Pesach Lichtenberg

A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression

Background Although previous meta-analyses have examined effects of antidepressants, psychotherapy, and alternative therapies for depression, the efficacy of these treatments alone and in combination has not been systematically compared. We hypothesized that the differences between approved depression treatments and controls would be small. Methods and Findings The authors first reviewed data from Food and Drug Administration Summary Basis of Approval reports of 62 pivotal antidepressant trials consisting of data from 13,802 depressed patients. This was followed by a systematic review of data from 115 published trials evaluating efficacy of psychotherapies and alternative therapies for depression. The published depression trials consisted of 10,310 depressed patients. We assessed the percentage symptom reduction experienced by the patients based on treatment assignment. Overall, antidepressants led to greater symptom reduction compared to placebo among both unpublished FDA data and published trials (F = 38.5, df = 239, p<0.001). In the published trials we noted that the magnitude of symptom reduction with active depression treatments compared to controls was significantly larger when raters evaluating treatment effects were un-blinded compared to the trials with blinded raters (F = 2.17, df = 313, p<0.05). In the blinded trials, the combination of antidepressants and psychotherapy provided a slight advantage over antidepressants (p = 0.027) and psychotherapy (p = 0.022) alone. The magnitude of symptom reduction was greater with psychotherapies compared to placebo (p = 0.019), treatment-as-usual (p = 0.012) and waiting-list (p<0.001). Differences were not seen with psychotherapy compared to antidepressants, alternative therapies or active intervention controls. Conclusions In conclusion, the combination of psychotherapy and antidepressants for depression may provide a slight advantage whereas antidepressants alone and psychotherapy alone are not significantly different from alternative therapies or active intervention controls. These data suggest that type of treatment offered is less important than getting depressed patients involved in an active therapeutic program. Future research should consider whether certain patient profiles might justify a specific treatment modality.

Subtyping Major Depressive Disorder

during their lifetime in epidemiological studies using current criteria [4] . It is unlikely that a syndrome as polymorphic and widely diagnosed as major depressive disorder (MDD) will reflect a single process. Attempts to delineate different forms of depression by statistically analyzing the symptomatology of large samples of patients without taking into consideration life events or childhood history have been unsuccessful. It may be necessary to consider childhood trauma, marital and employment stress, and medical health in diagnosing subtypes of depression. Epidemiologic data on the effects of childhood trauma, unemployment and divorce on depression incidence are strong [5, 6] . DSM-IV does make one allowance for circumstances by including a bereavement exclusion [7] . However, it seems that bereavement is not different from other losses and stresses that are associated with depression [8] . The pharmacotherapy of depression offers a plethora of medications. However, depression is often resistant to standard antidepressant medication, and a large percentage of patients respond just as well to placebo [9, 10] . The DSM broad diagnosis of MDD does not encourage a search for subtypes of depression that may require specific treatment. The current diagnostic system may be partly responsible for the rising placebo response rates and increasing numbers of subjects required to demonstrate efficacy in ever larger clinical trials. Introduction

Hypnotic Susceptibility: Multidimensional Relationships With Cloninger’s Tridimensional Personality Questionnaire, COMT Polymorphisms, Absorption, and Attentional Characteristics

One hundred and seven healthy volunteers were administered Cloninger’s Tridimensional Personality Questionnaire (TPQ), the Differential Attentional Processes Inventory (DAPI), the Tellegen Absorption Scale (TAS), and the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C). Polymorphisms of catechol O-methyltransferase (COMT), an enzyme involved in dopamine metabolism, were assessed. Highly hypnotizable subjects self-reported greater TPQ persistence, absorption, and focused attentional abilities. Hierarchical multiple regression analyses found that TPQ persistence, COMT, TAS, and the DAPI attentional scales explained 43.8% of the variance in women and 29% in men. Membership was correctly discriminated for the more extreme low (62.1%) and highly (81.5%) hypnotizable groups. These results suggest that highly hypnotizable persons have a more effective frontolimbic attentional system and further suggest the involvement of dopaminergic systems in hypnotizability.

The ethics of the placebo in clinical practice

While discussions of the ethics of the placebo have usually dealt with their use in a research context, the authors address here the question of the placebo in clinical practice. It is argued, firstly, that the placebo can be an effective treatment. Secondly, it is demonstrated that its use does not always entail deception. Finally guidelines are presented according to which the placebo may be used for clinical purposes. It is suggested that in select cases, use of the placebo may even be morally imperative. The argument is illustrated by three case vignettes.

Interrelationship of age, depression, and central serotonergic function: evidence from fenfluramine challenge studies.

The purpose of this study was to examine the relationship between age-associated changes in central serotonergic function and abnormalities associated with major depression. Under randomized double-blind conditions, prolactin and cortisol responses to the serotonin-releasing agent d,l-fenfluramine hydrochloride (60 mg orally) and placebo were examined in 30 normal subjects (15 men, 15 women; age range 21-84 years) and 39 patients with major depressive disorder, endogenous subtype (14 men, 25 women; age range 29-72 years). In the normal subjects, a significant Age x Challenge x Time interaction was observed in the prolactin response (p = .03). This was primarily due to the elevated prolactin responses of the younger healthy women. Peak minus baseline (delta) prolactin responses were negatively correlated with age (women, p = .004; men, p = .06). In the depressed patients there was no age-related decline in prolactin response to fenfluramine. When depressed and healthy younger subjects were compared, delta prolactin responses to fenfluramine were significantly blunted in young patients with depression (p = .003) irrespective of the significant effect of gender (p = .01), but not in older depressed patients. Cortisol responses to fenfluramine did not reveal consistent effects of age, gender, or diagnosis. Age-related decline in central serotonergic function may make older individuals more vulnerable to depression and possibly render depressive episodes more frequent, more severe, and less amenable to treatment.

De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample

Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent-offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities.

A New Hypnotic Technique for Treating Combat-Related Posttraumatic Stress Disorder: A Prospective Open Study

Abstract Many combat veterans with posttraumatic stress disorder (PTSD) have an olfactory component to their traumatic memories that might be utilized by a technique called hypnotherapeutic olfactory conditioning (HOC). Thirty-six outpatients with chronic PTSD, featuring resistant olfactory-induced flashbacks, were treated with six 1.5-hour sessions using hypnosis. The authors used the revised Impact of Events Scale (IES–R), Beck Depression Inventory, and Dissociative Experiences Scale as outcome measures. Significant reductions in symptomatology were recorded by the end of the 6-week treatment period for the IES–R, as well as for the Beck Depression Inventory and the Dissociative Experiences Scale; 21 (58%) of the subjects responded to treatment by a reduction of 50% or more on the IES–R. Improvement was maintained at 6-month and 1-year follow-ups. Use of medication was curtailed. HOC shows potential for providing benefit to individuals suffering from PTSD with olfactory components.

Hypnotherapeutic Olfactory Conditioning (HOC): Case Studies of Needle Phobia, Panic Disorder, and Combat-Induced PTSD

Abstract The authors developed a technique, which they call hypnotherapeutic olfactory conditioning (HOC), for exploiting the ability of scents to arouse potent emotional reactions. During hypnosis, the patient learns to associate pleasant scents with a sense of security and self-control. The patient can subsequently use this newfound association to overcome phobias and prevent panic attacks. This may be especially effective for posttraumatic stress disorder (PTSD) with episodes of anxiety, flashbacks, and dissociation triggered by smells. The authors present 3 cases, patients with needle phobia, panic disorder, and combat-induced PTSD who were successfully treated with the HOC technique.

The moral case for the clinical placebo

Placebos are arguably the most commonly prescribed drug, across cultures and throughout history. Nevertheless, today many would consider their use in the clinic unethical, since placebo treatment involves deception and the violation of patients’ autonomy. We examine the placebos definition and its clinical efficacy from a biopsychosocial perspective, and argue that the intentional use of the placebo and placebo effect, in certain circumstances and under several conditions, may be morally acceptable. We highlight the role of a virtue-based ethical orientation and its implications for the beneficent use of the placebo. In addition, the definitions of lying and deception are discussed, clarified and applied to the clinical placebo dilemma. Lastly, we suggest that concerns about patient autonomy, when invoked as a further argument against administering placebos, are extended beyond their reasonable and coherent application.

Reduced prepulse inhibition is associated with increased hypnotizability.

Hypnosis involves the manipulation of conscious attentional discrimination. The prepulse inhibition (PPI) paradigm assesses primary unconscious information processing. We investigated the correlation between hypnotizability and PPI of the startle reflex. Forty-eight healthy subjects were evaluated with the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) and acoustic PPI. Subjects were divided into low, medium, and high hypnotizable groups. The low-hypnotizable group showed a significantly higher inhibition of the startle response, at lead intervals 60 ms and 120 ms, than did the medium- and high-hypnotizable groups. We conclude that hypnotizability and PPI may be negatively correlated. These findings lend further support for the role of dopaminergic neurotransmission mechanisms in the determination of hypnotizability levels.