New Terminology Proposed for Drugs Used in Mental Disorders
27th European College of Neuropsychopharmacology conference, October 2014, Germany
Five leading psychiatry organizations recently proposed changes to the terminology used in naming drugs for mental disorders and released a smartphone and tablet app to help clinicians make treatment decisions. They made the announcement in October at the 27th European College of Neuropsychopharmacology conference in Berlin, Germany.
Instead of the current method of focusing on symptoms, the organizations want to base the names on the pharmacological target such as serotonin and dopamine. The groups advocating for the change acknowledged it could be a long process and include discussions and negotiations with academics, clinicians, pharmaceutical companies, and regulatory bodies.
Neuropsychopharmacologists are still using a classification system developed in the 1960s, which the organizations indicate is sometimes confusing. For instance, patients diagnosed with anxiety may receive prescriptions for antidepressants or antipsychotics, while patients with depression may take antipsychotics.
“As in many fields, what we know about drugs has evolved enormously since the 1960s, but the names we use to describe these drugs have not evolved in 50 years,” said Josef Zohar, MD, a professor of psychiatry in Tel Aviv, Israel. “As an analogy, I mostly use my smartphone to type SMS text messages, yet I would not call it a ‘typewriter,’ as I would have in the 1960's; the names need to reflect our contemporary knowledge. If this is true of electronics, it is certainly true of medicines.”
The organizations seeking the change are the European College of Neuropsychopharmacology, International College of Neuropsychopharmacology, American College of Neuropsychopharmacology, Asian College of Neuropsychopharmacology, and the International Union of Basic and Clinical Pharmacology.
The proposed naming system includes four components, including the pharmacological target and mode of action, approved indications, efficacy and major side effects, and a neurobiological description.
“There is a long period of negotiation and discussion to come before we get complete agreement,” said David Kupfer, a psychiatry professor at the University of Pittsburgh. “Nevertheless, this will mean a real change in the way we talk about the drugs used in psychiatry and neuroscience.”
—Tim Casey for PsychCongress Network
Psychotropic Medication and Osteoporosis
Osteoporosis is a serious, progressive, and potentially disabling disorder that affects both men and women and can occur at any age, though most commonly it affects the elderly and particularly women after menopause. Signs and symptoms can include back pain; bone fragility due to low bone mineral density; fractures (most commonly at the spine, hip, distal radius, and proximal humerus) that occur without significant accompanying trauma; and deformity.
Osteoporosis is often a silent disease whose first manifestation is a bone fracture. The so-called “gold standard” to measure bone mineral density is dual-energy X-ray absorptiometry (DXA), which is also incidentally one of the most accurate measures of body composition (and specifically our percentage of body fat).
In the United States, it is estimated that approximately 10 million people have osteoporosis, and another 34 million are estimated to have low bone density, that is, osteopenia, that increases their chances of developing full-blown osteoporosis. Osteoporosis can also occur in the context of nutritional deprivation such as seen in those patients with anorexia nervosa who severely restrict their food intake, as well as secondary to chronic diseases such as those of the liver, kidney, and lymph system, organ transplantation, prolonged physical immobilization, and medication intake such as glucocorticoids. Both smoking and excessive alcohol intake have been associated with an increased risk of lowered bone mineral density. Are our psychotropic medications also implicated?
There is a growing body of literature to suggest the answer is, unfortunately, in the affirmative. Both short-term and long-term use of antidepressant medications—predominantly tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs)—have been associated with fractures.
In the short-term, within the first weeks of beginning these medications, cardiovascular side effects such as bradycardia and other arrhythmias, orthostatic hypotension, dizziness, and syncope, as well as antihistaminic effects such as sedation and anticholinergic effects such as blurred vision, may lead to physical instability and an increased risk of falls and subsequent fractures, particularly with the tricyclic antidepressants. But after six months of use, it is suggested that medications like the SSRIs can lead to actual decreased bone mineral density. In other words, there is speculation that SSRIs may actually be affecting the “micro-architecture” of bone. The mechanism is not known, but it is likely due to their direct effect on the serotonin transporter system. Studies, though, are complicated due to many possible issues, including how depression is diagnosed across studies that are compared in meta-analyses, as well as to a lack of consistent information on dosages of medications used or even what other medications patients are taking.
Further, there are confounding factors: for example, depression itself may lead to less physical activity, loss of muscle mass, and increased muscle weakness, and depressed patients may have poor nutritional habits that lead to poor intake of calcium and vitamin D, weight loss and lowered body mass index, less sun exposure (also leading to lowered vitamin D levels), and higher intake of both alcohol and tobacco. And as a result of stress, these patients may also have higher levels of 24-hour cortisol and increased catecholamine levels, all of which can affect bone mineral density.
The situation is further complicated because it is not clear whether the association among SSRI use, low bone mineral density, and increased fracture incidence is an example of confounding by indication, that is, when a particular disease and its treatment both have the potential to be associated with the same outcome. For example, depression itself and its resultant consequences of weight loss, decreased activity, and overconsumption of alcohol have all been associated with decreased bone mineral density and increased risk of fractures, as has exposure to its treatment by antidepressants.
As a result, the specific relationship among SSRI use, low bone mineral density, and fracture risk remains unclear (and depends, to some extent, on the particular SSRI used), but a review of the literature that includes observational case-control and cohort-design studies strongly suggests that the use of antidepressant medication, particularly SSRIs, is associated with decreased bone mineral density and bone loss. Older people are particularly more vulnerable to their effects, and hip fractures are the most prevalently reported fractures. Some even suggest that SSRI use may be as detrimental to bone as has been reported with glucocorticoids and that SSRIs should be included in any list of medications associated with osteoporotic fractures. Depressed patients with a history of prior fractures, heavy smoking, and low body mass index, as well as postmenopausal women with depression should be considered candidates for measurement of bone mineral density by DXA scans.
What about antipsychotic medications? It has also been suggested that medications that increase prolactin levels such as risperidone are more likely to decrease bone mineral density than those that are “prolactin-sparing,” such as olanzapine, but patients on antipsychotics may develop reduced bone mineral density through other mechanisms such as decreased exercise, excessive alcohol and tobacco use, and poor nutrition, just as those on antidepressants.
Researchers acknowledge that there is probably not enough evidence yet to recommend routine monitoring of bone mineral density in patients taking antipsychotic drugs, but they do suggest that clinicians have a “lower threshold” for investigating bone mineral density in patients on antipsychotics, especially when patients have additional risk factors for decreased bone mineral density, such as a low body mass index, a history of corticosteroid use, family history of osteoporosis, or a history of previous fractures.
The bottom line is that further studies are warranted, and most researchers believe it is “too early” to suggest that all those on psychotropic medication have DXA testing for bone density. It behooves us as clinicians, though, to discuss with our patients who are on either antidepressants or antipsychotics the possibility that these medications may affect their bone health. Certainly, it is worthwhile to measure calcium and vitamin D levels and, when appropriate, recommend vitamin D and calcium supplementation, as well as recommend supervised exercise for maintaining bone health in those particularly at risk for developing osteopenia and osteoporosis.
Sylvia R. Karasu, M.D. for Psychiatric News.
Anti-inflammatories May Help Ease Depression
Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents.
To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions.
Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles.
Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression.
Data Extraction and Synthesis
Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated.
Main Outcomes and Measures
Depression scores after treatment and adverse effects.
Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 4258) and 4 investigated cytokine inhibitors (n = 2004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, −0.34; 95% CI, −0.57 to −0.11; I2 = 90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, −0.54; 95% CI, −1.08 to −0.01; I2 = 68%) and depressive symptoms (SMD, −0.27; 95% CI, −0.53 to −0.01; I2 = 68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, −0.29; 95% CI, −0.49 to −0.08; I2 = 73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2 = 0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2 = 0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity.
Conclusions and Relevance
Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.
Cornell Scientists Show That Amyotrophic Lateral Sclerosis (ALS) Is a Protein Aggregation Disease
Using a technique that illuminates subtle changes in individual proteins, chemistry researchers at Cornell have uncovered new insight into the underlying causes of Amyotrophic Lateral Sclerosis (ALS).
Brian Crane, professor of chemistry and chemical biology, led one study and co-authored a follow-up on a spectroscopic method that detects subtle changes to copper-containing proteins in solution. He and Jack Freed, the Frank and Robert Laughlin Professor of Physical Chemistry, have developed the method together with Petr Borbat, associate director of Cornell’s National Biomedical Center for Advanced ESR Technology.
The first study, which proved the principle of the technique – pulsed dipolar electron spin resonance (ESR) spectroscopy – was published Oct. 7 in Biophysical Journal; the second paper, which used the technique to connect ALS symptoms with protein aggregation, appeared Oct. 14 in Proceedings of the National Academy of Sciences (PNAS).
A complex neurodegenerative disease, ALS often has a genetic component – genetic defects that cause it can be inherited. Scientists have long known that one of the culprit genes codes for the protein “superoxide dismutase 1” or SOD1 – a critical copper-containing enzyme that protects cells against oxidative damage by destroying free radicals.
Scientists have surmised that ALS is a disease related to oxidative damage of neurons, and that might still be true, Crane said. But he and colleagues have provided strong evidence for another hypothesis: that SOD1 mutations cause ALS by destabilizing the SOD1 protein structure. This leads to increased motion of the proteins, which Crane likened to “breathing.” This movement promotes their aggregation, or clumping together – an event toxic to the healthy cell.
“ALS, in this form, appears to be a protein aggregation disease, much like Alzheimer’s and Parkinson’s diseases,” Crane said.
For a long time, people have studied mutations in SOD1 to try to understand ALS, but the properties of normal proteins and mutated ones were found to be very similar. By using ESR spectroscopy, the scientists for the first time have seen definitive differences. By verifying with other methods, Crane said, the researchers showed that the dynamics of the proteins were dramatically changed by mutation, and that they showed a tendency to aggregate.
In the PNAS paper, X-ray scattering was also used to study structural changes and the ability of the proteins to interact with each other. The researchers found that levels of protein aggregation correlated with the severity of ALS symptoms.
Their conclusions point to the possibility of ALS being more linked to toxicity of aggregation and perhaps less about the effect of the mutations on SOD1 activity, Crane said. ALS is a late-onset disease, with people being affected in mid to late life. “Sporadic mutations in SOD1 arise from natural processes, but it’s not really clear if they’re actually going to generate the disease or not,” he said.
The new ESR might be a good diagnostic tool to identify harmful mutations early before symptoms become evident, Crane said. These methods could also aid in the development of drugs that would bind to and stabilize the proteins to prevent detrimental effects in the first place.
The Biophysical Journal paper, “Copper-Based Pulsed Dipolar ESR Spectroscopy as a Probe of Protein Conformation Linked to Disease States,” was co-authored with Freed, Borbat, and first-author Gregory Merz, a graduate student in chemistry.
The PNAS paper, “Aggregation Propensities of Superoxide Dismutase G93 Hotspot Mutants Mirror ALS Clinical Phenotypes,” was authored in collaboration with the groups of Elizabeth Getzoff and John Tainer at the Scripps Research Institute. Crane and Freed’s research was supported by the National Institutes of Health.
Fatty Fish Intake May Improve Antidepressant Response
27th European College of Neuropsychopharmacology conference, October 2014, Germany
Increased intake of fatty fish may be linked with greater likelihood of antidepressant response, according to researchers who presented their findings at the European College of Neuropsychopharmacology Congress in Berlin, Germany.
Investigators examined the relationship between metabolism of fatty acids and stress hormone regulation in a group of 70 patients with depression and 51 healthy controls.
Participants’ levels of fatty acids and of cortisol were measured, and patients with depression received 20 mg of an SSRI daily for six weeks. If patients did not respond to the SSRI, the dose was gradually escalated to 50 mg per day.
“Interestingly, we saw that depressed patients had an altered metabolism of fatty acids, and that this changed metabolism was regulated in a different way by stress hormones,” said lead researcher Roel Mocking, PhD candidate from the Department of Psychiatry of the Academic Medical Center at the University of Amsterdam, the Netherlands.
When researchers categorized participants into four groups of fatty fish intake, they found that those in the group who consumed the least amount of fish tended to respond most poorly to antidepressants. On the other hand, patients in the group that consumed the most fish had the best antidepressant response. For example, patients who ate fatty fish at least once per week had a 75% chance of responding to antidepressants, while patients who never ate fatty fish had a 23% chance of medication response.
The study authors noted that measures of fatty acid metabolism and their association with stress hormone regulation might be useful as an early indicator of antidepressant response. In addition, patients may benefit from eating fatty fish as a way to improve their fatty acid metabolism and antidepressant response.
“So far this is an association between fatty acids in blood and antidepressant response; so it’s not necessarily a causal effect. Our next step is to look at whether these alterations in fatty acid metabolism and hormonal activity are specific for depression, so we are currently repeating these measurements in patients with post-traumatic stress disorder and schizophrenia,” said Mocking. He added that the current study is preliminary and larger scale studies will be “of considerable interest.”
—Lauren LeBano for PsychCongress Network
Cocoa-derived Flavanols Can Improve Memory and Cognition in Older Adults
The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50–69-year-old subjects who consumed either a high or low cocoa–containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.
New Anti-Addiction Medications: Pharmacogenetics and Immunotherapies
27th Annual U.S. Psychiatric and Mental Health Congress
Advances in pharmacogenetics and in vaccine development mean that new tools for addiction treatment are nearing clinical application. In particular, recent data should empower clinicians to best identify patients who will benefit from naltrexone for alcoholism and from disulfiram for cocaine dependence.
Thomas Kosten, MD, Professor of Psychiatry, Pharmacology, and Neuroscience at Baylor College of Medicine in Houston discussed new anti-addiction medications, pharmacogenetics, and immunotherapies in a presentation at the 27th Annual U.S. Psychiatric and Mental Health Congress.
Studies show that patients taking naltrexone are significantly less likely to experience relapse during a 12-week period than patients receiving placebo, Dr. Kosten noted, but the drug may not be appropriate for all patients.
“More complex and severely dependent patients may be better for naltrexone,” he noted. Such patients may have a strong family history of alcoholism, low β-endorphin levels, and a μ-opioid receptor polymorphism that identifies them as genetically responsive to the medication.
These patient characteristics are linked with the mechanism of naltrexone for reducing alcohol relapse. Naltrexone raises β-endorphin levels through feedback inhibition via presynaptic opioid receptors, and it reduces alcohol stimulation and craving by maximal β-endorphin stimulation of postsynaptic μ-opioid receptors.
Because naltrexone maximizes β-endorphin levels, alcohol is unable to further raise β-endorphin or increase μ-opioid receptor stimulation. As a result, the drug works to reduce “high” or priming effect from alcohol, explained Dr. Kosten.
Approximately 24% to 36% of Europeans have the polymorphism that increases β-endorphin binding to the μ-opioid receptor. “The polymorphism occurs in the northern part of the world but not in the southern part of the world,” said Dr. Kosten. “In Africa this polymorphism does not occur at all.”
In addition to alcohol dependence, pharmacogenetics can help optimize treatment for patients experiencing addiction with other substances, such as cocaine. Disulfuram, although not yet approved by the FDA for cocaine dependence, appears to be a promising agent for treating that disorder.
The drug is typically used to treat alcohol dependence but promotes cocaine abstinence by inhibiting dopamine beta-hydroxylase (DBH) and altering the dopamine to norepinephrine ratio.
In a recent study examining average biweekly cocaine use by medication and DBH genotype, researchers found that disulfuram increases cocaine-free urines more than placebo (55% vs 40%) and that genetically high plasma DBH levels were associated with 30% more cocaine-free urines with disulfuram.
These positive outcomes might result from reduced craving and withdrawal and increased cocaine-induced dysphoria, explained Dr. Kosten.
Use of the dopamine beta hydroxylase “-1200 CT” polymorphism for matching cocaine dependent patients with disulfuram treatment is not ready for clinical application due to the unapproved status of disulfuram for cocaine dependence, but Dr. Kosten and other researchers continue to investigate the drug in studies.
Researchers are pursuing vaccines as another avenue for treating addiction.
A vaccine for cocaine dependence works not by eliminating the desire for cocaine but by preventing the user from experiencing a drug-associated high. Patients receiving the treatment are injected with a cocaine molecule attached to a protein from a cholera-causing bacteria.
In response, the patient’s immune system creates cocaine antibodies that will bind to cocaine if the substance ever again enters the patient’s body. This reaction thus inhibits the cocaine from crossing the blood-brain barrier and prevents the user from feeling high.
“Can someone smoke enough to overcome the vaccine titer? Yes, but with effort,” said Dr. Kosten, noting that the situation seemed unlikely.
Animal results from the vaccine have been promising in terms of safety and efficacy, according to Dr. Kosten. There has been no toxicity at several times a clinically relevant dose, and rodents decreased self-administration of cocaine after receiving the vaccine.
The positive results have continued into human studies. The current results are “encouraging,” said Dr. Kosten. The vaccine has been well tolerated and patients have reliably produced more antibodies in conjunction with greater doses of the vaccine. Furthermore, patients who produce antibodies have showed substantially less cocaine intoxication.
As with naltrexone and disulfuram treatment, vaccine treatment is enhanced by considering genetic factors.
Low DBH was a pharmacogenetic marker for good clinical response, but low DBH was not associated with high antibody levels. In addition, four HLA SNPs were associated with cocaine-positive urines during a clinical trial. “One is a Class 1 paralogue also associated with anti-cocaine IgG levels,” said Dr. Kosten.
He added that the clinical trial “provides leads as to the cocaine vaccine’s mechanism of action and development of more effective cocaine vaccines.”
What to Expect
In the future, immunotherapy for substance abuse might include overdose treatment, relapse prevention after abstinence, prevention of addiction in adolescents, and prevention of fetal complications by vaccinating mothers who are dependent on drugs.
Clinicians can also anticipate that vaccines may eventually be administered orally or nasally or through a one-time, slow-release injection. Improvements to adjuvants will mean greater vaccine response rates and high antibody levels in patients, and human genetics may predict who will be a non-responder.
—Lauren LeBano for PsychCongress Network