Antidepressants and advertising: psychopharmaceuticals in crisis

As the efficacy and science of psychopharmaceuticals has become increasingly uncertain, marketing of these drugs to both physicians and consumers continues to a central part of a multi-billion dollar per year industry in the United States. We explore how such drug marketing portrays idealized scientific relationships between psychopharmaceuticals and depression; how multiple stakeholders, including scientists, regulatory agencies, and patient advocacy groups, negotiate neurobiological explanations of mental illness; and how the placebo effect has become a critical issue in these debates, including the possible role of drug advertising to influence the placebo effect directly. We argue that if and how antidepressants "work" is not a straightforward objective question, but rather a larger social contest involving scientific debate, the political history of the pharmaceutical industry, cultural discourses surrounding the role of drugs in society, and the interpretive flexibility of personal experience.     

The mathematical biophysics of some mental phenomena

In this paper some aspects of the mathematical biophysics of the central nervous system, which hitherto have not been treated, are discussed. First, a neurobiophysical mechanism for consciousness is suggested. It provides for the possibility of conscious and unconscious rractions. Next, a mechanism of memory, both on the conscious and subconscious level, is suggested. The gradual forgetting of remote events is ascribed to the inhibition of older memory traces by the more recent ones. On the average, an exponential decay of memory with time is thus obtained, although memory for unusually strong experiences follows a somewhat different law of decay. A homeostatic mechanism is then considered which regulates the level of accumulated excitation or inhibition. Such a mechanism, under certain disturbing conditions, will result in periodical fluctuations of the total cortical excitation with periods varying within a very wide range. Finally, a mechanism for foresight and desire of future events is suggested. The latter provides for the possibility of the formation of subconscious reactions and habits, which may be abolished by bringing them into consciousness.     

Mechanisms of placebo effect and of conditioning: neurobiological data in human and animals

A placebo is a sham treatment such as pill, liquid, injection, devoid of biological activity and used in pharmacology as a control for the activity of a drug. In many cases, this placebo induces biological or psychological effects in the human. Two theories have been proposed to explain the placebo effect: the conditioning theory which states that the placebo effect is a conditioned response, and the mentalistic theory for which the patient expectation is the primary basis of the placebo effect. The mechanisms involved in these processes are beginning to be understood through new techniques of investigation in neuroscience. Dopamine and endorphins have been clearly involved as mediators of the placebo effect. Brain imaging has demonstrated that the placebo effect activates the brain similarly as the active drug and in the same brain area. This is the case for a dopamine placebo in the Parkinson'disease, for analgesic-caffeine- or antidepressor-placebo in the healthy subject. It remains to be understood how conditioning and expectancy are able to activate, in the brain, memory loops that reproduce the expected biological response.     

Fluid Biosemiotic Mechanisms Underlie Subconscious Habits

Although research into the biosemiotic mechanisms underlying the purposeful behavior of brainless living systems is extensive, researchers have not adequately described biosemiosis among neurons. As the conscious use of signs is well-covered by the various fields of semiotics, we focus on subconscious sign action. Subconscious semiotic habits, both functional and dysfunctional, may be created and reinforced in the brain not necessarily in a logical manner and not necessarily through repeated reinforcement. We review literature that suggests hypnosis may be effective in changing subconscious dysfunctional habits, and we offer a biosemiotic framework for understanding these results. If it has been difficult to evaluate any psychological approach, including hypnosis, this may be because contemporary neuroscience lacks a theory of the sign. We argue that understanding the fluid nature of representation in biological organisms is prerequisite to understanding the nature of the subconscious and may lead to more effective of treatments for dysfunctional habits developed through personal experience or culture.     

When peers are not peers and don't know it: The Dunning‐Kruger effect and self‐fulfilling prophecy in peer‐review

The fateful combination of (i) the Dunning‐Kruger effect (ignorance of one's own ignorance) with (ii) the nonlinear dynamics of the echo‐chamber between reviewers and editors fuels a self‐reinforcing collective delusion system that sometimes spirals uncontrollably away from objectivity and truth. Escape from this subconscious meta‐ignorance is a formidable challenge but if achieved will help correct a central deficit of the peer‐review process that stifles innovation and paradigm shifts.     

Latitudinal gradients in species diversity and Rapoport's rule revisited: a review of recent work and what can parasites teach us about the causes of the gradients?

A review is given of recent work on latitudinal gradients in species diversity and their explanations, including Rapoport's rule. Energy input, measured by temperature or potential evapotranspiration. correlates best with the gradients. However, such a correlation does not "explain" them. It merely suggests explanations, which may be either different ceilings to diversity set by different energy levels under equilibrium conditions, recent historical events, or a gradient in effective evolutionary time (determined by speed of evolution directly driven by temperature, and by relative constancy of conditions over evolutionary time) under non-equilibrium conditions. Marine parasites are used to show that equilibrium conditions are the exception rather than the rule among animals, It is concluded that latitudinal gradients in species diversity result from a gradient in effective evolutionary time modulated by several other factors. Dispersal abilities of many marine invertebrates are likely to be greater at low than at high latitudes, suggesting an opposite Rapppoport effect.
This is an invited Minireview on the occasion of the 50th anniversary of the Nordic Ecological Society Oikos.     

Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study

ABSTRACT: The 5% Lidocaine patch is used for treating chronic neuropathic pain conditions such as chronic back pain (CBP), diabetic neuropathy and complex regional pain syndrome, but is effective in a variable proportion of patients. Our lab has reported that this treatment reduces CBP intensity and associated brain activations when tested in an open labelled preliminary study. Notably, effectiveness of the 5% Lidocaine patch has not been tested against placebo for treating CBP. In this study, effectiveness of the 5% Lidocaine patch was compared with placebo in 30 CBP patients in a randomised double-blind study where 15 patients received 5% Lidocaine patches and the remaining patients received placebo patches. Functional MRI was used to identify brain activity for fluctuations of spontaneous pain, at baseline and at two time points after start of treatment (6 hours and 2 weeks). There was no significant difference between the treatment groups in either pain intensity, sensory and affective qualities of pain or in pain related brain activation at any time point. However, 50% patients in both the Lidocaine and placebo arms reported a greater than 50% decrease in pain suggesting a marked placebo effect. When tested against an untreated CBP group at similar time points, the patch treated subjects showed significantly greater decrease in pain compared to the untreated group (n=15). These findings suggest that although the 5% Lidocaine is not better than placebo in its effectiveness for treating pain, the patch itself induces a potent placebo effect in a significant proportion of CBP patients.     

Two explanations of the dawn chorus compared: how monotonically changing light levels favour a short break from singing

I used optimality modelling to compare two of the most plausible and general explanations for the dawn and dusk peaks in bird song output. Kacelnik's explanation is that foraging is inefficient in poor light, but that social interactions are less affected, making singing more worthwhile than foraging. McNamara et al.'s explanation is based on stochasticity in foraging success and overnight energy requirements; it has been extensively analysed with stochastic dynamic programming models. Both explanations are now incorporated into this sort of model. I used various functions to link success of foraging and singing to time of day, but assumed that above some light level there is no further effect. Kacelnik's explanation has as strong an effect as stochasticity in generating dawn and dusk choruses. It also predicts short pauses in the singing output just after the dawn chorus and before the dusk chorus. The former arises because birds delay foraging when it will become more profitable later, until foraging success reaches a plateau, when the energetic debt accumulated makes them forage. The principle of this see-saw double switch in behaviours may apply to other explanations for the dawn chorus, and to other shifts in behaviour when conditions change gradually. The model predicts that from day to day cloud cover determines when a dawn chorus starts, but that overnight temperature and wind strength have more effect on chorus intensity and duration. I discuss what sort of observational and experimental data on singing routines would better test this model. Copyright 2002 The Association for the Study of Animal Behaviour. Published by Elsevier Science Ltd. All rights reserved.     

The stress of mortally dangerous conditions: the individual psychophysiological mechanisms of adaptation in life-threatening situations

Investigation into the mechanisms of the individual psychophysiological adaptation to life-threatening situations was performed. The data analysis of evoked potentials induced with verbal stimuli in 30-50-msec exposures was executed. Cross-correlation and wavelet analysis, as well as neurone algorithms were used to define total brain response to each stimulus and its duration. Correlation of the estimated parameters with subconscious aspects of psychic activity is discussed. Results of the studies performed with this neurosemantie method in various groups of subjects perceiving threat to life in the course of their performance, are presented. Described changes in the subconscious response mechanisms can help to clarify the direction for creation of new approaches with psychological correction and support.     

Placebo in the treatment of pain

Placebo is the use of the substance or procedure without specific activity for the condition that is trying to be healed. In medicine, benefits of placebo effect are used since 1985 and 1978 placebo effect was first scientifically confirmed. It was found that placebo induced analgesia depends on the release of endogenous opiates in the brain and that the placebo effect can be undone using the opiates antagonist naloxone. Functional magnetic resonance imaging of the brain showed that placebo analgesia was obtained regarding the activation and increased functional relationship between ant. cingulate, prefrontal, orbitofrontal, and insular cortex, nucleus accumlens, amygdala, periaqueduktalne gray matter and spinal cord. Placebo also facilitates descending inhibition of nociceptive reflexes through periacvaeductal gray substance. Placebo effect can be achieved in several ways: by using pharmacological preparations or simulation of operating or other procedures. This phenomenon is associated with perception and expectation of the patient. To achieve the effect of placebo it is essential degree of the suggestions of the person who prescribe a placebo, and the degree of belief of the person receiving the placebo. Expected effect of placebo is to achieve the same effect as the right remedy. Achieved placebo effect depends on the way of presentation. If a substance is presented as harmful, it may cause harmful effects, called 'nocebo" effect. Placebo effect is not equal in all patients, same as the real effect of the drug is not always equal in all patients. Application of placebo in terms of analgesia will cause a positive response in 35% of patients. Almost the same percentage (36%) of patients will respond to treatment with morphine in medium doses (6-8 mg). Therefore, one should remember that response to placebo does not mean that a person simulates the pain and then it is unethical to withhold the correct treatment especially in light of findings that the prefrontal cortex is activated expecting liberation of pain and how this action reduce activities in brain regions responsible for sensation of pain (thalamus, somatosensory cortex and other parts of the cortex). However, the use of placebos is ethically, legally and morally very dubious. The basis for the placebo effect is deception. It undermines honest relationship and trust between doctor and patient which is extremely important for successful treatment. Consciously giving placebos to patients for a condition that can be adequately treated, with prejudice the right of patients to the best care possible, opens up many bioethical issues. Despite all the current knowledge level, placebo effect remains still a scientific mystery.     

Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987‐2013

More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant‐placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p<0.001). Contrary to expectations, a similar increase has occurred in the magnitude of antidepressant response (6.0%, r=0.37, p<0.001). Thus, the effect sizes (0.30 vs. 0.29, p=0.42) and the magnitude of antidepressant‐placebo differences (10.5% vs. 10.3%, p=0.37) have remained statistically equivalent. Furthermore, the frequency of positive trial arms has gone up in the past 15 years (from 47.8% to 63.8%), but this difference in frequency has not reached statistical significance. Trial design features that were previously associated with a possible lower magnitude of placebo response were not implemented, and their relationship to the magnitude of placebo response could not be replicated. Of the 34 recent trials, two implemented enhanced interview techniques, but both of them were unsuccessful. The results of this study suggest that the relationship between the magnitude of placebo response and the outcome of antidepressant clinical trials is weak at best. These data further indicate that antidepressant‐placebo differences are about the same for all of the sixteen antidepressants approved by the FDA in the past thirty years.     

Individual features of subconscious adaptive psychological processes and adrenal reactivity in prolonged extreme situations

Ten athletes of the national Olympic team and 48 servicemen who had been in a combat zone for a long time were examined. Individual indices of the β-adrenal reactivity of the body (the methodical index of β-adrenal reactivity (β-ARM)) and neurosemantic diagnosis (NsD) were compared. The β-ARM index reflected desensitization of adrenoreceptors at an excessive content of catecholamines in the blood. The NsD indices reflected the tension of subconscious adaptive processes: psychological protection, i.e., displacement of psychotraumatic information and subconscious psychological tension (accentuation). The NsD indices at different functional levels of the brain were recorded by an automated software system analyzing the evoked potentials on presentation of verbal stimuli with durations below the recognition threshold. Reciprocal relations between the individual indices of protection and accentuation in the group of servicemen with three- to fourfold activation of the sympathoadrenal system assessed by β-ARM were determined at the level of perceptive protection (a psychological barrier to recognition of a negatively perceived stimulus). A positive correlation between the individual β-ARM and protection indices was found in the above group, and a negative correlation was found in the group with 1.5- to 2-fold sympathoadrenal system activation. The values of individual indices, their interactions, and their roles in the formation of adaptive psychological processes are discussed.     

Subconscious components of psychophysiological responses in the participants of a 105-day experiment in an isolated environment

Six participants of a 105-day experiment in an isolated environment were studied in order to identify subconscious mechanisms of their psychophysiological changes during the experiment. We used the method of neurocognitive diagnostics based on the analysis of the evoked electrocardiographic (EEG) potentials caused by stimuli that were below the conscious threshold. The technique included separation of evoked responses to each stimulus, cross-correlation and wavelet analyses, estimations using neural network algorithms, and an overall evaluation for all stimuli for each derivation and each period of stimulation. Comparison of the reactions to meaningful and meaningless groups of words elicited the extent of involvement of different brain areas in semantic information processing. Our results give grounds to indicate a number of changes in the psychological state of the subjects due to their participation in the experiment. These are list below:

1. An increase in subconscious tension between some of the crew members, such as representatives of different cultures.
2. An increase in psychological defense stress, primarily caused by basic fears of death and worries about health, as well as private family relations.
3. The appearance of addictive trends manifested in the changes in the subconscious attitude to alcohol and an increase in the role that alcohol plays in the emotional state.

These findings on the changes in the major mechanisms of unconscious responses are useful in defining the strategy for working out the methods of autonomous psychological support for crews and computer-assisted psychological correction.     

Ketanserin in the treatment of traumatic vasospastic disease.

The specific serotonin receptor blocker ketanserin was given orally to 12 patients with traumatic vasospastic disease in a double blind crossover study. The effect of treatment was assessed by measuring finger systolic pressure and rewarming time after cold provocation and by medical interview and diaries. Median (range) percentage change in finger systolic pressure after cooling was 50 (0-100)% after treatment with ketanserin compared with 0 (0-90)% after placebo. Median (range) rewarming time after cooling decreased from 320 (236-972)s with placebo to 160 (88-404)s after treatment with ketanserin. These changes were not significant. Ninety five percent confidence intervals for difference between the treatments, however, showed that finger systolic pressure may be 80% better and rewarming time 256 seconds faster after treatment with ketanserin than after placebo. The number of attacks did not differ significantly between the two treatments. Two patients had a feeling of warmth in their hands during treatment with ketanserin. The results suggest that orally administered ketanserin may improve digital circulation in patients with traumatic vasospastic disease, but larger numbers of patients are required to assess the true effect of treatment with ketanserin in this disease.     

Darwin was a teleologist

It is often claimed that one of Darwin's chief accomplishments was to provide biology with a non-teleological explanation of adaptation. A number of Darwin's closest associates, however, and Darwin himself, did not see it that way. In order to assess whether Darwin's version of evolutionary theory does or does not employ teleological explanation, two of his botanical studies are examined. The result of this examination is that Darwin sees selection explanations of adaptations as teleological explanations. The confusion in the nineteenth century about Darwin's attitude to teleology is argued to be a result of Darwin's teleological explanations not conforming to either of the dominant philosophical justifications of teleology at that time. Darwin's explanatory practices conform well, however, to recent defenses of the teleological character of selection explanations.I would like to thank John Beatty, David Hull and one of this journal's readers for constructive comments on an earlier draft of this paper.     

Understanding the placebo effect from an evolutionary perspective

A placebo is a treatment which is not effective through its direct action on the body, but works because of its effect on the patient's beliefs. From an evolutionary perspective, it is initially puzzling why, if people are capable of recovering, they need a placebo to do so. Based on an argument put forward by Humphrey [Great expectations: the evolutionary psychology of faith-healing and the placebo effect. In: Humphrey, N (2002). The mind made flesh. Oxford University Press, Oxford. 255–285], we present simple mathematical models of the placebo effect that involve a trade-off between the costs and benefits of allocating resources to a current problem. These models show why the effect occurs and how its magnitude and timing can depend on different factors. We identify a particular aspect of belief which may govern the effect and conclude that a deeper understanding of why the placebo effect exists may allow it to be invoked more easily in the future.     

Positive effect of lower body compression garments on subsequent 40-kM cycling time trial performance

This study aimed to investigate the effect of wearing graduated compression garments during recovery on subsequent 40-km time trial performance. In a randomized single-blind crossover experiment, 14 trained multisport male athletes (mean ± SD: age 33.8 ± 6.8 years, 40-km time 66:11 ± 2:10 minutes:seconds) were given a graduated full-leg-length compressive garment (76% Meryl Elastane, 24% Lycra) or a similar-looking noncompressive placebo garment (92% Polyester, 8% Spandex) to wear continuously for 24 hours after performing an initial 40-km time trial in their normal cycling attire. After the 24-hour recovery period, the compression (or placebo) garments were removed, and a second 40-km time trial was then completed to gauge the effect of each garment on subsequent performance. One week later, the groups were reversed and testing procedures repeated. The participant's hydration status, nutritional intake, and training were similar before each set of trials. Performance time in the second time trial was substantially improved with compression compared with placebo garments (1.2 ± 0.4%, mean ± 90% confidence interval). This improvement resulted in a substantially higher average power output after wearing the compression garment compared with that after wearing the placebo garment (3.3 ± 1.1%). Differences in oxygen cost and rating of perceived exertion between groups were trivial or unclear. The wearing of graduated compressive garments during recovery is likely to be worthwhile and unlikely to be harmful for well-trained endurance athletes.     

Bayesian discrimination with longitudinal data

The motivation for the methodological development is a double-blind clinical trial designed to estimate the effect of regular injection of growth hormone, with the purpose of identifying growth hormone abusers in sport. The data formed part of a multicentre investigation jointly sponsored by the European Union and the International Olympic Committee. The data are such that for each individual there is a matrix of marker variables by time point (nominally 8 markers at each of 7 time points). Data arise out of a double-blind trial in which individuals are given growth hormone at one of two dose levels or placebo daily for 28 days. Monitoring by means of blood samples is at 0, 21, 28, 30, 33, 42 and 84 days. We give a new method of Bayesian discrimination for multivariate longitudinal data. This involves a Kronecker product covariance structure for the time by measurements (markers) data on each individual. This structure is estimated by an empirical Bayes approach, using an ECM algorithm, within a Bayesian Gaussian discrimination model. In future one may have markers for an individual at one or more time points. The method gives probabilities that an individual is on placebo or on one of the two dose regimes.     

Placebo in emotional processing--induced expectations of anxiety relief activate a generalized modulatory network

Placebo analgesia and reward processing share several features. For instance, expectations have a strong influence on the subsequent emotional experience of both. Recent imaging data indicate similarities in the underlying neuronal network. We hypothesized that placebo analgesia is a special case of reward processing and that placebo treatment could modulate emotional perception in the same way as does pain perception. The behavioral part of this study indicates that placebo treatment has an effect on how subjects perceive unpleasant pictures. Furthermore, event-related fMRI demonstrated that the same modulatory network, including the rostral anterior cingulate cortex and the lateral orbitofrontal cortex, is involved in both emotional placebo and placebo analgesia. These effects were correlated with the reported placebo effect and were predicted by the amount of treatment expectation induced on a previous day. Thus, the placebo effect may be considered to be a general process of modulation induced by the subjects' expectations.