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Research Review for February

4/27/2015

0 Comments

 
SOURCE: Global Medical Education
Guest Commentary by Rajnish Mago, MD

Picture
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:
  • Testosterone improves antidepressant-emergent loss of libido in women: findings from a randomized, double-blind, placebo-controlled trial
  • Effects of antidepressants and soybean association in depressive menopausal women
  • Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation
  • EEG neurofeedback treatments in children with ADHD: an updated meta-analysis of randomized controlled trials
  • The McGill Geriatric Lithium-Induced Diabetes Insipidus Clinical Study (McGLIDICS)

Testosterone improves antidepressant-emergent loss of libido in women: findings from a randomized, double-blind, placebo-controlled trial.
Fooladi et al. 
J Sex Med. 2014;11(3):831-9.

Why is this paper important?

Serotonergic antidepressants (SSRIs or SNRIs) are associated with a high incidence of sexual dysfunction. While there are many strategies for managing this problem, each of them has some limitations, so there is no doubt that we need more options. Previously, testosterone has been shown in several studies to be efficacious for decreased libido in both menopausal and premenopausal women who were not depressed or on antidepressants. So, it is a good question as to whether testosterone would work for women with decreased libido that emerged or worsened after an antidepressant was started for the treatment of a depressive disorder.

Objective
  • To assess whether transdermal testosterone can treat loss of libido due to an SSRI or SNRI

Methods
  • Study design: Randomized, double-blind, placebo-controlled clinical trial
  • Subjects: Forty-four women, aged 35-55 years, on a stable dose of SSRI or SNRI, who had loss of libido that started during treatment with the antidepressant
  • Interventions:  12-week treatment with either transdermal testosterone patch (300 mcg of testosterone/day) or a placebo patch

Results
  • At baseline, there were no differences between the treatment groups. (Good that they checked for this.)
  • The authors looked at improvement in sexual functioning in three different ways:
  • First, they looked at their “primary outcome measure” — how much the score on the Sabbatsberg Sexual Self-rating Scale had changed from before treatment to after treatment. On this, there was no difference between patients on transdermal testosterone or on placebo. (Disappointing!)
  • Next, they looked at how many Satisfactory Sexual Events occurred over 4 weeks. The number of such Satisfactory Sexual Events increased more in patients on transdermal testosterone (average increase of 2.3 events) than in those on placebo (average increase of 0.1 events). This difference was statistically significant, which means that it is unlikely that this difference was just due to chance.
  • Thirdly, they looked at the change in scores on the Female Sexual Distress Scale-Revised before and after treatment. Patients on transdermal testosterone had greater improvement than patients on placebo, but the difference was not statistically significant. What this means is that we cannot rule out the possibility that the difference in improvement could have occurred by chance. But wait a minute…the p value was .06. That means that they estimated that there was a 6% chance that the difference could have occurred simply due to chance. We can say, as the authors did, that the finding “approached statistical significance.” As you know, we have collectively decided to only consider as “statistically significant” findings that have less than a 5% probability (p < .05) of being due to chance alone. (6% vs. less than 5% -- so close! But sorry guys, if we decided that less than 5% was the finishing line, it would be cheating to change it later.)
  • What did the transdermal testosterone do to the serum testosterone level? The mean total serum testosterone level at 12 weeks in patients on transdermal testosterone was 2.1 nmol/L.
  • Any side effects? No androgenic adverse effects.

Conclusions
  • Well, at least transdermal testosterone increased the number of Satisfactory Sexual Events in these patients.
  • The authors wondered if the lack of improvement in the Sabbatsberg Sexual Self-rating Scale total score may reflect lack of sensitivity of this scale for measuring change in sexual function.

Clinical Commentary
  • That testosterone was superior to placebo on some measures but not on the primary outcome measure may be because the relatively small sample size. When you study something in a smaller number of people, it is naturally hard to be sure that any differences observed are not due to chance alone. That is what “statistical significance” means.
  • Now, here’s another tip: whenever this happens, look at whether the treatment at least appeared to be better than placebo in terms of numbers, even if you cannot be sure that this apparent superiority was not just due to chance. In this study, testosterone was numerically superior to placebo on the Sabbatsberg scale total score as well as subscales.
  • It is important to note that patients in this study were not selected for having low testosterone levels. For total testosterone, the normal range for premenopausal women is 0.33–1.7 nmol/L. In this study, the mean level was 0.52 prior to treatment (both groups combined) and 2.1 after treatment (testosterone group). Unfortunately, they were not systematic in when in the day they measured testosterone and they did not measure free testosterone. Therefore, we don’t know whether baseline testosterone level or change in testosterone level can predict which patients are more likely to benefit. One would guess that testosterone would be most helpful in those with low levels before treatment that improve with the medication, but we must wait for this to be tested in a future study.

Effects of antidepressants and soybean association in depressive menopausal women.
Estrella et al. 
Acta Pol Pharm. 2014. PubMed PMID: 25272653.

Why is this paper important?
Patients frequently ask us about the use of complementary treatments. In addition, many patients use complimentary treatments without telling their physicians. Therefore, in my experience, clinicians are very interested in learning more about the potential use of complimentary treatments in mental health. One of these potential treatments is soy isoflavones that were evaluated in this study for augmenting an antidepressant.

Objective
  • Depressive disorders in menopausal women are well known and may be related in part to decline in estrogen levels after menopause.
  • This was a pilot study that assessed whether adding soy isoflavone extract to an SSRI may be more efficacious than an SSRI alone in menopausal women.
 
Methods
  • 40 menopausal women with clinical depression (diagnosis unspecified) were recruited
  • The subjects were treated with one of the following for three months:  
    - fluoxetine (10 mg/day),
    - soy isoflavone extract (100 mg/day),
    - sertraline (50 mg/day), or 
    - sertraline (50 mg/day) plus soy isoflavone extract (100 mg/day).
  • Soy isoflavone concentrate supplied by GNC was used. It comes as 50 mg capsules.

Results
  • Change in Hamilton Depression Rating Scale scores from baseline to end of three months of treatment was statistically significantly greater in patients who received the combination of sertraline and soy isoflavone compared to sertraline alone or to soy isoflavone alone.
  • The combination was not shown to be superior to fluoxetine alone.
  • On the Zung patient-rated depression scale, the combination of sertraline and soy isoflavone was statistically significantly superior to each of the other treatment groups.
 
Conclusions
  • This study suggests that in menopausal women with depression, adding 100 mg/day of soy isoflavone to an SSRI may be more efficacious than the SSRI alone.

Clinical Commentary
  • Soy isoflavones are phytoestrogens for which there is a lot of literature. A number of benefits have been claimed: relief of menopausal symptoms, and prevention of heart disease, breast cancer, prostate cancer, and osteoporosis. However, they may also be associated with some risks like increased risk of breast cancer, male hormonal and fertility problems, and hypothyroidism.
  • You must have noticed that the dose of fluoxetine was less than what we usually prescribe and the dose of sertraline, while within the therapeutic range, was on the low side. However, if this supplement does work (and that is not yet convincingly shown), maybe one could get away with using lower doses of the antidepressant?
  • My main concern with this study is that it is not clear from the paper that there was adequate blinding of the subjects and the treating clinicians. Thus, a placebo effect cannot be ruled out.
  • Because there was no placebo group, I cannot agree with the Authors’ conclusion that soy isoflavone alone was also efficacious. The finding that patients on soy isoflavone alone improved does not mean that it was efficacious. The improvement may have been spontaneous or due to a placebo effect. 
  • At GNC (a chain of stores that sell health- and nutrition-related products), sixty capsules of soy isoflavone concentrate 50 mg each (a month’s supply at two capsules per day) costs about $12, so at least this supplement is not particularly expensive.

Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation.
Beach et al. 
J Clin Psychiatry. 2014;75(5)

Why is this paper important?
  • Ever since the FDA first issued a Drug Safety Communication in 2011 about the risk of QTc prolongation with citalopram, there has been a lot of interest in this topic.
  • Is it really true? If studies disagree, what should we conclude if we put all the prospective studies together? A well-done meta-analysis can move the literature forward by combining a large number of studies into one result
  • Also, does citalopram have a greater risk of prolonging QTc or is this something that all the SSRIs do equally?

Objective
  • To use meta-analysis of all available prospective studies to evaluate whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with prolongation of the corrected QT interval (QTc)

Methods
  • Search of PubMed/MEDLINE database (January 1, 1975-August 15, 2012)
  • Also, hand searching of references of the articles
  • Included articles in English, Spanish, and German (Good!)
  • Two reviewers independently identified the studies and three reviewers independently extracted the data (Very good!)

Results
  • Sixteen articles involving 4,292 patients were included.
  • SSRIs were associated with a statistically significant, increase in QTc interval compared to placebo (average of +6.10 milliseconds)
  • Tricyclic antidepressants (TCAs) were associated with a statistically significantly greater QTc increase than SSRIs (average 7.05 milliseconds greater than SSRIs)
  • Citalopram was associated with statistically significantly greater QTc prolongation than sertraline, paroxetine, and fluvoxamine.

Conclusions
  • SSRIs were associated with a small but statistically significant increase in the QTc interval
  • The increase in QTc interval with SSRIs was less than with TCAs.
  • Citalopram was associated with a greater QTc prolongation than three of the other SSRIs.

Clinical Commentary
  • By the way, I have reviewed this topic elsewhere (Mago et al. Cardiovascular adverse effects of newer antidepressants. Expert Rev Neurother. 2014;14(5):539-51. PubMed PMID: 24738823). Without going into more detail here, to me there is little doubt that SSRIs can prolong QTc. In my opinion, it would not be correct to say that this association has not been convincingly shown.
  • Thankfully, this is not a problem in most patients. But in a high-risk patient it can become an issue and may be associated with increased risk of serious ventricular arrythmias. In such patients, caution and monitoring are advisable.

EEG neurofeedback treatments in children with ADHD: an updated meta-analysis of randomized controlled trials.
Micoulaud-Franchi et al. 
Front Hum Neurosci. 2014;8:906

 Why is this paper important?
  • ADHD is diagnosed in an increasingly larger number of children
  • Two problems: sometimes the parents are reluctant to put the child on medication and medications are not usually 100% effective
  • There are many different non-medication treatments for children with ADHD that are talked about. One of these is biofeedback using EEG. But does it work? We hear contradictory things about it.
  • Well, this paper puts together the studies on this topic and helps us to come to a state-of-the-art conclusion

Objective

  • To conduct a meta-analysis of published randomized controlled trials that evaluated whether EEG neurofeedback works for children with Attention Deficit Hyperactivity Disorder (ADHD).

Methods

  • Only randomized controlled trials that used either a semi-active control (a control treatment that has known efficacy to some extent, e.g., EMG biofeedback) and sham control (a control “treatment” that does not have any efficacy other than a placebo effect) were included
  • The paper evaluates efficacy of EEG neurofeedback for overall symptoms, for inattention, and for hyperactivity/impulsivity
  • The studies included looked at 
    a) parent assessment that was probably unblinded assessment, and 
    b) teacher assessment that was probably blinded assessment

Results

  • Five studies were included
  • These included a total of 263 children with ADHD
  • On parent assessment (probably unblinded assessment), EEG neurofeedback was statistically significantly better than the control interventions on the overall ADHD score, the inattention score, and the hyperactivity/impulsivity score.
  • On teacher assessment (probably blinded assessment), EEG neurofeedback was superior to control on only the inattention score, and not on the overall ADHD score or on the hyperactivity/impulsivity score. 

Conclusions

  • EEG neurofeedback seems to be efficacious at least for inattention in children with ADHD

Clinical commentary

  • A limited number of patients have been studied, significant bias is introduced by how the assessment was conducted, and I have many technical questions about how to actually implement this intervention. Therefore, at this time I don’t think that we should be routinely recommending EEG neurofeedback for patients with ADHD.
  • Previous literature has shown that if you consider assessments that are probably unblinded, you will get a much greater apparent benefit from EEG neurofeedback. It is very important to realize that when parents are helping the child do the EEG neurofeedback, they are not blinded. Therefore, their assessment of how the child is doing is should not be the main way of evaluating the efficacy of a treatment. If we read a study of any intervention for ADHD in children, we should immediately look to see if the assessment was truly blinded.

The McGill Geriatric Lithium-Induced Diabetes Insipidus Clinical Study (McGLIDICS)
Rej et al. 
Can J Psychiatry. 2014;59(6):327-34

Why is this paper important?
  • While all prescribers are well aware of the importance of checking serum creatinine in patients being treated with lithium, in my experience, polyuria and nephrogenic diabetes insipidus are often not monitored for and are frequently missed even when present
  • Can’t we just monitor for nephrogenic diabetes insipidus by asking patients about their symptoms like how much they have been urinating?
  • We usually have serum sodium available as part of the Basic Metabolic Panel (a group of laboratory tests commonly done together, at least in the USA). Is that a good indicator for diabetes insipidus because serum sodium tends to increase in patients who have a decrease in the kidney’s ability to concentrate urine?
  • What about urine specific gravity? We get that result as part of a simple urinanalysis, but getting urine osmolality will require ordering it separately

Objective
  • Nephrogenic diabetes insipidus is a common and potentially serious condition associated with lithium treatment
  • This study aimed to compare nephrogenic diabetes insipidus symptoms and urine osmolality between elderly and adult patients.
  • It also assessed whether symptoms, serum sodium, and urine specific gravity can be used as surrogate measures of decreased urine osmolality
  • Lastly, it assessed whether certain clinical factors that may be associated with nephrogenic diabetes insipidus are independently correlated with decreased urine osmolality.

Methods

  • Cross-sectional study (i.e., no follow up)
  •  100 consecutive outpatients treated with lithium from 6 tertiary care clinics
  • 45 of these patients were geriatric (aged 65 years and older) and 55 were adults (aged 18 to 64 years).
  • Assessments were a patient-rated symptom questionnaire and laboratory tests (including urine osmolality, serum sodium, and urine specific gravity)

Results

  • The proportion of patients on lithium who had decreased urine osmolality (defined as < 300 mOsm/kg) was not statistically significantly different between geriatric (12.5%) and adult (17.9%) adults
  • Geriatric patients reported statistically significantly less symptoms than adult patients
  • Urine osmolality did not correlate with symptoms or current serum sodium
  • However, low urine osmolality (i.e., < 300 mOsm/kg) was suggested by a urine specific gravity of < 1.010
  • Age, duration of lithium treatment, and serum lithium level were independently associated with urine osmolality.
 
Conclusions
  • Older patients are less likely to report urinary and thirst symptoms.
  • Subjective symptoms and serum sodium do not correlate with urine osmolality
  • However, urine specific gravity may be a cost-efficient surrogate measure for urine osmolality.
  • Clinicians should be carefully looking for nephrogenic diabetes insipidus, especially in patients who are older, have taken lithium for a longer time, and have higher lithium levels.
  •  These patients are at risk of lithium intoxication, falls, hypernatremia, and renal dysfunction.

Clinical Commentary
  • The key thing to learn from this study is that just asking for symptoms and looking at serum sodium are not adequate.
  • When we suspect nephrogenic diabetes insipidus in a particular patient, then what we need to do is to get a combination of urine and serum osmolality, done simultaneously
0 Comments

Research Review in January

4/24/2015

0 Comments

 
SOURCE: Global Medical Education
Guest Commentary by Rajnish Mago, M.D

Picture
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

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.

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. 



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.



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.

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Lyme Disease: The Diagnosis and Treatment

4/23/2015

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BTB Author's note: I have a number of clients who suffer from mood and fatigue issues related to chronic Lyme Disease. My hope in posting this article is to help facilitate the understanding of Lyme and its treatment in psychiatry. I, do not personally or professionally endorse or have an affiliation with any of the companies mentioned in the full article. 

SOURCE: Functional Medicine University
Ronald J. Grisanti, DC, DABCO, DACBN, MS, CFMP

Lyme disease is an infectious illness commonly caused by a tick bite infected with the spiral-shaped bacterium called Borrelia burgdorferi. Of special interest, the disease is named after the towns of Lyme and Old Lyme, Connecticut. There are different phases of infection in Lyme disease: early localized phase, early disseminated phase, and chronic phase. The earlier the infection can be identified, the greater the success in treatment. 

Early Localized Lyme 
The classic sign of early local infection with Lyme disease is a circular, outwardly expanding rash called erythema migrans, or EM rash, which may occur at the site of the tick bite three to 30 days after the bite. The textbook presentation of the EM rash commonly appears as a bull’s eye, hence its nickname “bull’s eye rash.” Unfortunately, the EM rash is absent in more than 50% of Lyme disease cases, which is one reason an acute Lyme infection may be missed by many physicians. The physician should consider Lyme when a patient presents with flu-like illness, fever, malaise, muscle soreness, and headache after camping, hiking, or gardening. 

Early Disseminated Lyme 
In early disseminated Lyme, the bacteria will spread through the bloodstream, contributing to muscle, joint, and tendon pain. Dizziness and headaches, heart palpitations, severe fatigue, and mood changes are common. 

Chronic Lyme Disease 
Chronic Lyme disease presents a challenge to the astute clinician because the Infectious Diseases Society of America (IDSA) denies its very existence, while the International Lyme and Associated Diseases Society (ILADS) believes the Lyme infection exists past 30 days, causing ongoing symptoms and disability. 

Joseph Burrascano, MD, a physician at the forefront of Lyme disease treatment and research in the United States, and author of “Advanced Topics in Lyme Disease: Diagnostic Hints and Treatment Guidelines for Lyme and Other Tick Borne Illness,” offers the following definition: 

For a diagnosis of chronic Lyme disease, these three criteria must be present:
  1. Illness present for at least one year. 
  2. Persistent major neurologic involvement (such as encephalitis/encephalopathy, meningitis, etc.) or active arthritic manifestations (active synovitis). 
  3. Active infection with Borrelia burgdorferi (Bb), regardless of prior antibiotic therapy (if any). 

ILADS, the US-based organization that recognizes chronic Lyme disease, has adopted a set of treatment guidelines that have been widely used in clinical practice (available at www. ilads.org). 
They state the following: 

“Chronic Lyme disease is inclusive of persistent symptomatologies including fatigue; cognitive dysfunction; headaches; sleep disturbance; and other neurologic features such as demyelinating disease, peripheral neuropathy and sometimes motor neuron disease; neuropsychiatric presentations; cardiac presentations including electrical conduction delays and dilated cardiomyopathy; and musculoskeletal problems.”

Lyme disease is known as the “Great Imitator.” Its list of symptoms is long and 
varied.

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Read the full article HERE
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Pharmacotherapy of Treatment-Resistant OCD

4/22/2015

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SOURCE: Pharmacotherapy Institute
Dr. David Veale

Treatment of obsessive compulsive disorder is often challenging. Treatment resistance is quite common, between 40 to 60% of patients do not show and adequate response to first-line treatments.

This audio lecture covers the following topics:
  • Practical definition of treatment-resistant OCD
  • Stepped-approach to pharmacotherapy
  • Efficacy of second-generation antipsychotics as augmentation strategy
  • Other treatment options
>> Download audio file: HERE

Featured Study: Atypical antipsychotic augmentation in SSRI treatment refractory obsessive-compulsive disorder: a systematic review and meta-analysis

Background
In 2006, the National Institute of Clinical and Health Excellence (NICE) guidelines for Obsessive Compulsive Disorder (OCD) recommended anti-psychotics as a class for SSRI treatment resistant OCD. The article aims to systematically review and conduct a meta-analysis on the clinical effectiveness of atypical anti-psychotics augmenting an SSRI.

Methods
Studies that were double-blind randomized controlled trials of an atypical antipsychotic against a placebo, for a minimum of 4 weeks, in adults with OCD, were included. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores were the primary outcome measure. Inclusion criteria included Y-BOCS score of 16 or more and at least one adequate trial of a SSRI or clomipramine for at least 8 weeks prior to randomization. Data sources included Medline, Embase, PsycINFO, Cochrane Database of Systematic Reviews (CDSR), trial registries and pharmaceutical databases and manufacturers up to September 2013. Forest-plots were drawn to display differences between drug and placebo on the Y-BOCS.

Results
Two studies found aripiprazole to be effective in the short-term. There was a small effect-size for risperidone or anti-psychotics in general in the short-term. We found no evidence for the effectiveness of quetiapine or olanzapine in comparison to placebo.

Conclusions
Risperidone and aripiprazole can be used cautiously at a low dose as an augmentation agent in non-responders to SSRIs and CBT but should be monitored at 4 weeks to determine efficacy.


>> Full PDF HERE
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Pruritus in Psoriasis: A Study of Personality Traits, Depression and Anxiety

4/21/2015

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SOURCE: DocGuide

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Pruritus intensity is often not proportional to disease severity in patients with psoriasis or other pruritic dermatoses. Increasing evidence indicates that psychological factors may play an important role in the overall aetiology of pruritus. The aim of this study was to examine whether patients with psoriasis and severe pruritus differ psychologically from those with mild pruritus. In this study of 101 patients with plaque psoriasis, those with severe pruritus reported significantly higher scores for both depression and anxiety. 

Using the Swedish universities Scales of Personality, 4 personality traits were significantly associated with severe pruritus: Somatic trait anxiety, Embitterment, Mistrust, and Physical trait aggression. These results indicate that patients with psoriasis and severe pruritus might have a more vulnerable psychological constitution. This suggests important opportunities for clinicians to identify patients who could benefit from psychological interventions.

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Co-Associations of Multiple Sclerosis With Schizophrenia and Bipolar Disorder

4/8/2015

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SOURCE: DocGuide
September 15, 2014  |  Brian Hoyle

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A study that matched the records of all hospital admissions and treatment in England from 1999 through 2011 has revealed the co-associations of multiple sclerosis (MS), schizophrenia, and bipolar disorder.

While it cannot be concluded that MS is the cause of schizophrenia and bipolar disorder, or vice versa, the data argue for shared similar risk factors, such as infection, that increase the risk of schizophrenia and bipolar disorder in patients with MS.

Recent population-based studies concerning a suggested link between MS and schizophrenia and bipolar disorder have been equivocal, with analysis of national register data from Denmark indicating increased risk of schizophrenia and decreased risk of bipolar disorder in MS patients (Eaton et al. 2010), with the opposite findings apparent from an analysis of Swedish registry data (Johansson et al. 2014).


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Parenting Young Adults: 9 Vital Answers About Depression And Suicide

4/7/2015

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SOURCE: Yellowbrick

Young adults and late teens may be closed-off and unwilling to talk with their parents or other influential adults, making it difficult to determine if they are going through depression, having suicidal thoughts, or just going through a brief period of“the blues.” Young adult and teen suicide is the third leading cause of death for those between ages 10 and 24, and mental health wellness advocates are working to provide suicide and depression treatment for young adults. But what resources are available for parents?

As a parent, you may feel helpless if you suspect that your young adult is suffering from depression or considering suicide. However, there are some parenting strategies that you can employ to support your young adult during this difficult time. You may look for warning signs, such as secrecy, isolation, depression, or expressions of despair. Substance abuse and addiction and certain mental illnesses can also increase a young adult’s risk of suicide. If a suicide attempt takes place, the young adult may experience more intense emotions of shame, guilt, and isolation; building connections with others and participating in meaningful activities may help young adults avoid repeated attempts. In this difficult situation, parents should show acceptance, a lack of judgment, empathy, and build safe, trustworthy, and open communication with their child.

Knowledge is power, and you can learn how to help young adults by knowing what warning signs to look for, the potential health impact of a suicide attempt, and how you can seek help and offer support. Remember, if you suspect that someone you love is having suicidal thoughts, help is available. Reach out immediately and you’ll find support during a difficult time.

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Schizophrenia Deemed Group of Eight Separate Disorders

4/2/2015

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SOURCE: MPR
September 16, 2014

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Schizophrenia is not a single disorder but rather a group of eight distinct disorders, each caused by changes in gene clusters that lead to different symptoms, according to research published online September 15 in The American Journal of Psychiatry.

Javier Arnedo, from the Washington University School of Medicine in St. Louis, and colleagues conducted a large genome-wide study involving cases with schizophrenia and controls to examine sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals. For each SNP set, they examined the risk of schizophrenia, and tested the replicability in two independent samples. Genomic networks composed of SNP sets sharing SNPs or subjects were identified. Clinical features that cluster in particular cases were identified, and the correlation between SNP sets and distinct phenotypic sets was examined.

The researchers identified 42 SNP sets that were associated with a risk of schizophrenia of ≥70%; ≥81% were confirmed in two independent samples. Seventeen of the SNP networks were disjointed and did not share any SNP or subject; these correlated with distinct gene products and clinical syndromes. Complex associations showing multifinality and equifinality were seen for genotypic networks and clinical syndromes. The interactive networks accounted for more of the risk of schizophrenia than the average effects of all SNPs (24%).

"Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes," the authors write.


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Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders

4/1/2015

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SOURCE: MGH Center For Women's Mental Health 
October 15, 2014 | Adele Viguera, MD

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Autism spectrum disorders (ASDs), which include childhood autism, autistic disorder, Asperger syndrome, atypical autism, and other pervasive developmental disorders, are characterized by social and communication difficulties and by stereotyped or repetitive behaviors and interests. It is estimated that autism spectrum disorders affect about 1% of children.

While genes play a significant role in the risk of autism, and can be identified in up to 25% of children with autism, there has been increasing interest in examining whether environmental factors also play a role in the development of childhood autism. Various environmental exposures have been implicated, including vaccinations, mercury, air pollution, insecticides, and infection, as well as more recently, psychiatric medications including SSRIs (see previous post) and other classes of medications such as valproate (Depakote).

Prenatal exposure to valproate has been associated with an elevated risk (10%) for a broad range of congenital malformations including spina bifida, as well as adverse neurodevelopmental sequelae, such a lowered IQ and developmental delays in offspring. As a result, the American Academy of Neurology has recommended avoidance of valproate during pregnancy whenever possible.

In addition to these risks, several preliminary case series have suggested that fetal valproate exposure may also increase the risk of autism. However, the magnitude of this association has been unclear due to the methodological limitations of such reports.

Now, new data adds the risk of autism spectrum disorders to the list of possible negative outcomes from prenatal valproate exposure. In a recent study, Christensen and colleagues report the results of a population-based study of 655,615 children born in Denmark from 1996 to 2006.  Children were followed from birth for a maximum of 14 years.  Among these children, 5437 were identified as having autism spectrum disorders (absolute risk of 1.53%), including 2067 with childhood autism (absolute risk 0.48%).


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