Real-world effectiveness of antipsychotic treatments in 1011 acutely hospitalized patients with schizophrenia: A one-year follow-up study.

PURPOSE: To compare the real-world effectiveness of antipsychotic treatments focusing on long-acting injectable antipsychotic medications (LAIs) and antipsychotic polytherapies except polytherapy involving clozapine (APEC) for patients with schizophrenia. METHODS: This prospective study was conducted over a 19-month period in 12 psychiatric emergency hospitals in Japan. Patients who were newly admitted to psychiatric emergency wards between September 2019 and March 2020 because of acute onset or exacerbation of Schizophrenia and Other Psychotic Disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were included. All patients were followed for one-year after discharge or until March 31, 2021. The primary outcome was the risk of treatment failure defined as psychiatric rehospitalization, discontinuation of medication, death, or continuation of hospitalization for one year. Cox proportional hazards multivariate regression was used for analyses. RESULTS: A total of 1011 patients were enrolled (women, 53.7%; mean [SD] age, 47.5 [14.8] years). During follow-up, 588 patients (58.2%) experienced treatment failure including rehospitalization (513 patients), discontinuation of medication (17 patients), death (11 patients), and continuation of hospitalization for one-year (47 patients). Switching to LAIs (hazard ratio [HR] 0.810, 95%CI 0.659-0.996) and APEC (HR 0.829, 95%CI 0.695-0.990) were significantly associated with a low rate of treatment failure. CONCLUSIONS: Switching to LAIs and APEC in early non-responders seems to be beneficial for the prevention of treatment failure in acutely admitted patients with schizophrenia. The risk of treatment failure was about 19% and 17% lower in patients treated with LAIs and APEC, respectively, than in patients treated without them.

Real-world effectiveness of antipsychotic monotherapy and polytherapy in 1543 patients with acute-phase schizophrenia.

PURPOSE: The effectiveness of antipsychotic treatments in the acute phase of schizophrenia in actual clinical practice remains somewhat unclear. Therefore, the purpose of the present naturalistic, multi-center study conducted from 1 year starting in September 2017 was to examine the response rate to an initial or second antipsychotic in newly admitted patients with acute-phase schizophrenia, as well as the response rate and quality of augmentation with two antipsychotics in patients who failed to respond to both the initial and second antipsychotics. RESULTS: In total, there were 660 (42.8%) and 243 (15.7%) responders to an initial and a second antipsychotic, respectively; thus, 58.5% of all patients were responders to an initial or second antipsychotic. Among 581 nonresponders (37.7%), the initial antipsychotic or a third antipsychotic was added to the second antipsychotic. Among these patients, 89.8% showed a Clinical Global Impression-Improvement score ≤3 (from 'minimally improved' to 'very much improved'). The rates of adverse events such as hyperglycemia, hyper-low-density lipoprotein cholesterolemia, hypertriglyceridemia, hyperprolactinemia, QTc prolongation, and extrapyramidal symptoms were not high in patients receiving augmentation with two antipsychotics compared with all patients, and no serious adverse events were reported. CONCLUSION: Antipsychotic augmentation may be an option in acute-phase treatment for patients who do not respond to either an initial or a second antipsychotic.

Predicting postictal suppression in electroconvulsive therapy using analysis of heart rate variability.

BACKGROUND: Postictal suppression on an electroencephalogram (EEG) represents electrical silence during electroconvulsive therapy (ECT) and has been considered as a key feature associated with the efficacy of treatment. The present study aimed to predict postictal suppression using heart rate variability (HRV). METHODS: Participants comprised 21 consecutive patients with depression who underwent bilateral pulse wave ECT. We analyzed the frequency domains of resting HRV before ECT. HRV indices such as the high-frequency component (HF) reflecting parasympathetic activity and the ratio of low-frequency component (LF)/HF reflecting sympathetic activity were natural log transformed for analysis. We evaluated ictal and peri-ictal EEG parameters and investigated their associations with HRV indices. RESULTS: Postictal suppression and regularity were positively associated with ln[HF]. Postictal suppression remained significantly associated with ln[HF] after adjusting for age in multiple regression analysis of patients with depression. LIMITATIONS: The present study could not examine the influence of diabetes mellitus, hypertension and polarity on HRV. In addition, the small sample size resulted in low statistical power. CONCLUSIONS: These results suggested that ln[HF] before ECT could be utilized as a predictor of postictal suppression on EEG during ECT.

Is prolongation of corrected QT interval associated with seizures induced by electroconvulsive therapy reduced by atropine sulfate?

BACKGROUND: Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. METHODS: We analyzed heart rate, QT interval, and QTc in 32 patients with depression who underwent ECT (25 women, 67.4 ± 8.7 years of age). The QTc from -30 to 0 seconds prestimulation was used as baseline, which was compared with QTc at 20-30 seconds and 140-150 seconds poststimulus onset. RESULTS: QTc was significantly prolonged at 20-30 seconds poststimulus, then significantly decreased at 140-150 seconds poststimulus, compared with baseline. QTc prolongation induced by ECT was significantly decreased by atropine sulfate. CONCLUSIONS: These data suggest that the risk of TdP may be enhanced by ECT. Further, the risk of cardiac ventricular arrhythmias, including TdP, may be reduced by administration of atropine sulfate.

Runx1 contributes to the functional switching of bone morphogenetic protein 4 (BMP4) from neurite outgrowth promoting to suppressing in dorsal root ganglion.

The runt-related transcription factor Runx1 regulates cell-type specification and axonal projections of nociceptive dorsal root ganglion (DRG) neurons, whereas bone morphogenetic protein 4 (BMP4) is required for axonal growth during neuronal development. Although Runx1 has been shown to be involved in BMP4 signaling in non-neural tissues, the Runx1 function in BMP4-dependent regulation of neuronal development is unclear. To investigate interactions between Runx1 and BMP4 in neurite outgrowth, we cultured DRGs from wild-type and Runx1-deficient mouse embryos in the presence or absence of BMP4. Neurite outgrowth was decreased in BMP4-treated wild-type DRGs and untreated Runx1-deficient DRGs, suggesting the inhibitory effect of BMP4 and facilitatory effect of Runx1 on neurite outgrowth. In addition, the combination of BMP4 treatment and Runx1 deficiency increased neurite outgrowth, suggesting that Runx1 is required for BMP4-induced suppression of neurite outgrowth and that the loss of Runx1 results in a functional switch of BMP4 from neurite growth suppressing to neurite growth promoting. Both BMP4 treatment and Runx1 deficiency increased calcitonin gene-related peptide (CGRP)-positive neurons, and CGRP expression was not increased by BMP4 treatment in Runx1-deficient mice, suggesting that Runx1 contributes to BMP4-induced CGRP expression in DRG neurons. Thus, Runx1 contributes to BMP4 regulation of neurite outgrowth and CGRP expression in DRG and may control BMP4 functional switching during embryogenesis.

Runx3-regulated expression of two Ntrk3 transcript variants in dorsal root ganglion neurons.

Somatosensation is divided into proprioception and cutaneous sensation. Dorsal root ganglion (DRG) neurons project their fibers toward peripheral targets including muscles and skin, and centrally to the spinal cord. Proprioceptive DRG neurons transmit information from muscle spindles and Golgi tendon organs to the spinal cord. We previously showed that Runt-related transcription factor 3 (Runx3) is expressed in these neurons and their projections to the ventral spinal cord and muscle spindles are lost in Runx3-deficient (Runx3(-/-) ) mouse embryos. Although Runx3 is likely to contribute to the fate decision and projection of proprioceptive DRG neurons, the precise roles for Runx3 in these phenomena are unknown. To identify genes regulated by Runx3 in embryonic DRGs, we performed microarray analyses using cDNAs isolated from wild-type and Runx3(-/-) DRGs of embryonic day (E) 12.5 and selected two transcript variants of the tyrosine kinase receptor C (TrkC) gene. These variants, Ntrk3 variant 1 (Ntrk3-v1) and variant 2 (Ntrk3-v2), encode full-length and truncated receptors of neurotrophin-3, respectively. Using double in situ hybridization, we found that most of Ntrk3-v1 mRNA expression in E14.5 DRGs depended on Runx3 but that more than half of Ntrk3-v2 mRNA one were expressed in a Runx3-independent manner. Furthermore, our data revealed that the rate of Ntrk3-v1 and Ntrk3-v2 colocalization in DRGs changed from E14.5 to E18.5. Together, our data suggest that Runx3 may play a crucial role in the development of DRGs by regulating the expression of Ntrk3 variants and that DRG neurons expressing Ntrk3-v1 but not Ntrk3-v2 may differentiate into proprioceptive ones.

Contribution of the Runx1 transcription factor to axonal pathfinding and muscle innervation by hypoglossal motoneurons.

The runt-related transcription factor Runx1 contributes to cell type specification and axonal targeting projections of the nociceptive dorsal root ganglion neurons. Runx1 is also expressed in the central nervous system, but little is known of its functions in brain development. At mouse embryonic day (E) 17.5, Runx1-positive neurons were detected in the ventrocaudal subdivision of the hypoglossal nucleus. Runx1-positive neurons lacked calcitonin gene-related peptide (CGRP) expression, whereas Runx1-negative neurons expressed CGRP. Expression of CGRP was not changed in Runx1-deficient mice at E17.5, suggesting that Runx1 alone does not suppress CGRP expression. Hypoglossal axon projections to the intrinsic vertical (V) and transverse (T) tongue muscles were sparser in Runx1-deficient mice at E17.5 compared to age-matched wild-type littermates. Concomitantly, vesicular acetylcholine transporter-positive axon terminals and acetylcholine receptor clusters were less dense in the V and T tongue muscles of Runx1-deficient mice. These abnormalities in axonal projection were not caused by a reduction in the total number hypoglossal neurons, failed synaptogenesis, or tongue muscles deficits. Our results implicate Runx1 in the targeting of ventrocaudal hypoglossal axons to specific tongue muscles. However, Runx1 deficiency did not alter neuronal survival or the expression of multiple motoneuron markers as in other neuronal populations. Thus, Runx1 appears to have distinct developmental functions in different brain regions.

Coexpression of Runx1 and Runx3 in mechanoreceptive dorsal root ganglion neurons.

Runt-related transcription factors (Runx) regulate the development of various cells. It has been reported that Runx1 and Runx3 are expressed in distinct subpopulations of primary sensory neurons in the dorsal root ganglion (DRG), and play important roles in the differentiation of nociceptive and proprioceptive neurons, respectively. In the present study, we examined the developmental changes of the expression of Runx1 and Runx3 in the mouse DRG during embryonic and postnatal stages. We found that the expression of Runx3 preceded that of Runx1, but dramatically decreased before birth, whereas the Runx1 expression was maintained during postnatal periods. These results suggest that roles of Runx1 and Runx3 may change dynamically in the differentiation and maturation of DRG neurons. In addition, several DRG neurons expressed both Runx1 and Runx3 throughout embryonic and postnatal stages and many Runx3-expressing DRG neurons coexpressed Runx1 at postnatal day 28. Double and triple labeling studies suggest that some of the Runx1/Runx3-double expressing neurons coexpressed TrkB, c-ret, and TrkC, which have been shown in the mechanoreceptive DRG neurons. These results suggest that Runx1/Runx3-double expressing neurons may represent mechanoreceptive properties in the DRG.

The influence of passband limitation on the waveform of extracellular action potential.

The duration of the extracellular action potential (EAP) in single neuronal recording has often been used as a clue to infer biochemical, physiological or functional substrate of the recorded neurons, e.g. neurochemical type. However, when recording a neuronal activity, the high-pass filter is routinely used to achieve higher signal-to-noise ratio. Signal processing theory predicts that passband limitation stretches the waveform of discrete brief impulse. To examine whether the duration of filtered EAP could be the reliable measure, we investigated the influence of high-pass filter both by simulation and unfiltered unit recording data from monkey dorsal raphe. Consistent with the findings in recent theoretical study, the unfiltered EAPs displayed the sharp wave without following bumps. The duration of unfiltered EAP was not correlated with that of filtered EAP. Thus the duration of original EAP cannot be estimated from filtered EAP. It is needed to reexamine the EAP duration measured for classifying the neurons whose activities were recorded under the passband limitation in the related studies.

Runx1 promotes neuronal differentiation in dorsal root ganglion.

Transcription factor Runx1 controls the cell type specification of peptidergic and nonpeptidergic nociceptive dorsal root ganglion (DRG) neurons by repressing TrkA and calcitonin gene-related peptide (CGRP) expression and activating Ret expression during late embryonic and early postnatal periods (Chen et al., 2006b; Kramer et al., 2006; Yoshikawa et al., 2007). Because Runx1 is expressed in DRG from early developmental stages, we examined the roles of Runx1 in the proliferation and the neuronal differentiation of DRG cells. We used transgenic Runx1-deficient (Runx1(-/-)::Tg) mice which are rescued from early embryonic lethality by selective expression of Runx1 in hematopoietic cells under the control of GATA-1 promoter. We found that TrkA-expressing (TrkA(+)) DRG neurons were decreased at embryonic day (E) 12.5 in contrast to the previous study showing that TrkA(+) DRG neurons were increased at E17.5 in Runx1(-/-)::Tg mice (Yoshikawa et al., 2007). The number of DRG neurons which express neuronal markers Hu, NeuN and Islet1 was also reduced in Runx1(-/-)::Tg mice at E12.5, suggesting that the neuronal differentiation was suppressed in these mice. The cell cycle analysis using BrdU/IDU revealed that the number of DRG cells in S-phase and G2/M-phase was increased in Runx1(-/-)::Tg mice at E12.5, while the length of S-phase was not changed between Runx1(+/+)::Tg and Runx1(-/-)::Tg mice, suggesting that Runx1 negatively controls the proliferation of DRG progenitor cell subpopulation in early embryonic period. Hes1 is a negative regulator of neuronal differentiation (Ishibashi et al., 1995; Tomita et al., 1996), and we found that the number of Hes1(+) DRG cells was increased in Runx1(-/-)::Tg mice at E12.5. In summary, the present study suggests a novel function that Runx1 activates the neuronal differentiation of DRG cell subpopulation through the repression of Hes1 expression in early embryonic period.

Comparative study of suicide risk in depressive disorder patients with and without problem drinking.

The present study sought to determine whether the co-occurrence of problem drinking heightens suicide risk in individuals with depression in Japan, using a sample of 784 outpatients (287 men and 497 women) with depressive disorder. Female subjects with at least a moderate problem drinking showed significantly more severe depression and suicidality than those without, but no such difference was identified in men.

[Current situation and clinical characteristics of sedative-related disorder patients in Japan: a comparison with methamphetamine-related disorder patients].

PURPOSE: The purpose of the present study was to examine the current situation regarding sedative (mainly benzodiazepines)-related disorder in Japan and the clinical characteristics of Japanese patients with this disorder. SUBJECTS: Subjects were 671 drug-related disorder patients diagnosed according to the ICD-10 classification as "F1: mental and behavioural disorders due to psychoactive substance use," who abused psychoactive substances other than alcohol. Of all the psychiatric hospitals in Japan between September and October 2010, these drug-related disorder patients had consecutively consulted or were admitted to 153 psychiatric hospitals. METHODS: The present study was conducted by means of a mail survey. Subjects' clinical information, including history of psychoactive substance use, means of access to the primary drug of abuse, other ICD-10 diagnoses including the F1 subcategory and comorbid psychiatric disorders, and recent history of self-destructive behavior, were collected from the attending psychiatrists of each subject. The data thus gathered concerning sedative-related disorder patients were compared with those of patients with methamphetamine-related disorder, which has been the most serious drug-related problem in Japan since the 1950s. RESULTS: Out of the 671 subjects, 119 patients mainly abusing sedatives (SRD group) were identified, while 361 patients were identified as mainly abusing methamphetamine (MRD group). The MRD group was the largest population (53.8% of the total subjects), followed by the SRD group (17.7%), and then the inhalant-related disorder group with 56 patients (8. 3%). Compared with the MRD group, the SRD group was younger, contained more female patients, and had a lower incidence of a history of involvement with anti-social societies and anti-social behavior. Patients in the SRD group were more likely to have started abusing drugs with the intention of reducing the unpleasant symptoms of insomnia (42.9%), anxiety (26.1%), and depression (16.0%), and to acquire the drugs they abused from medical institutions such as psychiatric or primary care clinics (82.1%), while patients in the MRD group were more likely to have started out of curiosity (35.1%) or in response to peer pressure (47. 1%), and to acquire their drugs from a "pusher" (32.8%). Additionally, in the SRD group, the ICD-10 F1 subcategory diagnoses that were the clinically most important were "dependence syndrome" (64.0%), "harmful use" (16.2%), and "acute intoxication" (16.2%), while the most important subcategory diagnosis in the MRD group was "psychotic disorder" (34.3%) and "residual disorder and late-onset psychotic disorder" (32.9%). Further, comorbid psychiatric disorders were more frequently found in the SRD group than in the MRD group; notably, co-occurrence of mood disorder was found in 45.0% of the SRD group in contrast to the MRD group (11.9%). Recent episodes of deliberate self-harm behavior were also more frequently found in the SRD group than the MRD group (33.6 vs. 10.5%, respectively) ; the major means by which these patients harmed themselves was by overdosing on prescribed drugs (23.5 vs. 4.7%, respectively). CONCLUSION: The present study suggests that sedative-related disorder is an important clinical issue in the field of drug-related disorders in Japan today, and that SRD patients may represent a distinct type of drug abuser whose clinical characteristics are different from those of MRD patients. The development and spread of treatment programs for "dependence syndrome" and "harmful use" will help SRD patients, and educating psychiatrists about SRD will help prevent future sedative abuse.

Characterization of sensory neurons in the dorsal root ganglia of Bax-deficient mice.

During development, the rescue of spinal motoneurons as well as sensory neurons in the dorsal root ganglion (DRG) from programmed cell death (PCD) depends on the integrity of peripheral target innervation. Following deletion of the pro-apoptotic gene Bax, both motoneurons and DRG neurons are rescued from PCD. In the present paper, we asked whether different cell types in the DRG exhibit distinct responses to Bax deletion. In 1-month-old Bax-deficient (Bax-/-) mice, distinct subsets of DRG neurons that were immunopositive for TrkA, CGRP, TRPV1 or TrkC, were all increased in number and exhibited cell atrophy compared to wild type DRG neurons. In addition there was hyperinnervation of the epidermis by CGRP immunopositive processes and a correlated functional hypersensitivity of mechanical nociception in Bax-/- mice. By contrast, the functional properties of populations of rescued thermoreceptor and mechanoreceptor DRG neurons were unchanged. These data indicate that although Bax deletion rescues all of the DRG cell types examined here from PCD, the functional consequences of having excess cells differ between sensory phenotypes.

Runx3 is required for the specification of TrkC-expressing mechanoreceptive trigeminal ganglion neurons.

Sensory neurons project axons to specific peripheral and central targets according to their sensory modality. Runx3 is crucially involved in proprioceptive dorsal root ganglion neuron development. Runx3 is also expressed in trigeminal ganglion (TG) neurons. The role of Runx3 in the TG, however, is largely unknown because the TG does not contain proprioceptive neurons. In Runx3-deficient (Runx3(-/-)) mice, TrkB-expressing TG neurons were increased, whereas TrkC-expressing TG neurons were decreased during TG neuron development. In Runx3(-/-) neonatal mice, TrkC-expressing TG neurons did not project to the Merkel cells in the outer root sheath (ORS) of whisker vibrissae peripherally and the spinal trigeminal nucleus pars interpolaris (Sp5I) centrally. These findings suggest that Runx3 is required for the specification of TrkC-expressing TG neurons, conveying mechanoreceptive signals from the Merkel cells in the ORS of the whisker vibrissae to the Sp5I.

[Current situation of and the political measures for drug abuse/dependence].

More than 10 years has passed since 1995 when the third epidemic of methamphetamine abuse started in Japan. We are now still in the third epidemic of methamphetamine abuse, thought the current situation of drug abuse/dependence has obviously changed from previously. Considering several kinds of nationwide surveys and censuses, the authors summarized the change as follows: a) obvious decrease in solvent abuse/dependence, b) stabilization of methamphetamine abuse/dependence, c) increase in abuse of such drugs as cannabis or MDMA which don't have high potential to cause drug-induced psychosis, and d) emergence of non-regulatory drugs represented by designer drugs. These imply the change a) from "hard drugs" to "soft drugs", b) from Japanese unique situation which is symbolized by solvent abuse to Western situation which is symbolized by cannabis abuse, and c) from "illicit drugs" to "non-regulatory drugs". These characteristics reveal that there is the limitation to the Japanese Government policy which has tried to control the drug issue mainly as criminal cases for many years and that it is time now to change its policy. The authors stress the necessities of development of medical treatment targeting drug dependence and of its social support system.

Dynamic regulation of the expression of neurotrophin receptors by Runx3.

Sensory neurons in the dorsal root ganglion (DRG) specifically project axons to central and peripheral targets according to their sensory modality. However, the molecular mechanisms that govern sensory neuron differentiation and the axonal projections remain unclear. The Runt-related transcription factors, Runx1 and Runx3, are expressed in DRG neuronal subpopulations, suggesting that they might regulate the cell specification and the trajectories of specific axons. Here, we show that parvalbumin-positive DRG neurons fail to differentiate from the onset in Runx3(-/-) mice. By contrast, TrkC-positive DRG neurons differentiate normally at embryonic day (E) 11.5, but disappear by E13.5 in Runx3(-/-) mice. Subsequently, TrkC-positive DRG neurons reappear but in smaller numbers than in the wild type. In Runx3(-/-) mice, central axons of the TrkC-positive DRG neurons project to the dorsal spinal cord but not to the ventral and intermediate spinal cord, whereas the peripheral axons project to skin but not to muscle. These results suggest that Runx3 controls the acquisition of distinct proprioceptive DRG neuron identities, and that TrkC-positive DRG neurons consist of two subpopulations: Runx3-dependent early-appearing proprioceptive neurons that project to the ventral and intermediate spinal cord and muscle; and Runx3-independent late-appearing cutaneous neurons that project to the dorsal spinal cord and skin. Moreover, we show that the number of TrkA-positive DRG neurons is reduced in Runx3(-/-) mice, as compared with the wild type. These results suggest that Runx3 positively regulates the expression of TrkC and TrkA in DRG neurons.

Runx1 selectively regulates cell fate specification and axonal projections of dorsal root ganglion neurons.

Runx1-deficient mice die around embryonic day 11.5 due to impaired hematopoiesis. This early death prevents the analysis of the role of Runx1 in the development of sensory ganglia. To overcome the early embryonic lethality, we adopted a new approach to utilize transgenic Runx1-deficient mice in which hematopoietic cells are selectively rescued by Runx1 expression under the control of GATA-1 promoter. In Runx1-deficient mice, the total number of dorsal root ganglion (DRG) neurons was increased, probably because of an increased proliferative activity of DRG progenitor cells and decreased apoptosis. In the mutant DRG, TrkA-positive neurons and peptidergic neurons were increased, while c-ret-positive neurons were decreased. Axonal projections were also altered, in that both central and peripheral projections of CGRP-positive axons were increased. In the dorsal horn of the spinal cord, projections of CGRP-positive axons expanded to the deeper layer, IIi, from the normal terminal area, I/IIo. Our results suggest that Runx1 is involved in the cell fate specification of cutaneous neurons, as well as their projections to central and peripheral targets.

Characteristics of methylphenidate dependence syndrome in psychiatric hospital settings.

The characteristics of methylphenidate (MPD) cases reported in a nationwide mental hospital survey on substance-related psychiatric disorders are studied compared to methamphetamine cases. Although the two groups did not differ in terms of age and sex, the MPD group revealed longer educational histories and lower antisocial traits. About half of the MPD group had a history of methamphetamine use and 30% had used the substance as the initial substance of abuse. They exhibited a general tendency toward multiple substance use. These results indicate that a significant number of MPD cases exist who used MPD as a substance alternative to methamphetamine and also suggest that they may potentially have a tendency to develop abuse or dependence. The MPD cases most likely had a psychiatric diagnosis of "Dependence syndrome (F15.2)," according to the ICD-10 guidelines. The SDS scores also indicated a more severe dependence syndrome, particularly psychological dependence, which they may possibly develop more quickly. An abundance of information for MPD abusers to utilize is available through the internet, including the pharmacological properties, such as increased sensation or elation through MPD intake and how and where to easily acquire the substance. They may even forge a prescription to obtain MPD. This behavior can be recognized as "substance-seeking behavior" in behavioral pharmacology terms, accompanied by craving based on psychological dependence on the substance, and can be very difficult to control. Little evidence exists regarding the effectiveness and necessity of MPD as a treatment for depression, and thus MPD prescriptions must be carefully considered by psychiatrists or physicians. The application of MPD as an antidepressant in the health insurance system must be re-examined as well.