Benzodiazepines: Pharmacology Up-to-Date and Practical Issues / 신경정신의학

Benzodiazepines have been widely used as anxiolytics, sedatives, hypnotics, anticonvulsants, or central muscle relaxants since the 1960s despite significant adverse effects, the potential for misuse, and consequent overdose. Benzodiazepines exert their pharmacological action by binding to gamma-aminobutyric acid type A (GABA-A) receptors in the brain and facilitateing the inhibitory actions of the neurotransmitter GABA. Recent findings have also elucidated the effects of benzodiazepines on the allosteric modulation of GABA-A receptors, including receptor subtypes and transmembrane proteins, which is a significant step in our understanding of GABA pharmacology. In clinical practice, the use of benzodiazepines to treat psychiatric disorders has been limited due to the challenges associated with the long-term use, namely the risks of abuse, misuse, and overdose, as well as withdrawal effects. Furthermore, the approval of selective serotonin reuptake inhibitors for anxiety disorders has led to their extensive use as a first-line pharmacological option and they have also been promoted in various practice guidelines for the treatment of anxiety disorders. However, although recent systematic reviews and meta-analyses have shown that benzodiazepines are useful and effective drugs for the treatment of various neuropsychiatric disorders, including anxiety, debates over the clinical use of benzodiazepines continue. More than 60 years after the introduction of benzodiazepines in clinical practice, it is necessary to revisit the controversies associated with benzodiazepine use and to update the discussion current approach to practice with thethrough an understanding of the new data on their pharmacological actions and to identify appropriate indications according to the new diagnostic systems of psychiatric disorders through an extensive literature review.

Practical Issues With Clonazepam Use / 신경정신의학

Clonazepam, a 7-nitrobenzodiazepine, has been used for the treatment of various neuropsychiatric disorders such as seizures, sleep disorders, panic disorders, anxiety, and movement disorders. However, clonazepam is officially approved as a therapeutic drug only for epilepsy and panic disorders in Korea. This raises ethical issues in clinical practice, as clonazepam is prescribed off-label for most neuropsychiatric disorders in many other countries as well. The misuse and abuse of clonazepam as a recreational drug have also been commonly reported in global literature. In this review, as a therapeutic drug as the authors aim to highlight the pharmacological aspects, clinical effects, and potential addictive risks of clonazepam use, by reviewing the current literature on clonazepam to increase its clinical use by accurately understanding and identifying its psychopharmacological benefits and characteristics. However, establishing the risk/benefit ratio of clonazepam for use in specific clinical situations is difficult because of the lack of adequate updated data. Therefore, the use of clonazepam needs to be approached from the point of view of personalized drug treatment rather than following fixed guidelines which would not reflect the current real-world clinical practices.

A Conceptual Review on ADHD and Adult ADHD (2): Psychopathology, Diagnostic and Therapeutic Implications of ADHD / 신경정신의학

The prevalence of attention-deficit/hyperactivity disorder (ADHD) has been increasing, and the growing number of people with this disorder, especially the non-pediatric population, get prescriptions for this condition. However, controversies are also growing around this disease. To provide optimal treatment to a patient presumed to have adult ADHD, it is crucial to understand the implications of diagnosing and treating adult ADHD. In this article, we proposed a critical review on the concept of ADHD from various points of view and suggested the diagnostic and therapeutic implications of adult ADHD. This article will serve as a small cornerstone for a valid diagnosis and a proper treatment of ADHD, especially in the adult population.

A Conceptual Review on ADHD and Adult ADHD (1): Historical Change of ADHD-Based on the DSM / 신경정신의학

The prevalence of attention-deficit/hyperactivity disorder (ADHD) has been increasing, and the growing number of people with this disorder, especially the non-pediatric population, get prescriptions for this condition. However, controversies are also growing around this disease. In order to provide optimal treatment to a patient presumed to have adult ADHD, it is crucial to understand the implications of diagnosing and treating adult ADHD. We examined the history of ADHD and changes in the diagnostic criteria postulated by the DSM system (Part I), proposed a critical review on the concept of ADHD from various points of view and suggested the diagnostic and therapeutic implications of adult ADHD (Part II). This study may serve as a small cornerstone for a valid diagnosis and a proper treatment of ADHD, especially in the adult population.

Electroconvulsive Therapy for Psychiatric Disorders in Elderly Adults

Electroconvulsive therapy (ECT) is indicated for various mental disorders (e.g., major depressive disorder, schizophrenia, and bipolar disorder) and the behavioral and psychological symptoms of dementia in elderly patients. Furthermore, ECT is a useful first-line treatment in emergency and crisis situations such as suicide risk, violent behavior, catatonia, and food refusal, which are more frequent in elderly patients. ECT is also effective in the treatment of the motor symptoms of neurological disorders, such as Parkinson’s disease and Huntington’s disease. Due to the high risk of various physical diseases, the comorbid physical conditions of elderly patients should be individually controlled to optimize ECT treatment. Compared to young adults, in elderly patients the seizure threshold is higher, the seizure duration is shorter, and the anesthetic dose is lower. On the contrary, the response rate in the elderly is both faster and higher. Considering potential cognitive decline and the prevention of further deterioration of cognitive function in elderly patients, in the absence of significant comorbidities, twice weekly sessions and right unilateral electrode placement with a lower seizure threshold and less cognitive effect are preferred to bilateral electrode placement, which has a high risk of adverse cognitive effects. After an acute course of ECT, continuation and maintenance of ECT, combined with prescription of therapeutic drugs, may prevent possible relapse or recurrence of mental disorders. In conclusion, ECT can be used to treat mental disorders in elderly adults, with safety and effectiveness comparable to that in young adults.

Electroconvulsive Therapy for Psychiatric Disorders in Elderly Adults

Electroconvulsive therapy (ECT) is indicated for various mental disorders (e.g., major depressive disorder, schizophrenia, and bipolar disorder) and the behavioral and psychological symptoms of dementia in elderly patients. Furthermore, ECT is a useful first-line treatment in emergency and crisis situations such as suicide risk, violent behavior, catatonia, and food refusal, which are more frequent in elderly patients. ECT is also effective in the treatment of the motor symptoms of neurological disorders, such as Parkinson’s disease and Huntington’s disease. Due to the high risk of various physical diseases, the comorbid physical conditions of elderly patients should be individually controlled to optimize ECT treatment. Compared to young adults, in elderly patients the seizure threshold is higher, the seizure duration is shorter, and the anesthetic dose is lower. On the contrary, the response rate in the elderly is both faster and higher. Considering potential cognitive decline and the prevention of further deterioration of cognitive function in elderly patients, in the absence of significant comorbidities, twice weekly sessions and right unilateral electrode placement with a lower seizure threshold and less cognitive effect are preferred to bilateral electrode placement, which has a high risk of adverse cognitive effects. After an acute course of ECT, continuation and maintenance of ECT, combined with prescription of therapeutic drugs, may prevent possible relapse or recurrence of mental disorders. In conclusion, ECT can be used to treat mental disorders in elderly adults, with safety and effectiveness comparable to that in young adults.

Prescribing Opioids for Chronic Pain / 신경정신의학

Opioids are effective analgesics, but they are often difficult to use properly, due mainly to adverse events, such as constipation, respiratory depression, addiction, tolerance, and opioid induced hyperalgesia. In the past, the problem of opioids around the world was usually caused by drugs traded illegally, so there was no need for medical and social attention in Korea. On the other hand, with the dramatic increase in the therapeutic use of opioids, which commenced more than a decade ago, problems caused by legally prescribed drugs have emerged, and now a more serious opioid crisis is being experienced than in the days of illegal drugs. A growing number of patients are chronically prescribed opioids, and a growing number of health care providers and hospitals suffer from problems related to chronic prescription. Currently, in Korea, it is the time to pay serious attention to achieve the safe and effective use of prescribed opioids. This paper consists of the following parts. 1) A summary of the issues related to chronic pain, opioids, and problems associated with the use of opioids. 2) Some case examples the authors' experienced. 3) Simple guidelines on the use of opioids in the treatment of chronic non-cancer pain are proposed based on the author's experience and existing literature. These guidelines are by no means comprehensive, and hopefully in the future, related experts will join forces to develop better guidelines.

Electroconvulsive Seizure Alters the Expression and Daily Oscillation of Circadian Genes in the Rat Frontal Cortex

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for mood disorders. Accumulating evidence has suggested the important role of circadian genes in mood disorders. However, the effects of ECT on circadian genes have not been systemically investigated. METHODS: We examined the expression and daily oscillation of major circadian genes in the rat frontal cortex after electroconvulsive seizure (ECS). RESULTS: Firstly, mRNA and protein level were investigated at 24 hr after single ECS (E1X) and repeated ECS treatements for 10 days (E10X), which showed more remarkable changes after E10X than E1X. mRNA expression of Rorα, Bmal1, Clock, Per1, and Cry1 was decreased, while Rev-erbα expression was increased at 24 hr after E10X compared to sham. The proteins showed similar pattern of changes. Next, the effects on oscillation and rhythm properties (mesor, amplitude, and acrophase) were examined, which also showed more prominent changes after E10X than E1X. After E10X, mesor of Rorα, Bmal1, and Cry1 was reduced, and that of Rev-erbα was increased. Five genes, Rev-erbα, Bmal1, Per1, Per2, and Cry2, showed earlier acrophase after E10X. CONCLUSION: The findings suggest that repeated ECS induces reduced expression and phase advance of major circadian genes in the in vivo rat frontal cortex.

Reduction in Alpha Peak Frequency and Coherence on Quantitative Electroencephalography in Patients with Schizophrenia

BACKGROUND: The aim of the study was to examine the characteristics of alpha wave peak frequency, power, and coherence in patients with schizophrenia. METHODS: Thirty-one patients with schizophrenia and age- and sex-matched subjects with no psychopathology were enrolled. All study participants underwent quantitative electroencephalography (QEEG). Alpha-related values, including peak frequency, power, and coherence, were evaluated. RESULTS: Alpha peak frequency on the Oz area was slower in the schizophrenia group than that in the control group. However, no differences in absolute or relative power were observed between the two groups. Significant reductions in absolute and relative coherence were observed at the C3–C4 and T3–T4 nodes in the patients with schizophrenia. Relative coherence was reduced at the P3–P4 nodes. CONCLUSION: This study focused on alpha variables detected in QEEG as intrinsic values to distinguish schizophrenia from a healthy control. The results suggest decreased alpha peak frequency of the occipital lobe and decreased coherence between the two hemispheres in patients with schizophrenia. A further study could elucidate the causal relationship and biological meaning of the variations in alpha waves in patients with schizophrenia.

Long-Term Evolution of Metabolic Status in Patients with Schizophrenia Stably Maintained on Second-Generation Antipsychotics

OBJECTIVE: Second-generation antipsychotics (SGAs) increase the risk of metabolic syndrome (MetS). Despite the risk of MetS, SGAs may have to be continued with change in some patients. The aim of this study was to trace the evolution of MetS in these patients. METHODS: Patients with schizophrenia who had been maintained on a fixed SGA regimen for more than a year were followed-up without changing the regimen. Metabolic indicators were evaluated at baseline and at follow-up. Prevalence, incidence and spontaneous normalization rate of MetS were estimated. Risk factors that might have influenced the evolution were scrutinized. RESULTS: A total of 151 subjects were included. During the mean observation period of 389.9±162.4 days, the prevalence of MetS was increased from 35.1 to 45.0%. The incidence rate was 29.6%, while the normalization rate was 26.4%, risk factors affecting incidence were age (OR=1.09, 95% CI: 1.03–1.17), baseline continuous values of metabolic syndrome risk scores (cMetS, OR=1.77, 95% CI:1.29–2.55) and baseline body weight (OR=1.06, 95% CI: 1.01–1.13). Normalization was influenced by age (OR=0.74, 95% CI: 0.57–0.89) and baseline body weight (OR=0.85, 95% CI: 0.72–0.95). CONCLUSION: The prevalence of MetS steadily increased with the continuous use of SGAs. However, individual difference was extensive and about a quarter of the patients were able to recover naturally without specific measurements.

Evolutionary Psychiatry II-Mental Functions and Diseases from the Evolutionary Perspective / 신경정신의학

Previously (Part I) the authors introduced the evolutionary biology and psychology. In the present part (Part II) of the review article, we discuss what disease is, and how diseases are explained in terms of the evolutionary perspective. Various psychologic phenomena and psychopathologic conditions are also illuminated under this evolutionary light. Through this approach, the authors hope that clinicians would search for the “normality” as well as pathology in patients, and would utilize this insight to understand and treat them accordingly.

Evolutionary Psychiatry I-Concept of Evolutionary Psychology and Evolutionary Psychopathology / 신경정신의학

The evolutionary theory is applied to explain a multitude of natural and social phenomena. In medicine, evolutionary biology and psychology enables us to take perspectives beyond the biomedical paradigm of disease. The evolutionary pathophysiology looks for the ultimate cause of disease rather than the proximate causes. The ultimate cause of disease lies in the evolved psychological mechanisms (EPMs). This recognition fundamentally alters the traditional view of pathogenesis that a disease is the result of alien pathogens invading our bodies. Especially in psychiatry, the insight that the pathologic and normal mind have a common basis and that discriminating between them solely by means of natural science is rather impossible, this makes us rethink the validity of current reductionistic approaches to psychiatric nosology. In this article (Part I), the authors introduce evolutionary biology and psychology. Detailed application of the evolutionary perspective to psychiatric disorders will be discussed in the continuing article (Part II).

Clinical Usefulness of Long-term Application of Fentanyl Matrix in Chronic Non-Cancer Pain: Improvement of Pain and Physical and Emotional Functions

BACKGROUND: Opioids are recently recommended for those who do not gain adequate pain relief from the use of acetaminophen or nonsteroidal anti-inflammatory drugs. Medical opioids are administered in various routes, and transdermal opioid products that can make up for the weaknesses of the oral or intravenous products have been developed. This study is to evaluate the clinical usefulness of fentanyl matrix in terms of the long-term improvement in pain and physical and mental functions. METHODS: This was a multicenter, open, prospective, observational study that was conducted in 54 institutions in Korea. Patients with non-cancerous chronic pain completed questionnaires, and investigators also completed questionnaires. A total of 1,355 subjects participated in this study, and 639 subjects completed the study. Subjects received transdermal fentanyl matrix (12 µg/hr, 25 µg/hr, or 50 µg/hr depending on the patient's response and demand). Subjects visited at 29 ± 7 days, 85 ± 14 days, and 169 ± 14 days after administration, respectively, to receive drug titration and fill out the questionnaires. The results were analyzed using the intention-to-treat (ITT) analysis, full analysis set (FAS), and per-protocol (PP) analysis. The FAS analysis included only 451 participants; the PP analysis, 160 participants; and the ITT analysis, 1,355 participants. RESULTS: The intensity of pain measured by the Numeric Rating Scale decreased from 7.07 ± 1.78 to 4.93 ± 2.42. The physical assessment score and mental assessment score of the Short-Form Health Survey 12 improved from 28.94 ± 7.23 to 35.90 ± 10.25 and from 35.80 ± 11.76 to 42.52 ± 10.58, respectively. These differences were significant, and all the other indicators also showed improvement. Adverse events with an incidence of ≥ 1% were nausea, dizziness, vomiting, and pruritus. CONCLUSIONS: The long-term administration of fentanyl matrix in patients with non-cancerous pain can reduce the intensity of pain and significantly improves activities of daily living and physical and mental capabilities.

Recent Trends for Optimization of Electroconvulsive Therapy / 신경정신의학

Electroconvulsive therapy (ECT) is a safe and effective treatment not only for various mental disorders including depression, mania, and schizophrenia, but also for inadequacy and resistance to pharmacotherapy and the psychiatric emergences. The historical ups and downs of ECT treatment since its first introduction in 1938 were ended by the validation impacts of evidence-based medicine in the 1980s and by other clinical issues. Clinical research for the optimization of ECT to maximize therapeutic effects and to minimize adverse effects is ongoing to establish standardized procedures and educational programs through the ECT center. In addition, guidelines for ECT practices are also being developed for the clinical excellence of ECT practices in accordance with the recommendations of international organizations such as World Psychiatric Association and American Psychiatric Association. This article was prepared by reviews of the literature, direct observations of ECT practices abroad, and interviews with ECT experts around the world in order to enhance therapeutic effects with recently updated ECT practices under the belief that the most appropriate treatments should be provided to the patients in need.

History of Schizophrenia / 신경정신의학

Fundamental difficulties in psychiatric nosology lie in the most basic fact that it deals with subjective states of the human mind. Modern instrumental diagnostic classification systems, which amount to lists of symptom inventories, could not provide accurate concepts of psychiatric disorders. This is also true for schizophrenia, a representative mental disorder. Kraepelin's dementia praecox was a collection of controversially proposed diseases, which had some critical similarities in their clinical features, i.e., the course and outcome. Despite initial debates on the adequacy of this concept, dementia praecox was recognized as a disease entity quite early, so that the concept of dementia praecox or schizophrenia proliferated, became diversified, and was then altered. We can now find large discrepancies between Kraepelin's dementia praecox and today's schizophrenia. However, the myth of disease entity was seldom challenged and psychiatrists today implicitly believe that they are dealing with what Kraepelin had proposed. In order to navigate this impasse, we thought that historical studies on the concept of dementia praecox and underlying taxonomic principles established by 19th century alienists including Kraepelin would shed some light. The aim of this article is to comprehensively review the history of concepts of dementia praecox or schizophrenia, and to question critically how much today's schizophrenia has received the conceptual inheritance from original concepts. Through this process, we expect to attain a renewed understanding of schizophrenia.

Effects of Clozapine, Haloperidol, and Fluoxetine on the Reversal of Cocaine-Induced Locomotor Sensitization

OBJECTIVE: Repeated treatment with psychostimulants induces sensitization of the dopaminergic system in the brain. Dopaminergic sensitization has been proposed as a mechanism of psychosis. Although antipsychotics block the expression of sensitized behavior, they are ineffective for reversing the sensitized state. We investigated the effect of clozapine, haloperidol, and fluoxetine on the reversal of cocaine-induced behavioral sensitization. METHODS: Male ICR mice were sensitized to cocaine with repeated treatment. Animals were then split into four groups, and each group was treated with vehicle or one of the above drugs for 5 days. After a 3-day drug washout, locomotor activity was assessed before and after a cocaine challenge. RESULTS: Clozapine reversed the sensitized state, whereas haloperidol did not. Fluoxetine seemed to reverse the sensitization partially. CONCLUSION: We confirmed that D2 blockade was not effective for reversing sensitization. The reversal by clozapine is partially explained in terms of its strong 5-HT2 and weak D2 affinity. The partial reversal by fluoxetine seemed to be related to its serotonin-augmenting action.

The Meaning of P50 Suppression: Interaction of Gamma and Alpha Waves

OBJECTIVES: Sensory gating dysfunctions in patients with schizophrenia and bipolar disorder have been investigated through two similar methods ; P50 suppression and prepulse inhibition paradigms. However, recent studies have demonstrated that the two measures are not correlated but rather constitute as distinct neural processes. Recent studies adopting spectral frequency analysis suggest that P50 suppression reflects the interaction between gamma and other frequency bands. The aim of the present study is to investigate which frequency component shows more significant interaction with gamma band. METHODS: A total of 108 mood disorder patients and 36 normal subjects were included in the study. The P50 responses to conditioning and test stimuli with an intra-pair interval of 500 msec were measured in the study population. According to P50 ratio (amplitude to the test stimulus/amplitude to the conditioning stimulus), the subjects with P50 ratio less than 0.2 were defined as suppressed group (SG) ; non-suppressed group (NSG) consisted of P50 ratio more than 0.8. Thirty-five and 25 subjects were included in SG and NSG, respectively. Point-to-point correlation coefficients (PPCCs) of both groups were calculated between two time-windows : the first window (S1) was defined as the time-window of one hundred millisecond after the conditioning auditory stimulus and the second window (S2) was defined as the time-window of 100 msec after the test auditory stimulus. Spectral frequency analysis was performed to investigate which frequency band results in the difference of PPCC between SG and NSG. RESULTS: Significant reduction of PPCC between S1 and S2 was observed in the SG (Pearson's r = 0.24), compared to PPCC of the NSG (r = 0.58, p < 0.05). In spectral frequency analysis, gamma band showed "phase-reset" and similar responses after the two auditory stimuli in suppressed and non-suppressed group. However in the case of alpha band, comparison showed significantly low PPCC in SG (r = -0.14) compared to NSG (r = 0.36, p < 0.05). This may be reflecting "phase-out" of alpha band against gamma band at approximately 50 msecs after the test stimulus in the SG. CONCLUSIONS: Our study suggests that normal P50 suppression is caused by phase-out of alpha band against gamma band after the second auditory stimulus. Thus it is demonstrated that normal sensory gating process is constituted with attenuated alpha power, superimposed on consistent gamma response. Implications of preserved gamma and decreased alpha band in sensory gating function are discussed.

Treatment of Late-Life Depression by Brain Stimulation Techniques

Due to the low response rate of antidepressant treatment in late-life depression, brain stimulation techniques should be considered when treating elderly patients. Electroconvulsive therapy (ECT) is one of the most frequently used brain stimulation techniques, and shows favorable outcome and acceptable tolerability in the treatment of late-life depression. Hemodynamic change and cognitive impairment are common side effects of ECT, which are transient in most cases. Since cognitive impairment can lead to treatment non-compliance, it should be minimized by controlling electrode position, pulse-width, treatment frequency, etc. Because ECT is followed by rapid cardiovascular change, risk factors should be evaluated and managed properly. Transcranial magnetic stimulation (TMS) and magnetic seizure therapy (MST) are also shown to be effective in treating depression, with less cognitive impairment. However, further research is needed to establish their efficacy in late-life depression.

Effects of Combined Treatments of Lithium and Valproate on the Phosphorylation of ERK1/2 and Transcriptional Activity of ELK1 and C-FOS in PC12 Cells

OBJECTIVES: Mechanisms of clinical synergistic effects, induced by co-treatments of lithium and valproate, are unclear. Extracellular signal-regulated kinase (ERK) has been suggested to play important roles in mechanisms of the action of mood stabilizers. In this study, effects of co-treatments of lithium and valproate on the ERK1/2 signal pathway and its down-stream transcription factors, ELK1 and C-FOS, were investigated in vitro. METHODS: PC12 cells, human pheochromocytoma cells, were treated with lithium chloride (30 mM), valproate (1 mM) or lithium chloride + valproate. The phosphorylation of ERK1/2 was analyzed with immunoblot analysis. Transcriptional activities of ELK1 and C-FOS were analyzed with reporter gene assay. RESULTS: Single treatment of lithium and valproate increased the phosphorylation of ERK and transcriptional activities of ELK1 and C-FOS, respectively. Combined treatments of lithium and valproate induced more robust increase in the phosphorylation of ERK1/2 and transcriptional activities of ELK1 and C-FOS, compared to those in response to single treatment of lithium or valproate. CONCLUSIONS: Co-treatments of lithium and valproate induced synergistic increase in the phosphorylation of ERK1/2 and transcriptional activities of its down-stream transcription factors, ELK1 and C-FOS, compared to effects of single treatment. The findings might suggest potentiating effects of lithium and valproate augmentation treatment strategy.

Phenomenological Psychopathology / 신경정신의학

Phenomenology was founded in the 19th century by Edmund Husserl. Apart from natural sciences and metaphysics, phenomenology is presented as a rigorous scientific discipline, which aims to provide an understanding of the subjective experiences of human beings. After the eras of descriptive and dynamic psychiatry, phenomenological methods were adopted by psychiatry, and phenomenological psychopathology suggested a new perspective for understanding the pathological experiences of psychiatric patients. However, after the development of psychopharmacology and the operational diagnostic system, the center of phenomenology in psychopathology was moved from comprehensive understanding to simple description. Thus, phenomenological psychopathology in its original meaning did not get remarkable repercussions, especially in the English-speaking world. In this article, some major concepts of phenomenology will be briefly presented and then phenomenological psychopathology in its original meaning will be introduced. Secondly, as an example of its application, symptoms of schizophrenia will be interpreted in terms of phenomenological psychopathology. Finally, the authors will present a neurobiological interpretation of the phenomenological psychopathology of schizophrenia and suggest a possible role of phenomenological psychopathology in mitigating the impasse in psychiatric genetics research.