SOURCE: Psychopharmacology Institute

NEW GUIDELINES
Below you can find some of the most important clinical guidelines published in 2014. Please note that this is not an exhaustive list.

CONTRAVE (naltrexone and bupropion)
Indication: Obesity and overweight treatment
Available:  Currently

BELSOMRA (suvorexant)
Indication: insomnia
Available: early 2015

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

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.

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


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 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.

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 

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. 

SOURCE: Functional Medicine University - Clinical Rounds

The published evidence is quite clear in documenting that the actual total cholesterol level itself is not the most important risk factor of cardiovascular disease.

It is the ratio between the level of HDL-"good" cholesterol and total cholesterol that we need to be concerned about.

Therefore, in adults, the HDL-"good" cholesterol/total cholesterol ratio should be higher than 0.24 (just divide your HDL level by your cholesterol).

Since HDL (high density lipoprotein) is protective against heart disease, the lower the ratio, the better
In other words, the lower your triglycerides, or the higher your HDL, the smaller this ratio becomes.

It is now believed that the triglycerides/HDL ratio is one of the most potent predictors of heart disease.

A Harvard-lead study author reported:
"High triglycerides alone increased the risk of heart attack nearly three-fold.

And people with the highest ratio of triglycerides to HDL -- the "good" cholesterol -- had 16 times the risk of heart attack as those with the lowest ratio of triglycerides to HDL in the study of 340 heart attack patients and 340 of their healthy, same age counterparts.

The citation stated, the ratio of triglycerides to HDL was the strongest predictor of a heart attack, even more accurate than the LDL/HDL ratio.

Supporting Citation:
Gaziano JM, Hennekens CH, O'Donnell CJ, Breslow JL, Buring JE. Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction. Circulation. 1997 Oct 21;96(8):2520-5.

SOURCE: HealthDay News

September 2, 2014 | Steven Reinberg

Stimulant medications -- such as Adderall, Ritalin and Concerta -- used to treat attention-deficit/hyperactivity disorder (ADHD) in children, won't stunt their growth, a new study suggests.

"Stimulant medication did not affect children's final height as adults," said study researcher Dr. Slavica Katusic, an associate professor of pediatrics at the Mayo Clinic in Rochester, Minn.

Katusic noted that results of earlier studies have been mixed, with some showing these drugs retard growth and others showing they don't. But, most of the previous studies had limitations, such as having too few children or spotty information about adult height, she said.

Katusic said this study is unique because it followed a group of people with ADHD who were taking stimulant medications and compared them with a group with ADHD who were not taking medication and also a group that didn't have ADHD. These individuals were followed from childhood to adulthood, she said.

ADHD is one of the most common disorders of childhood, according to the U.S. National Institute of Mental Health (NIMH). Symptoms include difficulty paying attention or staying focused on one task, overactivity and impulsive behavior, the NIMH explains.

Stimulant medications are a mainstay of ADHD treatment, and while it may seem odd to use stimulant medication on an overactive child, stimulant drugs have a calming, focusing effect on youngsters with ADHD, according to the NIMH. Katusic said these drugs are important for improving school and social functioning.

Katusic's team studied 340 children with ADHD and 680 without the condition. "We compared the height when they were children and when they were grown up," she said.

The average follow-up time was 26 years for those with ADHD and 23 years for people without ADHD. Approximately 70 percent of those with ADHD who completed the study had taken stimulant medication for more than three months, the researchers noted.

There was no difference in adult height between those who took ADHD drugs and those who didn't, the investigators found.

"Neither childhood ADHD itself nor stimulant medication was associated with shorter stature as adults," Katusic said.

Boys with ADHD who were treated with stimulants for three or more months had a later growth spurt than boys who didn't take these drugs, but there was no difference in the size of the growth spurt, the researchers noted.

In addition, no connection was seen between the amount of time a child took stimulant drugs and adult height, the study authors found.

"But despite our findings, doctors should monitor growth when making medication decisions," she said. "Our study says don't worry at all, but human beings are all different and you always have to be careful."

The report was published online Sept. 1 in the journal Pediatrics.

Dr. Marcel Deray, a pediatric neurologist at Miami Children's Hospital, said, "This is good news, because we discuss this issue with parents of kids with ADHD."

Deray hopes the study will be replicated to prove the point that these stimulants don't affect height. "It would good to have a couple of studies showing the same thing," he said.

He also said this finding should be reassuring to parents who may be reluctant to allow their children to use these drugs because of the potential risk of stunting their child's growth.

SOURCE: Doc Guide
September 3, 2014

ALEXANDRIA, Va --  -- According to a study published in the Journal of Dental Research, use of selective serotonin reuptake inhibitors (SSRIs) is linked to an increased risk of osseointegrated implant failure.

SSRIs, the most widely used drugs for the treatment of depression, have been reported to reduce bone formation and increase the risk of bone fracture. Since osseointegration is influenced by bone metabolism, Khadijeh Al-Abedalla, MD, McGill University, Montreal, Quebec, and colleagues investigated the association between SSRIs and the risk of failures in osseointegrated implants.

The retrospective cohort study was conducted on patients treated with dental implants from January 2007 to January 2013. A total of 916 dental implants in 490 patients (94 implants on 51 patients using SSRIs) were used to estimate the risk of failure associated with the use of SSRIs.

After 3 to 67 months of follow-up, 38 dental implants failed and 784 succeeded in non-users while 10 failed and 84 succeeded in SSRIs-users.

SSRIs usage was associated with an increased risk of dental implants failure (hazard ratio [HR] = 2.31; P< .01). The failure rates were 4.6% for SSRI non-users and 10.6% SSRI users, respectively.

Small implant diameters (≤4 mm; P = .01), bone augmentation (P = .04), and smoking habits (P< .01) were also associated with higher risk of implant failure.

The main limitation of the study was that drug compliance and treatment period could not be acquired from the files of the patients.

When insurance companies deny the mentally ill the treatment their doctors prescribe, seriously ill people are often discharged, and can be a danger to themselves or others

Personal/professional note: I battle with this phenomena in the form of prior authorizations everyday, just trying to get people the medications that they require to be healthy. It is one of the most stressful/disappointing/frustrating aspects of my position as a Psych NP. 

SOURCE: MPR
December 11, 2014 

The Food and Drug Administration (FDA) is warning that ziprasidone, an atypical antipsychotic agent, has been linked to a rare but serious skin reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), which can progress to other parts of the body.

DRESS, a potentially fatal reaction, may start as a rash that can spread to all parts of the body. Signs and symptoms include fever, swollen lymph nodes, and inflammation of organs (eg, liver, kidney, lungs, heart, pancreas). DRESS also causes an increase in the number of eosinophils in the blood. The pathogenesis of DRESS is unclear; however, it is thought to be the result of a combination of genetic and immunologic factors, such as detoxification defects in the drug metabolism pathway, resulting in toxic metabolite formation and an immune response.

Data from six patients in whom DRESS appeared between 11–30 days after ziprasidone treatment initiation was reviewed. No deaths have occurred, but the FDA has required the manufacturer to add a new warning for DRESS to the Warnings and Precautions section of the drug labels for its capsule, oral suspension, and injection formulations.

Clinicians should explain the signs and symptoms of severe skin reactions to patients and alert them as to when to seek immediate care.

DRESS consists of three or more of the following:

• Cutaneous reaction (such as rash or exfoliative dermatitis)
• Eosinophilia
• Fever
• Lmphadenopathy, and
• One or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, pericarditis, and pancreatitis.

If DRESS is suspected, ziprasidone treatment should be stopped immediately.

Ziprasidone is currently approved for the treatment of schizophrenia, for acute and maintenance treatment of manic or mixed episodes in bipolar disorder as monotherapy; or as adjunct therapy to lithium or valproate. The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. As with other drugs having efficacy in bipolar disorder, the mechanism of action of ziprasidone in bipolar disorder is unknown.

For more information call or visit FDA.gov.

SOURCE: Reuters News
November 12,2014 | Laura Tedesco

Clearing the air: New science reveals that toking up may be more addictive than previously thought. 

Although there’s a lot of buzz about marijuana being nonaddictive, the evidence is stacking up that people can — and do — become dependent on the drug. A study released earlier this year, for example, found that 40 percent of marijuana users in an outpatient treatment program showed signs of withdrawal, a classic indicator of addiction. Now, new research in the journal PNAS sheds light on how lighting up changes the brain — and potentially primes people for withdrawal.

It’s long been known that exposure to THC, the primary psychoactive ingredient in pot, can lead to changes in the brain. Problem is, different studies have shown different structural alterations, making it difficult to pinpoint exactly how the stuff affects people mentally. That’s why a group of researchers decided to use three different magnetic resonance imaging (MRI) techniques to examine the brains of 48 chronic marijuana users and 62 nonusers, while also assessing IQ and negative life consequences of pot smoking.

The most obvious difference: The people who regularly toked up had less volume in the orbitofrontal gyri. This brain region is part of the orbitofrontal cortex, “one of the primary areas within the reward system, which is basically a network of brain regions implicated in the addiction process,” said study author Francesca Filbey, an addiction researcher at the Center for BrainHealth at the University of Texas at Dallas. “More specifically, the orbitofrontal cortex is important for decision-making. This is the area of the brain that would learn something is good for us or bad for us.”

So why does pot cause shrinkage in this area? Simple: The orbitofrontal cortex is highly concentrated with cannabinoid receptors, the places in your brain where THC binds. As a result, it’s much more vulnerable to the effects of a chronic flood of the substance. In animal studies, “the number of those receptors decreased as a result of THC exposure as a way to regain balance in that system,” Filbey told Yahoo Health. “So too much THC basically leads to lower numbers of those receptors in the brain.”

It’s this effect that gives credence to the “pot is addictive” camp. As Filbey explained, the fewer cannabinoid receptors a marijuana user has, the more THC he requires to achieve the desired high. “This really describes tolerance,” she said. “Around 10 percent of users, on average, report changes in tolerance and also increased craving and withdrawal.” The marijuana users in this study weren’t just casual smokers — they used the drug at least four times per week.

Although this study may help illuminate the addiction process, the findings are a little hazier when it comes to how these brain changes affect people’s behavior and intelligence, if at all. The researchers did find that marijuana users scored lower on an IQ test than non-users did. But as tempting as it is to link this to the changes in their brains, the researchers weren’t able to firmly establish that connection, suggesting there’s another factor behind the users’ lower IQs. One possibility: “If these individuals were using during their adolescent years, then they may have missed a lot of the verbal knowledge that IQ is testing for,” Filbey said.

And, incredibly, the brain seems capable of compensating for the volume loss associated with consistent marijuana use: The pot smokers showed increased connectivity in the orbitofrontal cortex. What does that mean, exactly? “Structural connectivity refers to the actual white matter tracks that connect the gray areas in our brain,” said Filbey. “Functional connectivity is how well brain regions coactivate — if they respond synchronously. This basically suggests there’s greater communication within the network.” The positive effects on connectivity were greatest in people who’d started using marijuana at a young age.

If this sounds too good to be true, that’s because it is — at least if you’ve been toking up for years. After about six years of chronic pot smoking, these compensatory increases in connectivity began to reverse. “[Connectivity] actually started to decline,” Filbey said. “[The brain] isn’t able to sustain itself past continued use of about six years.”