shows a 20% advantage over simply continuing the sertraline and adding placebo. This is clinically considered a strong effect.
• Note, by the way, that the 17% remission rate in the sertraline plus placebo group should not be interpreted as “simply continuing the sertraline.” Addition of placebo and the TLC that comes from being in a clinical trial have considerable therapeutic effects.
• To further clarify the relative benefits of various treatment options, two types of future research is needed: longer-term treatment studies and studies that include cognitive-behavior therapy, as one of the treatments, both by itself and in addition to medication.
Pollack et al.
Am J Psychiatry. 2014;171(1):44-53. PMID: 24399428
Objective
• Despite initial treatment for generalized social anxiety disorder, most patients continue to have symptoms.
• This study assessed next-step medications for these patients
Methods
• A three site, 12-week, double-blind randomized controlled trial was conducted
• Patients were first treated for 10 weeks with sertraline alone
• Patients who had a Liebowitz Social Anxiety Scale score of > 50 after 10 weeks of treatment with sertraline were enrolled in the next phase of the study
• These patients were randomly allocated to receive one of the following three treatment options:
1) 3 mg/day of clonazepam added to the sertraline
2) Switch to venlafaxine (up to 225 mg/day)
3) Continuation of sertraline treatment with addition of placebo
Results
• 397 were patients treated with sertraline
• Of these, 181 nonresponders at week 10 were randomly assigned to one of the three treatment options
• Patients achieving remission (LSAS score ≤30) at the end of the study were as follows:
- Sertraline plus clonazepam 27%
- Venlafaxine 19%
- Sertraline plus placebo 17%
• However, these proportions were not statistically significantly different.
• Sertraline plus clonazepam was associated with a significantly greater drop in LSAS severity (p=0.020) and disability (p=0.0028) compared with sertraline plus placebo
• When looking at response rather than remission, a significantly greater proportion of patients in the sertraline plus clonazepam group (56%) compared with the sertraline plus placebo group (36%) showed a response to the treatment (p=.027).
• There was no statistically significant difference when venlafaxine was compared to the either of the other two groups on either remission or response
Conclusions
• For patients who do not show a response to sertraline alone for generalized social anxiety disorders, addition of clonazepam seems to be efficacious, while switching to venlafaxine does not.
Clinical Commentary
• Social anxiety disorder or social phobia is a relatively common and disabling condition. Its 12- month prevalence (6.8% of the population) is exactly the same as that of major depressive disorder (6.7%; Kessler et al., 2005).
• As noted in the accompanying Editorial (Roy-Byrne, 2014), second-step treatment studies are almost non-existent for anxiety disorders. Thus, this study is very welcome.
• While remission is a laudable goal, in short-term studies like this one, there may be benefit to focusing on response, i.e., significant but not near-complete improvement. Here, adding clonazepam shows a 20% advantage over simply continuing the sertraline and adding placebo. This is clinically considered a strong effect.
• Note, by the way, that the 17% remission rate in the sertraline plus placebo group should not be interpreted as “simply continuing the sertraline.” Addition of placebo and the TLC that comes from being in a clinical trial have considerable therapeutic effects.
• To further clarify the relative benefits of various treatment options, two types of future research is needed: longer-term treatment studies and studies that include cognitive-behavior therapy, as one of the treatments, both by itself and in addition to medication.
Prescribing thiamine to inpatients with alcohol use disorders: how well are we doing?
Isenberg-Grzeda et al.
J Addict Med. 2014;8(1):1-5. PMID: 24343128
Objective
• Thiamine deficiency is well known to be a potentially dangerous consequence of excessive use of alcohol
• To avoid consequences of thiamine deficiency such as Wernicke-Korsakoff syndrome, it is well known that thiamine should be given to all persons with excessive alcohol use.
• However, its proper dosing and route of delivery have not been standardized.
• The authors point out the following regarding facts to guide us regarding how to use thiamine in these patients:
- The 50 to 100 mg orally that has classically been prescribed was based on an estimate of what would be a high dose compared to daily nutritional requirements.
- Even in healthy individuals, only a small part of orally given thiamine is actually absorbed into the blood
- In patients with an alcohol use disorder, the proportion of orally given thiamine that is absorbed is even less
- This problem of low absorption is prevented by giving thiamine parenterally
- Also, the half-life of thiamine IV is 96 minutes. Therefore, multiple doses per day may be needed
• No data were available about how much thiamine is actually prescribed, and how, to patients with alcohol use disorders who are admitted to a hospital in the US.
Methods
• Inpatients at a large, inner city (Bronx) teaching hospital who were referred to the addiction psychiatry service were assessed
• The amount, route, and frequency of thiamine that had been prescribed to these patients were examined.
Results
• 217 inpatients were studied
• 18% of the inpatients had not been prescribed thiamine at all! The same was true of 17% of high-risk patients.
• 72% of these patients (69% of high risk patients) had been prescribed thiamine at a traditional dose of 100 mg orally per day.
Conclusions
• More education is needed to improve adequate dosing of thiamine to prevent and treat Wernicke-Korsakoff syndrome.
Clinical Commentary
• Previously, autopsy data has shown that Wernicke-Korsakoff syndrome is much more common than we think. Unfortunately, the diagnosis is missed in up to 80% of cases. One reason for this is that the classic triad of symptoms occurs in only a minority of patients.
• The American Psychiatric Association’s Practice Guideline for Treatment of Patients With Substance Use Disorders, Second Edition (2006) asks us to give thiamine “routinely to all patients receiving treatment for a moderate to severe alcohol use disorder.” However, it does not recommend a particular dose or route for this routine, prophylactic use.
• The APA guideline does recommend that for the treatment of Wernicke-Korsakoff syndrome, thiamine should be given at 50 to 100 mg IM or IV per day.
• In my opinion, we should take into consideration the uncertainty about dosing, the biological arguments in favor of using parenteral dosing, the low cost and relative safety of giving thiamine, and the serious consequences of failing to give thiamine where it was needed. Therefore, in high-risk inpatients (e.g., those in alcohol withdrawal, those with particularly heavy use, those with any signs at all of Wernicke-Korsakoff syndrome), we should err on the side of giving thiamine IM or IV and in moderate or high doses.
Isenberg-Grzeda et al.
J Addict Med. 2014;8(1):1-5. PMID: 24343128
Objective
• Thiamine deficiency is well known to be a potentially dangerous consequence of excessive use of alcohol
• To avoid consequences of thiamine deficiency such as Wernicke-Korsakoff syndrome, it is well known that thiamine should be given to all persons with excessive alcohol use.
• However, its proper dosing and route of delivery have not been standardized.
• The authors point out the following regarding facts to guide us regarding how to use thiamine in these patients:
- The 50 to 100 mg orally that has classically been prescribed was based on an estimate of what would be a high dose compared to daily nutritional requirements.
- Even in healthy individuals, only a small part of orally given thiamine is actually absorbed into the blood
- In patients with an alcohol use disorder, the proportion of orally given thiamine that is absorbed is even less
- This problem of low absorption is prevented by giving thiamine parenterally
- Also, the half-life of thiamine IV is 96 minutes. Therefore, multiple doses per day may be needed
• No data were available about how much thiamine is actually prescribed, and how, to patients with alcohol use disorders who are admitted to a hospital in the US.
Methods
• Inpatients at a large, inner city (Bronx) teaching hospital who were referred to the addiction psychiatry service were assessed
• The amount, route, and frequency of thiamine that had been prescribed to these patients were examined.
Results
• 217 inpatients were studied
• 18% of the inpatients had not been prescribed thiamine at all! The same was true of 17% of high-risk patients.
• 72% of these patients (69% of high risk patients) had been prescribed thiamine at a traditional dose of 100 mg orally per day.
Conclusions
• More education is needed to improve adequate dosing of thiamine to prevent and treat Wernicke-Korsakoff syndrome.
Clinical Commentary
• Previously, autopsy data has shown that Wernicke-Korsakoff syndrome is much more common than we think. Unfortunately, the diagnosis is missed in up to 80% of cases. One reason for this is that the classic triad of symptoms occurs in only a minority of patients.
• The American Psychiatric Association’s Practice Guideline for Treatment of Patients With Substance Use Disorders, Second Edition (2006) asks us to give thiamine “routinely to all patients receiving treatment for a moderate to severe alcohol use disorder.” However, it does not recommend a particular dose or route for this routine, prophylactic use.
• The APA guideline does recommend that for the treatment of Wernicke-Korsakoff syndrome, thiamine should be given at 50 to 100 mg IM or IV per day.
• In my opinion, we should take into consideration the uncertainty about dosing, the biological arguments in favor of using parenteral dosing, the low cost and relative safety of giving thiamine, and the serious consequences of failing to give thiamine where it was needed. Therefore, in high-risk inpatients (e.g., those in alcohol withdrawal, those with particularly heavy use, those with any signs at all of Wernicke-Korsakoff syndrome), we should err on the side of giving thiamine IM or IV and in moderate or high doses.
Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial.
Porsteinsson et al. for the CitAD Research Group.
JAMA. 2014;311(7):682-91. PMID: 24549548
Objective
• Agitation in patients with Alzheimer’s disease is important for three reasons: it is common, it tends to persist, and it can lead to a variety of other problems.
• Medications used to treat this agitation are problematic
• This study was called the Citalopram for Agitation in Alzheimer Disease Study (CitAD)
• It evaluated whether citalopram reduces agitation in patients with Alzheimer disease
Methods
• A randomized, placebo-controlled, double-blind, study was conducted at several academic medical centers
• 186 patients with probable Alzheimer disease and clinically significant were included
• All patients received a psychosocial intervention
• In addition, patients were randomized to receive either citalopram or placebo for 9 weeks
• Citalopram was started at 10 mg/day with plan to increase gradually to 30 mg/day if needed and tolerated
• There were to primary outcome measures: 1) the Neurobehavioral Rating Scale agitation subscale (NBRS-A), and 2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC).
Results
• On both of the primary outcome measures, patients who received citalopram showed statistically significantly greater reduction than those who received placebo.
• How many patients had at least moderate improvement in the agitation, i.e., either moderate or marked improvement? 40% of patients on citalopram vs. 26% of patients on placebo.
• It should be noted that many different outcome measures were used in this study. On many but not all of these measures, patients on citalopram showed greater improvement than patients on placebo.
• For example, patients receiving citalopram did not do better than patients who received placebo on activities of daily living and in lesser use of rescue lorazepam.
• However, two important adverse effects were statistically significantly greater on citalopram than on placebo occurred however:
1) Worsening of cognition
2) QT interval prolongation (mean 18.1 ms)
Conclusions
• Citalopram reduced agitation and caregiver distress significantly more than placebo.
• However, cognitive and cardiac adverse effects of citalopram may limit its use in a dose of 30 mg/day.
Clinical Commentary:
• This important study builds on previous literature suggesting that citalopram works for this problem, though not for all patients.
• Given the risks associated with use of antipsychotics to treat agitation in patients with Alzheimer’s disease, citalopram should probably be used more widely as one of treatment choices for this common problem.
• However, we would be wise to refrain from using the higher doses due to the risk of significant adverse effects like cognitive impairment and cognitive dysfunction.
