Biomarkers in the diagnosis and study of psychogenic nonepileptic seizures: A systematic review.

OBJECTIVE: Video electroencephalography (vEEG) is the gold-standard method for diagnosing psychogenic nonepileptic seizures (PNES), but such assessment is expensive, unavailable in many centers, requires prolonged hospitalization, and many times is unable to capture an actual seizure episode. This paper systematically reviews other non-vEEG candidate biomarkers that may facilitate both diagnosis and study of PNES as differentiated from epileptic seizures (ES). METHODS: PubMed database was searched to identify articles between 1980 and 2015 (inclusion: adult PNES population with or without controls, English language; exclusion: review articles, meta-analyses, single case reports). RESULTS: A total of 49 studies were examined, including neuroimaging, autonomic nervous system, prolactin, other (non-prolactin) hormonal, enzyme, and miscellaneous marker studies. Functional MRI studies have shown PNES is hyperlinked with dissociation and emotional dysregulation centers in the brain, although conflicting findings are seen across studies and none used psychiatric comparators. Heart rate variability suggests increased vagal tone in PNES when compared to ES. Prolactin is elevated in ES but not PNES, although shows low diagnostic sensitivity. Postictal cortisol and creatine kinase are nonspecific. Other miscellaneous biomarkers (neuron specific enolase, brain derived neurotropic factor, ghrelin, leptin, leukocytosis) showed no conclusive evidence of utility. Many studies are limited by lack of psychiatric comparators, size, and other methodological issues. CONCLUSION: No single biomarker successfully differentiates PNES from ES; in fact, PNES is only diagnosed via the negation of ES. Clinical assessment and rigorous investigation of psychosocial variables specific to PNES remain critical, and subtyping of PNES is warranted. Future investigational and clinical imperatives are discussed.

Role of cortisol in mood and memory in patients with intractable temporal lobe epilepsy.

OBJECTIVE: This study prospectively examined the relationships among late night salivary cortisol (NSC) levels and depressive symptoms, memory performance, and hippocampal volumes in patients with medically intractable temporal lobe epilepsy (TLE) and the potential mediating effects of cortisol in the relationships between these variables. METHODS: Participants included 24 adults with well-characterized medically refractory TLE (right = 11; left = 12; bitemporal = 1). All patients provided saliva samples and completed measures of mood, anxiety, and memory (objective and subjective). MRI-based volumetric analyses of the hippocampi were also conducted. RESULTS: As hypothesized, cortisol was found to be negatively related to several memory measures such that patients with higher cortisol levels demonstrated lower memory performance. However, unexpectedly, cortisol was not related to current symptoms of depression or anxiety, subjective memory ratings, or hippocampal volumes. Consistent with previous findings in the literature, a number of other relationships among the study variables were observed (objective memory and hippocampal volume; subjective memory and mood/anxiety). Results of mediator analyses suggested that cortisol does not mediate the relationship between depression and memory dysfunction or the relationship between depression and hippocampal atrophy. CONCLUSIONS: While cortisol may play a role in memory performance in patients with TLE, it does not fully explain the relationship between depression and mesial temporal dysfunction, likely reflecting the complex and multifactorial relationships among these variables. Results confirm the relationship between memory performance and structural brain integrity and provide further support for a role of depression in subjective memory complaints.

The relationship between depression and cardiovascular disorders.

Expanding scientific evidence supports a long-recognized link between cardiovascular disease and depression. As an independent risk factor, depression increases patient vulnerability to both cardiac events and mortality. Several important pathophysiologic mechanisms have been proposed, including hypothalamic-pituitary axis hyperactivity, autonomic nervous system dysfunction, and increased platelet reactivity, among others. The recently completed Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) inaugurates a series of studies intended to address the impact of antidepressant therapy on cardiovascular risk.

Use of stimulants in the medically ill.

This article discusses the use of psychostimulants, such as dextroamphetamine, methylphenidate, and pemoline, in a variety of illnesses, including depression in the medically ill, cancer, HIV, and AIDS. The chemistry and pharmacology, side effects, drug interactions, dosing, and abuse potential also are reviewed.

Long-term outcome after acute treatment with alprazolam or clonazepam for panic disorder.

The relative effectiveness of the available treatments for panic disorder may best be understood in the context of the longitudinal course of the disorder. This study examines a number of clinically relevant issues, including long-term outcome after acute treatment, the proportion of patients remaining on single-agent treatment or requiring multiple medications or nonpharmacologic interventions over time, evidence for dose escalation during maintenance high-potency benzodiazepine therapy, and predictors of acute and long-term response to treatment. Fifty-nine panic disorder patients originally randomized to treatment in a controlled trial comparing alprazolam, clonazepam, and placebo were reevaluated in a follow-up study. At a mean follow-up of 1.5 years, 78% of patients remained on medication and the mean dosage of alprazolam and clonazepam did not increase. Our data suggest that most patients maintain benefit with long-term pharmacotherapy but that residual symptomatology may require more intensive or additional treatment strategies. Response at the endpoint of the acute trial was significantly associated with pretrial baseline Clinical Global Impression Scale score and the presence of dysthymia. Poor outcome at follow-up was associated with total duration of the disorder, agoraphobic subtype, and the presence of comorbid social phobia. We underscore the potential importance of comorbid affective and anxiety disorders as well as phobic patterns in determining long-term response to treatment.

Double-blind, placebo-controlled comparison of clonazepam and alprazolam for panic disorder.

To test the reported antipanic efficacy of clonazepam, the authors randomized 72 subjects with panic disorder to 6 weeks of treatment with either alprazolam, clonazepam, or placebo. Endpoint analysis demonstrated a significant beneficial effect of both active treatments, but not placebo treatment, on the frequency of panic attacks, overall phobia ratings, and the extent of disability. Comparison of the two active treatments revealed no significant differences and no consistent tendency for one agent to be favored over another, although power to detect small differences was limited. Sedation and ataxia were the most common side effects reported, but these effects were mild and transient and did not interfere with treatment outcome. The results of this double-blind, placebo-controlled trial are consistent with previous reports of clonazepam's antipanic efficacy.

High-potency benzodiazepines for short-term management of panic disorder: the U.S. experience.

Interest in benzodiazepines for treatment of panic attacks followed a report of the success of alprazolam, used for generalized anxiety, in blocking such attacks. Twelve controlled trials and several open studies have substantiated the antipanic and antiphobic activity of alprazolam and concluded it is comparable to but more rapid than antidepressants in its effects and better tolerated. In a controlled trial of clonazepam, alprazolam, and placebo, the two active agents had similar positive effects. Diazepam and lorazepam have been effective in other studies. Clonazepam, with its relatively long half-life, permits less frequent dosing than possible with benzodiazepines with shorter half-lives and more continuous control of anxiety, although around 20% of patients experience unacceptable sedative effects or no reduction in anxiety. In general, benzodiazepines are safe and well tolerated. The most common adverse effects are intoxication, dependence, rebound, withdrawal, hostility, and affective disturbances. Discontinuation of alprazolam is particularly difficult and is sometimes associated with serious rebound and withdrawal symptoms. The morbidity and mortality associated with panic disorder suggest that the benefits of benzodiazepine treatment outweigh its risks.

Dehydroepiandrosterone-sulfate/cortisol ratio in panic disorder.

We hypothesized that the dehydroepiandrosterone-sulfate (DHEA-S)/cortisol ratio, which has been used as an index of adrenocortical function, would be altered in panic disorder patients and would change after treatment. We evaluated 10 male and 14 female outpatients meeting DSM-III-R criteria for panic disorder. Of these 24 subjects, 13 were treated with clonazepam, 8 were treated with alprazolam, and 3 were treated with placebo as part of a double-blind study. The DHEA-S/cortisol ratio values in the 24 patients with panic disorder (mean = 20.5, SD = 11.6) were significantly higher than those of a group of 60 normal controls (mean = 11.5, SD = 6.01) and were also significantly higher than those of a group of 22 depressed patients (mean = 10.6, SD = 6.33). Although there was no significant difference in the pretreatment DHEA-S/cortisol ratio values between male (mean = 23.6, SD = 11.8) and female (mean = 18.2, SD = 11.3) panic disorder patients, the effects of treatment on this ratio differed between the two sexes. In fact, in the female patients there was a significant decrease in the DHEA-S/cortisol ratio at the end of the study (mean = 15.1, SD = 7.9), while in the male patients there was no significant change in this ratio at the end of the study (mean = 30.2, SD = 21.4). No significant differences were noted between pretreatment and posttreatment DHEA-S/cortisol ratio values in patients treated with alprazolam (n = 8), in patients treated with clonazepam (n = 13), or in patients treated with placebo (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Clonazepam versus alprazolam in the treatment of panic disorder: interim analysis of data from a prospective, double-blind, placebo-controlled trial.

The authors present interim results of a prospective, random assignment, double-blind, placebo-controlled trial conducted to determine whether clonazepam is as effective as alprazolam in reducing the frequency of panic attacks and whether both agents are superior to placebo. Analysis on 44 of 60 randomized subjects showed no statistically significant differences between the clonazepam and alprazolam groups on the following clinically meaningful outcome measures: total number of panic attacks and percent of time subjects experienced anticipatory anxiety, extent of phobic avoidance, and fear. Statistically significant differences did exist among the drug and placebo groups on these measures. The authors conclude that this interim analysis of the data supports the inclusion of clonazepam in the treatment of panic disorder.