Putnam,Merritt, and the Discovery of Dilantin®

In the first part of this essay, the “common wisdom” about Putnam and Merritt's contributions to the treatment of epilepsy was summarized (Rowland, 1982). Based on the history that has been presented here, how true are these “wisdoms”? Putnam and Merritt did devise “a simple and reliable method to test drugs of anticonvulsant effect” and they did show “that anticonvulsant effects in cats accurately predicted effects in humans,” but others before them had done these same things. Dilantin, contrary to common wisdom, was not the first anticonvulsant drug to be tested in animals before it was given to human subjects; at least a year before, Cobb and his co-workers had done the same thing using vital dyes. However, Dilantin did represent the first time an anticonvulsant tested in animals was subsequently studied in a large series of patients. Nor were Putnam and Merritt the first to show that “anticonvulsant and sedative effects of drugs could be separated.” Potassium borotartrate, ketogenic diet, ketone bodies, and vital dyes were anticonvulsive without necessarily being sedative. However, Putnam and Merritt were probably the first to make so explicit a statement to this effect. It may well have been this particular statement—and the fact that it was so well heard by other researchers—that represented their greatest achievement. In Kuhn's theory of scientific revolutions, the great step forward may not be so much the accumulation of evidence that the existing paradigm is not a feasible one, but rather the use of this evidence to form a new model or paradigm which is then accepted by normal science in such a fashion that the results prove to be productive. This, it would seem, is what Putnam and Merritt did. From it came their own major discovery, Dilantin, which, in Rowland's words, remains “a mainstay of treatment” for epilepsy up to the present time, and which “opened the way to the development of other anticonvulsant drugs.”     

AN EVALUATION OF THE DOUBLE-BLIND DESIGN IN A STUDY COMPARING LITHIUM CARBONATE WITH PLACEBO

As part of a study of drug treatment of aggressive behavior to be reported separately, we have evaluated the double-blind procedure in a recently completed comparison of the efficacy of lithium carbonate versus placebo in modifying aggressive behavior in nonpsychotic incarcerated delinquents. We conclude that the side effects of lithium carbonate are sufficient to reveal the medication to most subjects receiving it. Thus, while the study staff could not identify lithium-receivers at better than chance levels, and while subjects who received placebo could not identify their medication at better than chance levels, subjects who received lithium could accurately identify it. On a weekly symptom check list there was no difference between lithium and placebo groups on average lithium target symptoms reported during 4-week pre- and postmedication control periods; however, lithium-receivers reported significantly more target symptoms every week medication was administered. Of 16 subjects who quit the study, 14 had received lithium and nearly all of those who gave reasons for quitting specified side effects, most often nausea. The methodological problems of using lithium in a double-blind design might be overcome by employing a “discontinuation” design, or, speculatively, a double-blind, cross-over design utilizing an “active placebo”.     

Is Anticonvulsant Treatment of Mania a Class Effect? Data from Randomized Clinical Trials

Our aim was to evaluate the efficacy and tolerability of anticonvulsant agents for the treatment of acute bipolar mania and ascertain if their effects on mania are a “class” effect. We conducted a systematic review of randomized controlled trials (RCTs) with placebo or active comparator, in acute bipolar mania in order to summarize available data on anticonvulsant treatment of mania/mixed episodes. We searched (PubMed/MEDLINE) with the combination of the words “acute mania” and “clinical trials” with each one of the following words: “anticonvulsants/antiepileptics,”“valproic/valproate/divalproex,”“carbamazepine,”“oxcarbazepine,”“lamotrigine,”“gabapentin,”“topiramate,”“phenytoin,”“zonisamide,”“retigabine,”“pregabalin,”“tiagabine,”“levetiracetam,”“licarbazepine,”“felbamate,” and “vigabatrin.” Original articles were found until November 1, 2008. Data from 35 randomized clinical trials suggested that not all anticonvulsants are efficacious for the treatment of acute mania. Valproate showed greater efficacy in reducing manic symptoms, with response rates around 50% compared to a placebo effect of 20–30%. It appears to have a more robust antimanic effect than lithium in rapid cycling and mixed episodes. As valproate, the antimanic effects of carbamazepine have been demonstrated. Evidences did not support the efficacy of the gabapentin, topiramate as well as lamotrigine as monotherapy in acute mania and mixed episodes. Oxcarbazepine data are inconclusive and data regarding other anticonvulsants are not available. Anticonvulsants are not a class when treating mania. While valproate and carbamazepine are significantly more effective than placebo, gabapentin, topiramate, and lamotrigine are not. However, some anticonvulsants may be efficacious in treating some psychiatric comorbidities that are commonly associated to bipolar illness.     

Effects and after-effects of the common cold and influenza on human performance

Volunteers who develop a cold following virus challenge were significantly slower on choice reaction time tasks than those with no illness. This effect was still observed after the clinical symptoms had gone. In contrast to this, influenza illnesses only impaired performance in tasks in which subjects were uncertain where the target stimulus would appear. These results demonstrate that the CNS effects of respiratory virus infections depend on the type of virus, and that performance impairments may remain even after the symptoms of a cold have gone.     

Evidence based migraine prophylactic drug therapy

Prophylactic drug therapy is a major component of overall migraine management. However, because we do not know how currently used prophylactic drugs exert their beneficial effects in migraine, their use is based primarily on clinical trials. In general, prophylactic drugs are indicated when patients have three or more attacks a month and symptomatic medication use alone is not satisfactory. The choice of drug must be individualized, and is influenced by contraindications, potential side effects, the need to treat associated symptoms like tension-type headache and insomnia, and drug cost. Whether an individual patient will respond to a given drug cannot be predicted, but there are varying degrees of scientific evidence supporting the use of each prophylactic drug in migraine. This evidence is best for metoprolol, divalproex, amitriptyline, atenolol, flunarizine and naproxen. Based on placebo-controlled crossover studies, it would appear that at least some prophylactic drugs exert the greater part of their prophylactic effects very quickly, and that these also disappear very quickly once the drug is stopped. This may not apply to all prophylactic drugs and more research is needed. More well designed clinical trials are needed to guide our use of migraine prophylactic drugs. Although clinical experience is useful, placebo responses and variations in the migraine tendency over time can make interpretation of this experience difficult. Major advances will likely only occur once the pathogenesis of migraine and the mode of action of the prophylactic drugs is better understood.     

Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression: A randomized,placebo-controlled study

A randomized, placebo-controlled study was performed to evaluate whether the onset of the glucose metabolic effects of a selective serotonin reuptake inhibitor (paroxetine) would be accelerated by total sleep deprivation (TSD). Patients were randomly assigned to one of three groups: TSD and paroxetine treatment, TSD and 2 weeks of placebo followed by paroxetine treatment, or 2 weeks of paroxetine treatment. Sixteen elderly depressed patients who met DSM-IV criteria for major depressive disorder and nine age-matched comparison subjects underwent positron emission tomography (PET) studies of cerebral glucose metabolism at baseline, post-TSD (or a normal night's sleep for the paroxetine- only group), post-recovery sleep and 2 weeks post-paroxetine or placebo treatment (patients only). TSD was not consistently associated with a decrease in depressive symptoms between groups nor with decreases in cerebral metabolism in cortical regions that have been associated with rapid and sustained clinical improvement (e.g. anterior cingulate gyrus). The observation of a synergistic antidepressant effect of combined TSD and paroxetine treatment that was observed in a previous “open label” pilot study was not observed in the present randomized study, consistent with lack of a cerebral metabolic effect in brains regions previously shown to be associated with improvement of depressive symptoms.     

Confusing placebo effect with natural history in epilepsy: A big data approach

For unknown reasons, placebos reduce seizures in clinical trials in many patients. It is also unclear why some drugs showing statistical superiority to placebo in one trial may fail to do so in another. Using Seizuretracker.com , a patient‐centered database of 684,825 seizures, we simulated “placebo” and “drug” trials. These simulations were employed to clarify the sources of placebo effects in epilepsy, and to identify methods of diminishing placebo effects. Simulation 1 included 9 trials with a 6‐week baseline and 6‐week test period, starting at time 0, 3, 6…24 months. Here, “placebo” reduced seizures regardless of study start time. Regression‐to‐the‐mean persisted only for 3 to 6 months. Simulation 2 comprised a 6‐week baseline and then 2 years of follow‐up. Seizure frequencies continued to improve throughout follow‐up. Although the group improved, individuals switched from improvement to worsening and back. Simulation 3 involved a placebo‐controlled “drug” trial, to explore methods of placebo response reduction. An efficacious “drug” failed to demonstrate a significant effect compared with “placebo” (p = 0.12), although modifications either in study start time (p = 0.025) or baseline population reduction (p = 0.0028) allowed the drug to achieve a statistically significant effect compared with placebo. In epilepsy clinical trials, some seizure reduction traditionally attributed to placebo effect may reflect the natural course of the disease itself. Understanding these dynamics will allow future investigations into optimal clinical trial design and may lead to identification of more effective therapies. Ann Neurol 2015;78:329–336     

Life event ratings in relation to sex and marital status in a 70-year-old urban population

A subsample of 151 subjects from the population study “70-year-olds in Gothenburg” were given a questionnaire for life event ratings to be returned by mail. The 24 life events to be rated were events that are fairly common in advanced age. The ratings were in most cases similar for men and women. Some events, pertaining to children, were given more weight by the women, while “loss of sexual ability or interest” was given greater weight by the men. Single women gave less weight to events that could not happen to them. It thus seems that events that cannot happen to yourself are seen as less important than events that can. Married women who had never worked outside their homes attributed more weight to some events than married women who had worked outside their homes. Men and women attributed similar weight to the event “becoming mentally ill”, which event was given more weight than the event “becoming somatically ill”. The results do not explain the higher incidence of neurosis among the women in the population.     

Neuronal effects of nicotine during auditory selective attention in schizophrenia

Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention‐associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task‐associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task‐associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention‐dependent manner in schizophrenia. Hum Brain Mapp 37:410–421, 2016. © 2015 Wiley Periodicals, Inc.     

The relevance of object categorization to cross-modal performance by chimpanzees

Two hundred objects from the Yerkes collection were categorized by human subjects independently by size (“large”, “mediumly large”, “mediumly small” and “small”) and by texture (“rough”, “mediumly rough”, “mediumly smooth” and “smooth”). The human subjects showed impressive consistency. Three highly experienced chimpanzees were then each given 200 trials of cross-modal matching (tactile sample, visual objects) with 68 of the objects which had been assigned to each of the eight categories by agreement between four of four human subjects. It was expected that the apes would make fewer errors when the visual objects were drawn from classes on different sides of a dimensional boundary than when drawn from classes to the same side of the boundaries. This expectation was not fulfilled and the possible reasons are discussed.     

Placebo response and antidepressant response.

OBJECTIVE: Much of the response to an antidepressant is the result of placebo response. The placebo response embedded in drug response confounds studies seeking to identify brain mechanisms essential for pharmacologic response. Exclusion of patients who fail to meet entry criteria at the end of a placebo lead-in phase has been inadequate to reduce the effect of placebo during pharmacologic trials. This study focused on the placebo lead-in phase and examines whether change in severity of depression during placebo lead-in predicts change in depressive symptoms during antidepressant treatment. METHOD: The subjects were patients aged 60-85 years with nonpsychotic unipolar major depression not attributed to dementing disorders, medical illnesses, or drugs causing depression and had a 24-item Hamilton Depression Rating Scale score of 18 or greater. After a two-week placebo lead-in, subjects with Hamilton Depression Rating Scale score of 18 or greater received 10 mg escitalopram for 12 weeks. RESULTS: Worsening or limited change in depression during placebo treatment predicted improvement in depressive symptoms during escitalopram treatment. Limited change in anxiety, melancholia, helplessness, and paranoia during placebo treatment were the strongest predictors of improvement in depression while on escitalopram. CONCLUSIONS: These findings, if replicated, may be used to characterize depressed older patients likely to respond to the pharmacologic action of antidepressants rather than the placebo response embedded in drug trials and thus improve the methodology of biomarker studies of antidepressant response. On a clinical level, depressed older patients who improve during a prolonged evaluation may be candidates for nonpharmacologic treatments because their drug response may be limited.     

Lack of preference for diazepam in anxious volunteers

Using a choice procedure, these experiments tested whether diazepam is more highly preferred by anxious subjects than by normal control subjects. Subjects first sampled and then chose between two capsules containing diazepam (5 or 10 mg) and placebo, or amphetamine (5 mg) and placebo. The number of times each drug was chosen over placebo and the subjective effects of the drugs were measured. Anxious subjects did not differ from controls in their drug choices. Most subjects chose diazepam less often than placebo, especially at the higher dose, whereas they chose amphetamine more often than placebo. The subjective drug effects (including anxiety reduction after diazepam) were similar for anxious and nonanxious subjects, despite predrug differences in anxiety. The results suggest that individuals with high anxiety are not at greater risk for dependence on antianxiety drugs.     

Low CSF GABA in Parkinsonian patients who respond poorly to therapy or suffer from the "on-off" phenomenon

The γ-aminobutyric acid concentration in cerebrospinal fluid was measured by radioreceptor assay in 23 parkinsonian patients (“good responders” and “poor responders” to drug therapy, “on-off” state) and 11 age-matched control subjects. Mean concentrations were similar but significantly lower in the poor responders and the “on-off” state than in the good responders and control subjects. Patients who show good response to drug therapy appear to have a normal level of GABAergic activity that is not altered by drug therapy.     

Noncredible Psychiatric and Cognitive Symptoms in a Workers' Compensation “Stress” Claim Sample

Information is lacking regarding the prevalence of fraudulent psychiatric and cognitive symptoms in the “stress” claim workers' compensation population. Using various validity indices (Negative Impression Scale, the Malingering Index, and the Rogers Discriminant Function) of the Personality Assessment Inventory (PAI), between 9 and 29% of 233 workers' compensation “stress” claim litigants were identified as exhibiting noncredible psychiatric symptoms. In addition, 15% of the subjects were determined to have noncredible cognitive symptoms on the Dot Counting Test, although only 8% displayed suspect effort on the 15-Item Memorization Test, with 5% of subjects failing both cognitive effort tests. The percentage of positive identifications on both a PAI and cognitive credibility index ranged from only 2 to 4%. Further, correlations between PAI validity indices and cognitive effort scales were nonexistent to modest, indicating that the psychiatric and cognitive credibility indices are measuring different aspects of noncredible symptom production. It was predicted that the PAI profiles of the participants displaying suspect cognitive symptoms would be elevated on the Somatic Concerns, Antisocial, and/or Borderline scales; however, elevations (relative to subjects with credible cognitive performance) were instead noted on the Somatic Concerns, Depression, Anxiety, Anxiety-Related Disorders, and Schizophrenia scales.     

帕金森病丘脑底核脑深部电刺激术后的长期随访研究

目的 研究丘脑底核脑深部电刺激(STN-DBS)术治疗帕金森病(PD)的长期临床效果.方法 对采用STN-DBS术治疗的75例PD患者进行术后长期随访.对患者手术前抗PD药物“关”与“开”状态进行统一帕金森病评定量表(UPDRS)评估;术后第1、3、5和10年,在STN-DBS持续治疗下对患者药物“关”与“开”状态进行...     

Anticholinesterase effect on motor kinematic measures and brain activation in Parkinson's disease.

Anticholinesterase (AChE) drugs are being prescribed off label for nonmotor symptoms in Parkinson's disease (PD). Theoretically, these drugs can impair motor function. A small literature suggests AChE therapy has little effect on clinical motor evaluation; however, no study has made objective motor kinematic measures or evaluated brain function. We hypothesized that even if clinical examination was normal in PD patients on dopamine therapy, (1) sensitive kinematic measures would be abnormal during AChE therapy or (2) normal kinematic measures would be maintained by compensatory brain activation. We carried out a randomized, double-blind, placebo-controlled trial of 8 weeks donepezil (10 mg/day) in 17 PD subjects. Subjects carried out a computerized motor task during a positron emission tomography (PET) scan before starting the drug and again after 8 weeks of donepezil or placebo. Kinematic measures of motor function and PET scans were analyzed to compare the effects of donepezil and placebo. Neither placebo nor donepezil altered motor kinematic measures. Furthermore, movement integrity while on donepezil was maintained without compensatory brain activity. Donepezil 10 mg/day can be given for nonmotor symptoms in PD without adverse motor effects or compensatory brain activity.     

Treatment of medication overuse headache—A review

Medication overuse headache (MOH) is the most prevalent chronic headache disorder with a prevalence between 1% and 2% worldwide. The disease has been acknowledged for almost 30 years, yet experts still disagree on how best to treat MOH. By performing a search in PubMed on the terms “medication overuse headache,” “analgesics abuse headache,” “rebound headache,” “drug induced headache,” and “headache AND drug misuse” limited to human studies published in English between January 1, 2004, and November 1, 2017, we aimed to evaluate current literature concerning predictors of treatment outcome, inpatient and outpatient treatment programs, initial versus latent administration of prophylactic medications, and to review the effect of prophylactic medications. Selection criteria were prospective, comparative, or controlled trials on treatment of MOH in persons of at least 18 years of age. Several studies evaluated risk factors to predict the outcome of MOH treatment, but many studies were underpowered. Psychiatric comorbidity, high dependence score, and overuse of barbiturates, benzodiazepines, and opioids predicted a poorer outcome of withdrawal therapy. Patients with these risk factors benefit from inpatient treatment, whereas patients without risk factors benefit equally from inpatient and outpatient treatment. Some medications for migraine prophylactics have shown better effect on MOH compared with placebo, but not when combined with withdrawal. We conclude that detoxification programs are of great importance in MOH treatment. Latent administration of prophylactic medications reduces the number of patients needing prophylactic medication. Individualizing treatment according to the predictors of outcome may improve treatment outcome and thus reduce work‐related and treatment‐related costs.     

Disturbed sleep predicts hypnotic self-administration

OBJECTIVES: To evaluative whether polysomnographically determined sleep variables in a large group of subjects reflecting a wide range of sleep disturbance would be predictive of the self-administration of capsules before sleep. METHODS: Sixty-four healthy men and women with and without insomnia (aged 21-55 years) were given an opportunity to self-administer placebo or triazolam (0.25 mg) capsules (single-choice method - available capsule or no capsule) before sleep in three separate studies. All qualified using the identical criteria based on a standard nocturnal polysomnogram. Screening sleep measures then were used to predict subsequent placebo and triazolam self-administration. RESULTS: The percent of placebo and triazolam choices did not differ between or within the three studies. Persons with persistent psychophysiologic insomnia self-administered more capsules than persons with sleep state misperception or normals, with the subject groups not differing in placebo vs. active drug preference. Screening polysomnographic measures predicted percent of capsule choices. The single best predictor was the ratio of minutes of stage 3-4 sleep to minutes of wake plus stage 1 sleep with R=0.44. The addition of % stage 3-4 sleep, wake before sleep and total sleep time increased R to 0.49. On morning mood ratings less ability to concentrate and greater fatigue (Profile of Mood States) predicted percent of capsule choices with R=0.36. CONCLUSIONS: These results show that the extent of sleep disturbance predicts the likelihood of self-administering a capsule before sleep regardless of whether it is placebo or active drug.     

Improvement of anger at one week predicts the effects of sertraline and placebo in PTSD

In previous work we demonstrated an early, robust and sustained effect for sertraline vs placebo on irritability and anger in subjects with PTSD. In this report, we explore the same dataset to assess whether a clinician might usefully predict ultimate response to sertraline, on the basis of its effect upon anger after one week. Three hundred and eighteen subjects were assessed. Outcome was measured by whether or not the score was reduced by at least 50% from baseline. Ordinary least squares regression was used to estimate the effects of change in anger at one week. Logistic regression was applied to estimate the effects on odds of a 50% drop in score. Cut points were developed for one-week change scores on anger for sertraline and placebo. The best cut point was selected as predictive of non-response, i.e. a cue suggesting that treatment switch would be in order. An increase in anger of 30% at one-week best predicted the likelihood of not responding to treatment in both the drug and placebo groups. Twenty-five percent of all non-responders were incorrectly identified, while only 7% of all improvers were incorrectly categorized as non-responders using this cutoff. Our findings imply that, for patients similar to those in this study, an increase in anger after one week of treatment might be one factor to consider when making a decision about continuation of the medication.