Establishing a business case for setting up early detection services for preventing psychosis.

Under standard care, psychotic disorders can have limited response to treatments, high rates of chronicity and disability, negative impacts on families, and wider social and economic costs. In an effort to improve early detection and care of individuals developing a psychotic illness, early intervention in psychosis services and early detection services have been set up in various countries since the 1980s. In April 2016, NHS England implemented a new 'access and waiting times' standard for early intervention in psychosis to extend the prevention of psychosis across England. Unfortunately, early intervention and early detection services are still not uniformly distributed in the UK, leaving gaps in service provision. The aim of this paper is to provide a business case model that can guide clinicians and services looking to set up or expand early detection services in their area. The paper also focuses on some existing models of care within the Pan-London Network for Psychosis Prevention teams.

Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals.

'Smart drugs' (also known as 'nootropics' and 'cognitive enhancers' [CEs]) are being used by healthy subjects (i.e. students and workers) typically to improve memory, attention, learning, executive functions and vigilance, hence the reference to a 'pharmaceutical cognitive doping behaviour'. While the efficacy of known CEs in individuals with memory or learning deficits is well known, their effect on non-impaired brains is still to be fully assessed. This paper aims to provide an overview on the prevalence of use; putative neuroenhancement benefits and possible harms relating to the intake of the most popular CEs (e.g. amphetamine-type stimulants, methylphenidate, donepezil, selegiline, modafinil, piracetam, benzodiazepine inverse agonists, and unifiram analogues) in healthy individuals. CEs are generally perceived by the users as effective, with related enthusiastic anecdotal reports; however, their efficacy in healthy individuals is uncertain and any reported improvement temporary. Conversely, since most CEs are stimulants, the related modulation of central noradrenaline, glutamate, and dopamine levels may lead to cardiovascular, neurological and psychopathological complications. Furthermore, use of CEs can be associated with paradoxical short- and long-term cognitive decline; decreased potential for plastic learning; and addictive behaviour. Finally, the non-medical use of any potent psychotropic raises serious ethical and legal issues, with nootropics having the potential to become a major public health concern. Further studies investigating CE-associated social, psychological, and biological outcomes are urgently needed to allow firm conclusions to be drawn on the appropriateness of CE use in healthy individuals.

Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise.

Psychedelics alter the perception of reality through agonist or partial agonist interaction with the 2A serotoninergic receptor. They are classified as phenethylamines, tryptamines and lysergamides. These classes, according to the United Nations Office on Drugs and Crime (UNODC) and European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), account for an important percentage of the new psychoactive substances (NPS) current scenario.The paper aimed at: a) identifying and categorising psychedelic molecules from a list of psychonaut websites and NPS online resources; and b) comparing the NPSfinderⓇ results with those from the European and United Nations databases. A crawling software (i.e. 'NPSfinderⓇ') was created to automatically scan, 24/7, a list of URLs and to extract a range of information (chemical/street names, chemical formulae, etc.) to facilitate NPS identification. Data collected were manually analysed and compared with the EMCDDA and UNODC databases.The overall number of psychedelic NPS detected by NPSfinderⓇ (November 2017-February 2020) was 1344, almost ten-times higher than that reported by the UNODC and EMCDDA combined. Of these, 994 previously unknown molecules were identified as (potential) novel psychedelics, suggesting a strong discrepancy between online and real-world NPS scenarios. The results show the interest of psychonauts, and maybe of the much larger community of 'recreational' drug users, towards psychedelics. Moreover, examining online scenario may help in assessing the availability in the real world of psychedelic NPS; understanding drug trends; and in possibly predicting future drug scenarios.

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant.

Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α1-adrenceptors preferentially over α2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.

New psychoactive substances (NPS) and serotonin syndrome onset: A systematic review.

The use of several new psychoactive substances (NPS) has become very popular and is posing global health risks. Chemically and pharmacologically diverse molecules are constantly emerging and are presenting with a wide range of clinical implications. Serotonin toxicity, and specifically Serotonin Syndrome (SS), might develop as a result of an over-activation of the serotoninergic system caused by several mechanisms resulting in a classic triad of altered mental status, neuromuscular effects, and autonomic hyperactivity. In the present systematic review, we have investigated and summarized the available evidence related to the association between SS and NPS intake. Three retrospective studies, two case series and five case reports were included in this systematic review; several NPS were found to be implicated in SS occurrence These include psychedelic phenethylamines, e.g. 2, 5-dimethoxy-4-iodophenethylamine (2C-I); 2-(4-Iodo-2,5-dimethoxyphenyl)- N-I[(2-methyoxyphenyl)methyl]ethanamine (25I-NBOMe); and 5-(2-aminopropyl)indole (5-IT); and synthetic cathinones, e.g. mephedrone; 3,4-methylenedioxypyrovalerone (MDPV); methylone; butylone; NRG3; alpha-methyltryptamine (AMT); methoxphenidine (MXP); and the antidepressant bupropion. Bupropion was here misused at high dosages and/or in combination with other licit/illicit serotonergic drugs. Whilst most substances were ingested orally, nasal insufflation (with both 5-IT and 2C-I) and sublingual administration of blotter paper (with 25I-NBOMe) were reported as well. Interestingly, the psychiatric history was negative for most subjects, apart from two cases. Clinicians should be aware of NPS potential risks and the severe consequences of their recreational use, including SS. Also, due to their undetectability in routine and common drug screenings, the diagnostic challenges posed by NPS should not be underestimated during the treatment of such patients.

The Psychonauts' World of Cognitive Enhancers.

BACKGROUND: There is growing availability of novel psychoactive substances (NPS), including cognitive enhancers (CEs) which can be used in the treatment of certain mental health disorders. While treating cognitive deficit symptoms in neuropsychiatric or neurodegenerative disorders using CEs might have significant benefits for patients, the increasing recreational use of these substances by healthy individuals raises many clinical, medico-legal, and ethical issues. Moreover, it has become very challenging for clinicians to keep up-to-date with CEs currently available as comprehensive official lists do not exist. METHODS: Using a web crawler (NPSfinder®), the present study aimed at assessing psychonaut fora/platforms to better understand the online situation regarding CEs. We compared NPSfinder® entries with those from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and from the United Nations Office on Drugs and Crime (UNODC) NPS databases up to spring 2019. Any substance that was identified by NPSfinder® was considered a CE if it was either described as having nootropic abilities by psychonauts or if it was listed among the known CEs by Froestl and colleagues. RESULTS: A total of 142 unique CEs were identified by NPSfinder®. They were divided into 10 categories, including plants/herbs/products (29%), prescribed drugs (17%), image and performance enhancing drugs (IPEDs) (15%), psychostimulants (15%), miscellaneous (8%), Phenethylamines (6%), GABAergic drugs (5%), cannabimimetic (4%), tryptamines derivatives (0.5%), and piperazine derivatives (0.5%). A total of 105 chemically different substances were uniquely identified by NPSfinder®. Only one CE was uniquely identified by the EMCDDA; no CE was uniquely identified by the UNODC. CONCLUSIONS: These results show that NPSfinder® is helpful as part of an Early Warning System, which could update clinicians with the growing numbers and types of nootropics in the increasingly difficult-to-follow internet world. Improving clinicians' knowledge of NPS could promote more effective prevention and harm reduction measures in clinical settings.

Novel Opioids: Systematic Web Crawling Within the e-Psychonauts' Scenario.

BACKGROUND: A wide range of novel psychoactive substances (NPSs) are regularly searched and discussed online by e-psychonauts. Among NPSs, the range of prescription/non-prescription opioids (fentanyl and non-fentanyl analogs) and herbal derivatives currently represents a challenge for governments and clinicians. METHODS: Using a web crawler (i.e., NPS.Finder®), the present study aimed at assessing psychonaut fora/platforms to better understand the online situation regarding opioids. RESULTS: The open-web crawling/navigating software identified some 426 opioids, including 234 fentanyl analogs. Of these, 176 substances (162 were very potent fentanyls, including two ohmefentanyl and seven carfentanyl analogs) were not listed in either international or European NPS databases. CONCLUSION: A web crawling approach helped in identifying a large number, indeed higher than that listed by European/international agencies, of unknown opioids likely to possess a significant misuse potential. Most of these novel/emerging substances are still relatively unknown. This is a reason of concern; each of these analogs potentially presents with different toxicodynamic profiles, and there is a lack of docking, preclinical, and clinical observations. Strengthening multidisciplinary collaboration between clinicians and bioinformatics may prove useful in better assessing public health risks associated with opioids.

The e-Psychonauts' 'Spiced' World; Assessment of the Synthetic Cannabinoids' Information Available Online.

BACKGROUND: A wide range of novel psychoactive substances (NPS) is regularly searched and discussed online by web-based drug enthusiasts (i.e. the e-psychonauts). Among NPS, the range of synthetic cannabinoids (SC; 'Spice') currently represents a challenge for governments and clinicians. METHODS: Using a web crawler (i.e. the NPS.Finder®), the present study aimed at assessing psychonauts' fora/platforms to better understand the online mentions of SC. RESULTS: The open-web crawling/navigating software identified here some 1,103 synthetic cannabinoids. Of these, 863 molecules were not listed in either the international or the European NPS databases. CONCLUSION: A web crawling approach helped here in identifying a large range of unknown SC likely to possess a misuse potential. Most of these novel/emerging molecules are still relatively unknown. This is a reason for concern; each of these analogues potentially presents different toxicodynamic profiles and there is a lack of docking, preclinical, and clinical observations. Strengthening multidisciplinary collaboration between clinicians and bioinformatics may prove useful in better assessing SC-associated public health risks.

The clinical challenges of synthetic cathinones.

AIMS: Within the new psychoactive substances (NPS) scenario, several hundred different molecules, mostly including synthetic cannabinoids and cathinones, have been identified so far. The aims of the paper were to: (i) identify the number of synthetic cathinones mentioned in a range of psychonaut, NPS-related, online sources; and (ii) describe the associated acute/long term clinical scenario and the related treatment/management plan. METHODS: After about 18 months of operation and exclusion of false positives/duplicates, some 4204 unique NPS molecules were included in the NPSfinder® crawling/navigating software database. Most popular NPS included: 1265 psychedelic phenethylamines (30.1%; confidence interval [CI] 95%: 28.7-31.5%); 1253 synthetic cannabinoids (29.8%; CI 95%: 28.4-31.2%); 429 synthetic opioids (10.2%; CI 95%: 9.3-10.2%); and 171 synthetic cathinones (4.1%; CI 95% 3.5-4.7%). Conversely, the United Nations Office on Drugs and Crime and the European Monitoring Centre for Drugs and Drug Addiction databases respectively included 169 and 140 cathinones. Overall, the 3 databases reported some 222 synthetic cathinones, and 41 were uniquely identified by the NPSfinder®. RESULTS: In terms of clinical scenarios, synthetic cathinone ingestion is initially associated with stimulant effects; however, psychopathological disturbances, violence, suicidal behaviour, hyperthermia, coma and death have also been described. CONCLUSION: The proportion of cathinones commented on by psychonaut fora appeared to be relatively small, and similar to those reported by both the United Nations Office on Drugs and Crime and European Monitoring Centre for Drugs and Drug Addiction. This may be associated with a recent significant decline in both cathinone-related consumption and acute medical presentation. Due to their complex behavioural and medical toxicity issues, healthcare professionals should be, however, be educated to recognise the signs and symptoms of NPS, including synthetic cathinone, ingestion.

Neurobiological Evidence for the Primacy of Mania Hypothesis.

BACKGROUND: Athanasios Koukopoulos proposed the primacy of mania hypothesis (PoM) in a 2006 book chapter and later, in two peer-reviewed papers with Nassir Ghaemi and other collaborators. This hypothesis supports that in bipolar disorder, mania leads to depression, while depression does not lead to mania. OBJECTIVE: To identify evidence in literature that supports or falsifies this hypothesis. METHOD: We searched the medical literature (PubMed, Embase, PsycINFO, and the Cochrane Library) for peer-reviewed papers on the primacy of mania, the default mode function of the brain in normal people and in bipolar disorder patients, and on illusion superiority until 6 June, 2016. Papers resulting from searches were considered for appropriateness to our objective. We adopted the PRISMA method for our review. The search for consistency with PoM was filtered through the neurobiological results of superiority illusion studies. RESULTS: Out of a grand total of 139 records, 59 were included in our analysis. Of these, 36 were of uncertain value as to the primacy of mania hypothesis, 22 favoured it, and 1 was contrary, but the latter pooled patients in their manic and depressive phases, so to invalidate possible conclusions about its consistency with regard to PoM. All considered studies were not focused on PoM or superiority illusion, hence most of their results were, as expected, unrelated to the circuitry involved in superiority illusion. A considerable amount of evidence is consistent with the hypothesis, although indirectly so. LIMITATIONS: Only few studies compared manic with depressive phases, with the majority including patients in euthymia. CONCLUSION: It is possible that humans have a natural tendency for elation/optimism and positive self-consideration, that are more akin to mania; the depressive state could be a consequence of frustrated or unsustainable mania. This would be consistent with PoM.

Child and Adolescent Clinical Features Preceding Adult Suicide Attempts.

The objective of this study was to identify the predictive value of juvenile factors for adult suicidal behavior. We reviewed clinical records to compare factors identified in childhood and adolescence between adult suicidal versus nonsuicidal major affective disorder subjects. Suicide attempts occurred in 23.1% of subjects. Age-at-first-symptom was 14.2 vs. 20.2 years among suicidal versus nonsuicidal subjects (p < 0.0001). More prevalent in suicidal versus non-suicidal subjects by multivariate analysis were: depressive symptoms, hyper-emotionality, younger-at-first-affective-episode, family suicide history, childhood mood-swings, and adolescence low self-esteem. Presence of one factor yielded a Bayesian sensitivity of 64%, specificity of 50%, and negative predictive power of 86%. Several juvenile factors were associated with adult suicidal behavior; their absence was strongly associated with a lack of adult suicidal behavior.

Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia.

The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.

Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels.

Electroconvulsive therapy (ECT) is effective in treatment-resistant depression (TRD). It may act through intracellular process modulation, but its exact mechanism is still unknown. Animal research supports a neurotrophic effect for ECT. We aimed to investigate the association between changes in serum brain-derived neurotrophic factor (sBDNF) levels and clinical improvement following ECT in patients with TRD. Twenty-one patients with TRD (2 men, 19 women; mean age, 63.5 years; S.D., 11.9) were assessed through the Hamilton Depression Rating Scale (HDRS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impressions scale, Severity (CGIs) before and after a complete ECT cycle. At the same time-points, patients underwent blood withdrawal for measuring sBDNF levels. ECT significantly reduced HDRS, BPRS, and CGIS scores, but not sBDNF levels. No significant correlation was found between sBDNF changes, and each of HDRS, BPRS, and CGIs score changes. sBDNF levels in TRD patients were low both at baseline and post-ECT. Our results do not support that improvements in TRD following ECT are mediated through increases in sBDNF levels.

Features preceding diagnosis of bipolar versus major depressive disorders.

BACKGROUND: Better and earlier predictive differentiation of bipolar (BD) vs. unipolar major depressive disorder (UD) diagnoses should improve long-term clinical planning. METHODS: We reviewed randomly selected clinical records of 334 adults diagnosed with DSM-IV-TR BD-I (n=109), BD-II (n=106), and UD (n=119) and compared features preceding major affective episodes or diagnoses, using bivariate, multivariate, and Bayesian methods. RESULTS: We identified antecedents selectively associated with later BD vs. UD in 52.6% vs. 31.1% of subjects in childhood, starting at age 7.4 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than UD cases (10.3 vs. 4.64/100 person-years; p<0.001). In multivariate modeling, BD-selective factors were: younger at first clinical event > male sex > family BD-history > cyclothymic or hyperthymic temperament > antecedents/person-year. Nonaffective (anxiety, eating, or substance-use) disorders preceded BD vs. UD in 41.4% vs. 28.6% of subjects (p=0.02). By ROC analysis, differential prediction of BD vs. UD was optimal with any ≥ 3 factors/person. LIMITATIONS: The validity and timing of antecedent events and factors identified retrospectively from clinical records could not be verified independently, but information was recorded systematically and consistently by a single mood-disorder expert prior to diagnosis, and extracted by two independent observers. COMMENT: Early clinical features distinguished later BD from UD, often by years. Such prediction should improve treatment-planning and limit risk of mood-switching.

Mixed depression: clinical features and predictors of its onset associated with antidepressant use.

BACKGROUND: Mixed depression (MxD) is narrowly defined in the DSM-IV and somewhat broader in the DSM-5, although both exclude psychomotor agitation as a diagnostic criterion. This article proposes a clinical description for defining MxD, which emphasizes psychomotor excitation. METHODS: Two hundred and nineteen consecutive outpatients were diagnosed with an MxD episode using criteria proposed by Koukopoulos et al. [Acta Psychiatr Scand 2007;115(suppl 433):50-57]; we here report their clinical features and antidepressant-related effects. RESULTS: The most frequent MxD symptoms were: psychic agitation or inner tension (97%), absence of retardation (82%), dramatic description of suffering or weeping spells (53%), talkativeness (49%), and racing or crowded thoughts (48%). MxD was associated with antidepressants in 50.7% of patients, with similar frequency for tricyclic antidepressants (45%) versus selective serotonin reuptake inhibitors (38.5%). Positive predictors of antidepressant-associated MxD were bipolar disorder type II diagnosis, higher index depression severity, and higher age at index episode. Antipsychotic or no treatment was protective against antidepressant-associated MxD. CONCLUSIONS: MxD, defined as depression with excitatory symptoms, can be clinically identified, is common, occurs in both unipolar depression and bipolar disorder, and is frequently associated with antidepressant use. If replicated, this view of MxD could be considered a valid alternative to the DSM-5 criteria for depression with mixed features.

Koukopoulos׳ diagnostic criteria for mixed depression: a validation study.

BACKGROUND: Mixed depression (MxD) is one subtype of depressive experiences within the depressive spectrum. MxD definition is debated among experts. Koukopoulos׳ proposed diagnostic criteria focused primarily on psychic agitation, marked irritability, and intense mood lability as markers of a mixed depressive episode. The present study validates Koukopoulos׳ criteria as diagnostic for MxD. METHODS: A sample of 435 patients from the International Mood Network (IMN), multi-center, international network of sites, and the Centro LucioBini of Rome was analyzed. Koukopoulos׳ criteria were assessed in all patients. RESULTS: The most prevalent MxD criteria were "absence of psychomotor retardation" (84%), "mood lability or marked reactivity" (78%), and "psychic agitation or inner tension" (75%). Multivariable predictors of a MxD (+) diagnosis were: higher current CGI (OR=1.23, 95% CI 1.23, 2.84), lower rates of previous bipolar type I diagnosis (OR=0.54, 95% CI -3.28, -0.13), mixed symptoms on the index episode (OR=10.02, 95% CI 2.32, 24.12), rapid cycling course (OR=2.6 95% CI 1.45, 3.56), past substance abuse (OR=3.02, 95% CI 2.01, 5.67) and lower education status (OR=0.44, 95% CI -3.23, -0.98). This model showed a sensitivity of 76.4%, specificity of 86.3%, negative predictive value of 75%, and positive predictive value of 86%. LIMITATIONS: An external validation of these criteria in an independent sample is warranted. CONCLUSION: A broad definition of mixed depression was internally validated with multiple diagnostic validators and was sensitively and specifically predicted. Contrary to DSM-5, Koukopoulos׳ broad criteria include agitation, irritability and mood lability as core features.

Treatment of menstrual migraine: utility of control of related mood disturbances.

Menstrual migraine (MM) has a prevalence in the general population of approximately 7%, although it seems to be much higher within the population of females with migraine. Episodes of MM have been reported to be longer, more intense, more disabling, less responsive to acute therapy and more prone to recurrence than those of other types of migraine. MM is demonstrated to have a bi-directional link to affective illnesses such as premenstrual dysphoric disorder and depression. There is clinical and pathophysiological evidence suggesting that the relationship between MM and affective disorders could be linked to ovarian hormones. The aim of this review is to analyze treatment strategies in patients with co-existent MM and affective disorders.

Low-dose acetazolamide in the treatment of premenstrual dysphoric disorder: a case series.

The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms.

Sumatriptan in clinical practice: effectiveness in migraine and the problem of psychiatric comorbidity.

Migraine is a multifactorial and disabling syndrome often in comorbidity with psychiatric illnesses. Triptans are the first-line treatment in acute attacks and the most effective drugs in various types of migraine. Sumatriptan was the first medication of this group. Thanks to multiple types of formulations that greatly increase patient's compliance, sumatriptan is so far the most commonly used drug for moderate-to-severe acute migraine attacks. Although generally safe and well tolerated, sumatriptan has to be carefully administered in patients suffering from various types of medical conditions (such as cardiovascular and cerebrovascular disease and some psychiatric illnesses) and/or treated with various medications (such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors). The administration of sumatriptan in some psychiatric condition in which serotonin plays an important role (i.e., major depressive disorder and obsessive-compulsive disorder) has been underestimated so far. In fact, at present, literature studies are few, with non-conclusive and often contrasting findings. Thus, sumatriptan should continue to be used with caution in patients diagnosed with psychiatric illness and/or treated with drugs where serotonin is crucially involved in, until further data demonstrating complete safety become available.