Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial

Medication overuse headache (MOH) is a severe burden to sufferers and its treatment has few evidence-based indications. The aim of this study is to evaluate efficacy and safety of nabilone in reducing pain and frequency of headache, the number of analgesic intake and in increasing the quality of life on patients with long-standing intractable MOH. Thirty MOH patients were enrolled at the University of Modena’s Interdepartmental Centre for Research on Headache and Drug Abuse (Italy) in a randomized, double-blind, active-controlled, crossover study comparing nabilone 0.5 mg/day and ibuprofen 400 mg. The patients received each treatment orally for 8 weeks (before nabilone and then ibuprofen or vice versa), with 1 week wash-out between them. Randomization and allocation (ratio 1:1) were carried out by an independent pharmacy through a central computer system. Participants, care givers, and those assessing the outcomes were blinded to treatment sequence. Twenty-six subjects completed the study. Improvements from baseline were observed with both treatments. However, nabilone was more effective than ibuprofen in reducing pain intensity and daily analgesic intake (p < 0.05); moreover, nabilone was the only drug able to reduce the level of medication dependence (−41 %, p < 0.01) and to improve the quality of life (p < 0.05). Side effects were uncommon, mild and disappeared when nabilone was discontinued. This is the first randomized controlled trial demonstrating the benefits of nabilone on headache, analgesic consumption and the quality of life in patients with intractable MOH. This drug also appears to be safe and well-tolerated. Larger scale studies are needed to confirm these preliminary findings.     

Prospective analysis of factors related to migraine attacks: the PAMINA study

Migraine is related to numerous factors such as hormones, stress or nutrition, but information about their actual importance is limited. Therefore, we analysed prospectively a wide spectrum of factors related to headache in migraineurs. We examined 327 migraineurs recruited via newspapers who kept a comprehensive diary for 3 months. Statistical analysis comprising 28 325 patient days and 116 dichotomous variables was based on the interval between two successive headache attacks. We calculated univariate Cox regression analyses and included covariables with a P-value of <0.05 in two stepwise multivariate Cox regression analyses, the first accounting for a correlation of the event times within a subject, the second stratified by the number of headache-free intervals. We performed similar analyses for the occurrence of migraine attacks and for the persistence of headache and migraine. Menstruation had the most prominent effect, increasing the hazard of occurrence or persistence of headache and migraine by up to 96%. All other factors changed the hazard by <35%. The two days before menstruation and muscle tension in the neck, psychic tension, tiredness, noise and odours on days before headache onset increased the hazard of headache or migraine, whereas days off, a divorced marriage, relaxation after stress, and consumption of beer decreased the hazard. In addition, three meteorological factors increased and two others decreased the hazard. In conclusion, menstruation is most important in increasing the risk of occurrence and persistence of headache and migraine. Other factors increase the risk less markedly or decrease the risk.     

Prevalence of headache in Europe: a review for the Eurolight project

The main aim of the present study was to do an update on studies on headache epidemiology as a preparation for the multinational European study on the prevalence and burden of headache and investigate the impact of different methodological issues on the results. The study was based on a previous study, and a systematic literature search was performed to identify the newest studies. More than 50% of adults indicate that they suffer from headache in general during the last year or less, but when asked specifically about tension-type headache, the prevalence was 60%. Migraine occurs in 15%, chronic headache in about 4% and possible medication overuse headache in 1–2%. Cluster headache has a lifetime prevalence of 0.2–0.3%. Most headaches are more prevalent in women, and somewhat less prevalent in children and youth. Some studies indicate that the headache prevalence is increasing during the last decades in Europe. As to methodological issues, lifetime prevalences are in general higher than 1-year prevalences, but the exact time frame of headache (1 year, 6 or 3 months, or no time frame stated) seems to be of less importance. Studies using personal interviews seem to give somewhat higher prevalences than those using questionnaires.     

The impact of COVID-19 pandemic on headache symptoms and drug withdrawal among patients with medication overuse headache: a cross-sectional study

BackgroundCoronavirus disease 2019 (COVID-19) bring about a range of psychological distress and symptom deterioration to headache patients especially to some migraineurs. Compared to migraineurs or normal control, medication overuse headache (MOH) patients are more likely to experience a worse psychological distress and poorer outcome in non-COVID-19 time. However, in COVID-19 pandemic, whether MOH patients would have greater physical and mental symptom deterioration or worse relief of headache symptoms and medications overuse remained unclear. We aim to investigate the impact of COVID-19 on MOH patients to guide for a better management in this study.MethodsWe enrolled MOH patients who were diagnosed and treated at headache clinic of West China Hospital. Information of the pre-pandemic 3 months period and COVID-19 pandemic period was collected. Univariate and multivariate logistic regression were performed to identify independent factors associated with changes in headache symptoms and drug withdrawal.ResultsSeventy-eight MOH patients were enrolled into the study ultimately. In comparison to pre-pandemic period, fewer MOH patients reported decreased headache days, intensity and days with acute medications per month during the pandemic. Available access to regular prophylactic medications was significantly associated with a reduction of at least 50% in headache days and decrease in headache intensity per month with respective odds ratios of 39.19 (95% CI 3.75–409.15, P = 0.002) and 10.13 (95% CI 2.33–44.12, P = 0.002). Following abrupt withdrawal and high educational level were both significant factors in decreasing headache intensity. Male sex was significantly associated with decrease in days with acute medication per month during the pandemic (odds ratios 4.78, 95%CI 1.44–15.87, P = 0.011).ConclusionsOur findings reflect that MOH patients experienced a worse relief of headache symptoms and drug withdrawal during the pandemic. Available access to regular prophylactic medications was the significant independent factor for improvement of headache symptoms. Male sex was significantly associated with decreased days with acute medications per month.     

Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres

Aim of this study was to determine whether menstrual attacks differ from nonmenstrual attacks (NMA) as regards clinical features or response to abortive treatment in women affected by menstrually related migraine (MRM) referred to tertiary care centres. Sixty-four women with MRM were enrolled in a 2-month diary study. Perimenstrual attacks were split into three groups--premenstrual (PMA), menstrual (MA) and late menstrual (LMA)--and compared to nonmenstrual ones. Perimenstrual attacks were significantly longer than NMA. No other migraine attack features were found to differ between the various phases of the cycle. Migraine work-related disability was significantly greater in PMA and MA than in NMA. Acute attack treatment was less effective in perimenstrual attacks. Pain-free at 2 h after dosage was achieved in 13.5% of MA (OR 0.41; 95% CI 0.22, 0.76) vs. 32.9% of NMA. We concluded that, in MRM, perimenstrual attacks are longer and less responsive to acute attack treatment than NMA.     

Impact of headache in Europe: a review for the Eurolight project

A recent health economic survey in Europe has suggested that migraine is the costliest among the neurological disorders. According to many studies, migraine and other disorders lead to widespread suffering, reduction of quality of life, and marked impairment of participation, both in work and social activities. The present literature survey was made in order to summarize what is known on the subject, as a preparation for a EU-supported study to assess the impact in several EU countries with similar methodology and the same research instrument. Previous studies have yielded relatively reliable data only for migraine, whereas the impact of tension-type headache is virtually unknown or only very incompletely known for most dimensions of headache impact. Some data do suggest, however, that this headache may be as important from a health economic and a public health perspective as migraine. In future studies it is important to get population-based data from various countries relevant for estimation of indirect (mostly absenteeism from work and reduced working efficiency when having headache) and direct costs (related to medication, consultations, investigations and hospitalisations). Also, the impact on ability to get education and participate in the workforce is very relevant, as is the impact on love life and family planning. The quality of life of headache patients should be measured by validated instruments. To get a complete picture, one should also ask about the effect on the life of partners and children, and on the possible impact even when headache-free (e.g. fear of the next attack).     

Medication use in patients with migraine and medication-overuse headache: the role of problem-solving and attitudes about pain medication

Excessive medication intake is a risk factor for the development of medication-overuse headache (MOH), a condition characterized by an increase of headache frequency to a daily or near-daily pattern. As yet, it is largely unknown why some patients overuse medication. In this study, we examined to what extent attitudes about pain medication, especially perceived need and concerns, and problem-solving are related to MOH. Patients with migraine (n = 133) and MOH with a history of migraine (n = 42) were recruited from a tertiary headache referral center and completed questionnaires measuring problem-solving and attitudes about pain medication. A problem-solving mode aimed at solving pain was associated with a higher need for and concerns about medication intake. Interestingly, in a model accounting for demographic factors and pain intensity, attempts to control pain, need for medication, and concerns about scrutiny by others because of medication intake all had a unique value in accounting for MOH. Results are discussed in terms of how repeated attempts to solve pain may trigger overuse of medication, even in the presence of clear negative consequences.     

Characteristics of headache in migraine without aura and episodic tension-type headache in the Turkish population according to the IHS classification

We evaluated the characteristics of headache in migraine without aura and episodic tension-type headache diagnosed according to the International Headache Society (IHS) Classification. Fifty migraine without aura and 50 tension-type headache patients were selected prospectively. Fifty-eight percent of migraineurs had pain of a pulsating quality; 88% had severe pain and 74% had unilateral pain; aggravation by routine physical activity was reported by 96%. Episodic tension-type headache was of a pressing quality in 52%, moderate in 40%, bilateral in 82% and aggravated by routine physical activity in 16%. Nausea and/or vomiting, photophobia and phonophobia were reported significantly more commonly in migraineurs than tension-type headache patients.     

Placebo and other psychological interactions in headache treatment

We present a theory according which a headache treatment acts through a specific biological effect (when it exists), a placebo effect linked to both expectancy and repetition of its administration (conditioning), and a non-specific psychological effect. The respective part of these components varies with the treatments and the clinical situations. During antiquity, suggestions and beliefs were the mainstays of headache treatment. The word placebo appeared at the beginning of the eighteenth century. Controversies about its effect came from an excessive interpretation due to methodological bias, inadequate consideration of the variation of the measure (regression to the mean) and of the natural course of the disease. Several powerful studies on placebo effect showed that the nature of the treatment, the associated announce, the patients’ expectancy, and the repetition of the procedures are of paramount importance. The placebo expectancy is associated with an activation of pre-frontal, anterior cingular, accumbens, and periacqueducal grey opioidergic neurons possibly triggered by the dopaminergic meso-limbic system. In randomized control trials, several arms design could theoretically give information concerning the respective part of the different component of the outcome and control the natural course of the disease. However, for migraine and tension type headache attacks treatment, no three arm (verum, placebo, and natural course) trial is available in the literature. Indirect evidence of a placebo effect in migraine attack treatment, comes from the high amplitude of the improvement observed in the placebo arms (28% of the patients). This figure is lower (6%) when using the harder criterium of pain free at 2 h. But these data disregard the effect of the natural course. For prophylactic treatment with oral medication, the trials performed in the last decades report an improvement in 21% of the patients in the placebo arms. However, in these studies the duration of administration was limited, the control of attacks uncertain as well as the evolution of the co-morbid psycho-pathology. Considering the reviews and meta-analysis of complex prophylactic procedures, it must be concluded that their effect is mostly linked to a placebo and non-specific psychological effects. Acupuncture may have a slight specific effect on tension type headache, but not on migraine. Manual therapy studies do not exhibit difference between manipulation, mobilization, and controls; touch has no proven specific effect. A comprehensive efficacy review of biofeedback studies concludes to a small specific effect on tension type headache but not on migraine. A review of behavioral treatment conclude to an interesting mean improvement but did not demonstrated a specific effect with the exception of a four arm study including a pseudo meditation control group. Expectation-linked placebo, conditioning, and non-specific psychological effects vary according clinical situations and psychological context; likely low in RCT, high after anempathic medical contact, and at its maximum with a desired charismatic healer. The announcements of doctors strongly influence the beliefs of patients, and in consequence their pain and anxiety sensibilities; this modulates the amplitude of the placebo and the non-specific psychological effects and is therefore a major determinant of the therapeutic success. Furthermore, any repetitive contact, even through a placebo, may interfere positively with the psychopathological co-morbidity. One has to keep in mind that the non-specific psychological interactions play a major role in the improvement of the majority of the headache sufferers.     

Investigation of cortical thickness and volume during spontaneous attacks of migraine without aura: a 3-Tesla MRI study

BackgroundStructural imaging has revealed changes in cortical thickness in migraine patients compared to healthy controls is reported, but presence of dynamic cortical and subcortical changes during migraine attack versus inter-ictal phase is unknown. The aim of the present study was to investigate possible changes in cortical thickness during spontaneous migraine attacks. We hypothesized that pain-related cortical area would be affected during the attack compared to an inter-ictal phase.MethodsTwenty-five patients with migraine without aura underwent three-dimensional T1-weighted imaging on a 3-Tesla MRI scanner during spontaneous and untreated migraine attacks. Subsequently, 20 patients were scanned in the inter-ictal phase, while 5 patients did not show up for the inter-ictal scan. Four patients were excluded from the analysis because of bilateral migraine pain and another one patient was excluded due to technical error in the imaging. Longitudinal image processing was done using FreeSurfer. Repeated measures ANOVA was used for statistical analysis and to control for multiple comparison the level of significance was set at p = 0.025.ResultsIn a total of 15 patients, we found reduced cortical thickness of the precentral (p = 0.023), pericalcarine (p = 0.024), and temporal pole (p = 0.017) cortices during the attack compared to the inter-ictal phase. Cortical volume was reduced in prefrontal (p = 0.018) and pericalcarine (p = 0.017) cortices. Hippocampus volume was increased during attack (p = 0.007). We found no correlations between the pain side or any other clinical parameters and the reduced cortical size.ConclusionSpontaneous migraine attacks are accompanied by transient reduced cortical thickness and volume in pain-related areas. The findings constitute a fingerprint of acute pain in migraine patients, which can be used as a possible biomarker to predict antimigraine treatment effect in future studies.Trial registrationThe study was registered at ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02202486","term_id":"NCT02202486"}}NCT02202486).     

Migraine headache and obesity in women aged 40-74 years: a population-based study

This study investigates the associations between obesity and migraine. A neurologist clinically assessed 684 women aged 40-74 years attending a population-based mammography screening programme. Body height and weight were measured and body mass index (BMI) calculated. Obesity was defined as a BMI > or = 30 kg/m2. The proportion of obesity did not differ between women with active migraine, women with inactive migraine or women who had never experienced migraine (P = 0.96). The distribution of frequency, intensity, duration or severity of attacks did not differ between obese and non-obese women with migraine. In this study there were no significant associations between migraine or migraine characteristics on the one hand and obesity on the other.     

One-year prevalence and the impact of migraine and tension-type headache in Turkey: a nationwide home-based study in adults

Several studies have shown that the prevalence of migraine and tension-type headache (TTH) varied between different geographical regions. Therefore, there is a need of a nationwide prevalence study for headache in our country, located between Asia and Europe. This nationwide study was designed to estimate the 1-year prevalence of migraine and TTH and analyse the clinical features, the impact as well as the demographic and socio-economic characteristics of the participant households in Turkey. We planned to investigate 6,000 representative households in 21 cities of Turkey; and a total of 5,323 households (response rate of 89%) aged between 18 and 65 years were examined for headache by 33 trained physicians at home on the basis of the diagnostic criteria of the second edition of the International Classification of Headache Disorders (ICHD-II). The electronically registered questionnaire was based on the headache features, the associated symptoms, demographic and socio-economic situation and history. Of 5,323 participants (48.8% women; mean age 35.9 ± 12 years) 44.6% reported recurrent headaches during the last 1 year and 871 were diagnosed with migraine at a prevalence rate of 16.4% (8.5% in men and 24.6% in women), whereas only 270 were diagnosed with TTH at a prevalence rate of 5.1% (5.7% in men and 4.5% in women). The 1-year prevalence of probable migraine was 12.4% and probable TTH was 9.5% additionally. The rate of migraine with aura among migraineurs was 21.5%. The prevalence of migraine was highest among 35–40-year-old women while there were no differences in age groups among men and in TTH overall. More than 2/3 of migraineurs had ever consulted a physician whereas only 1/3 of patients with TTH had ever consulted a physician. For women, the migraine prevalence was higher among the ones with a lower income, while among men, it did not show any change by income. Migraine prevalence was lower in those with a lower educational status compared to those with a high educational status. Chronic daily headache was present in 3.3% and the prevalence of medication overuse headache was 2.1% in our population. There was an important impact of migraine with a monthly frequency of 5.9 ± 6, and an attack duration of 35.1 ± 72 h, but only 4.9% were on prophylactic treatment. The one-year prevalence of migraine estimated as 16.4% was similar or even higher than world-wide reported migraine prevalence figures and identical to a previous nation-wide study conducted in 1998, whereas the TTH prevalence was much lower using the same methodology with the ICHD-II criteria.     

Chronic daily headache in a primary care population: prevalence and headache impact test scores

BACKGROUND: Population-based surveys estimate the prevalence of chronic daily headache (CDH) in the general community to be approximately 4%. The prevalence of CDH among patients seen in the primary care setting in the United States, however, is unknown. PURPOSE: To estimate the prevalence and associated burden of suffering of CDH in a primary care patient population. METHODS: Cross-sectional survey of a randomly selected sample of 1500 adult patients in an academic Family Medicine Center was done. Outcome measures include self-reported headache frequency and Headache Impact Test scores. RESULTS: Completed questionnaires were returned by 853 (57%) patients. The mean age of respondents was 49 years (SD = 16), with a range of 18 to 94 years. Two hundred ninety-six (58%) patients reported having had 1 or more severe headaches in the past month. Seventy-four (9%) patients reported a frequency of headache consistent with CDH, defined as the occurrence of headache 15 or more days in the past month. Twenty-four patients (32%) with CDH either believed that none of their doctors know that they experienced headaches or were not sure if their doctors were aware of their headaches, and 21 (28%) reported that they have not needed a doctor's care for their headaches. CONCLUSIONS: The prevalence of CDH is greater among a primary care patient population compared to the general community. A substantial proportion of patients with CDH do not bring their headaches to the attention of their health-care providers. In light of the advances in the development of effective medications for migraines and the growing body of evidence implicating medications as a contributing cause of CDH, it may be appropriate to encourage patients to inform their health-care providers about their headaches and to encourage providers to identify patients with frequent headaches.     

Treatment with sumatriptan 50 mg in the mild phase of migraine attacks in patients with infrequent attacks: a randomised, double-blind, placebo-controlled study

Most migraine patients with infrequent attacks are currently not treated with migrainespecific medication such as triptans. The response of these patients to triptans is unknown. The objective of this study was to investigate the efficacy and tolerability of sumatriptan 50 mg vs. placebo in migraine patents with infrequent migraine attacks when medication is taken during the mild phase of an attack. The study design was double-blind, placebocontrolled, parallel-group and randomised. Migraine patients were recruited by general practitioners and referred to one of 4 study centres. Additional patients were recruited by advertising. The patients were eligible for the study if they had between 6 and 12 migraine attacks with or without aura per year. The patients were instructed to take the medication during the mild phase of a single attack. The primary efficacy measure was the percentage of patients pain-free after 2 h. Fortysix percent of treated attacks were moderate or severe. In the intention-to-treat analysis, sumatriptan was superior (20/51 patients were pain-free) to placebo (8/47 patients pain-free) (p=0.03). Adverse events (AEs) occurred more frequently after sumatriptan (40%) than after placebo (13%) (p=0.003) and most AEs were mild or moderate. In this migraine population with infrequent attacks, sumatriptan was superior to placebo and was generally well tolerated.     

Acute pharmacotherapy of migraine,tension-type headache,and cluster headache

Abstract In most migraine patients acute therapy is needed. Migraine can be treated either with specific drugs, the triptans and ergot alkaloids, or with NSAIDs. Triptans are a major step foreward in migraine therapy. The therapeutic gain for headache relief is 50% for subcutaneous sumatriptan whereas it is 30-40% for most oral triptans. After oral triptans sustained pain free is only 30%. There is thus still ample room for improvement of acute therapy in migraine. For tension-type headache there is no specific therapy and it is treated with NSAIDs. Only 17-32% become pain free after these drugs. For attacks of cluster headache oxygen and subcutaneous sumatriptan can be used. Intranasal triptans can be an alternative.     

The comorbidity of migraine and hypertension. A study in a tertiary care headache centre

Literature data concerning the comorbidity of migraine and hypertension are conflicting and lacking in consistency [1–4]. This study was designed to evaluate the distribution of hypertension in a sample of migraineurs in comparison with a group of tensiontype headache (TTH) patients. Hypertension prevalence was more elevated in headache sufferers than in the general population. This finding might be due to a Berkson’s bias; in fact individuals seeking medical care often show a high rate of association between two medical conditions which may be independent in the general population [5]. The highest hypertension prevalence was found in patients with TTH, supporting the hypothesis that this type of headache might be based upon vascular mechanisms [6].     

The natural course of migraine attacks. A prospective analysis of untreated attacks compared with attacks treated with a triptan

This study was designed to document prospectively and explore scientifically the natural course of untreated migraine attacks in detail. A new, integrated, time-intensity method for self-assessment of the intensity of symptoms was tested on 18 adult International Headache Society migraineurs who volunteered to refrain from treatment during one attack. The area under the curves (AUC) during 72 h of untreated attacks was compared with attacks treated with a triptan. Migraine attacks are heterogeneous both inter- and intra-individually. In untreated attacks, the pain can stabilize and fluctuate around a plateau with a wavelength of hours. In general, the symptoms of each separate migraine attack follow a similar temporal course, with only moderate deviations. In some cases photo- and/or phonophobia (hyperexcitability) were not experienced at all, despite severe pain and nausea. Moreover, there was sometimes no nausea despite severe pain and hyperexcitability. Vomiting does not always correlate to the intensity of nausea and is not always followed by decreased headache intensity. Treatment with a triptan usually only temporarily distorts the basic pattern of attacks. Hyperexcitability can respond before pain to treatment. These genuine findings of the classic symptoms of migraine attacks support the notion of a mutual underlying pathophysiological mechanism.     

Oxygen treatment for cluster headache attacks at different flow rates: a double-blind,randomized, crossover study

Background

Cluster headache attacks can, in many patients, be successfully treated with oxygen via a non-rebreather mask. In previous studies oxygen at flow rates of both 7 L/min and 12 L/min was shown to be effective. The aim of this study was to compare the effect of 100% oxygen at different flow rates for the treatment of cluster headache attacks.

Methods

In a double-blind, randomized, crossover study, oxygen naïve cluster headache patients, treated attacks with oxygen at 7 and 12 L/min. The primary outcome measure was the percentage of attacks after which patients (treating at least 2 attacks/day) were painfree after 15 min, in the first two days of the study. Secondary outcome measures were percentage of successfully treated attacks, percentage of attacks after which patients were painfree, drop in VAS score and patient preference in all treatment periods (14 days).

Results

Ninety-eight patients were enrolled, 70 provided valid data, 56 used both flow rates. These 56 patients recorded 604 attacks, eligible for the primary analysis. An exploratory analysis was conducted using all eligible attacks of 70 patients who provided valid data. We could only include 5 patients, treating 27 attacks on the first two days of the study, for our primary outcome, which did not show a significant difference (p?=?0.180). Patients tended to prefer 12 L/min (p?=?0.005). Contradicting this result, more patients were painfree using 7 L/min (p?=?0.039). There were no differences in side effects or in our other secondary outcome measures. The exploratory analysis showed an odds ratio of being painfree using 12 L/min of 0.73 (95% CI 0.52–1.02) compared to 7 L/min (p?=?0.061) as scored on a 5-point scale. The average drop in score on this 5-point scale, however, was equal between groups. Also slightly more patients noticed, no or not much, relief on 7 L/min, and found 12 L/min to be effective in all their attacks.

Conclusion

There is lack of evidence to support differences in the effect of oxygen at a flow rate of 12 L/min compared to 7 L/min. More patients were painfree using 7 L/min, but our other outcome measures did not confirm a difference in effect between flow rates. As most patients prefer 12 L/min and treatments were equally safe, this could be used in all patients. It might be more cost-effective, however, to start with 7 L/min and, if ineffective, to switch to 12 L/min.

Trial registration

European Union Clinical Trials Register (2012–003648-59), registered 1 October 2012. Dutch Trial Register (NTR3801), registered 14 January 2013.

     

The transient syndrome of headache with neurological deficits, cerebrospinal fluid pleocytosis and acute confusional state: a case report

The syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) now referred to in the IHS ICHD–II code 7.8, is only infrequently accompanied by a confusional state and severe agitation. We report the case of a 34–year–old man who suffered from three episodes of headache with transient focal neurological deficits that were consistent with HaNDL but that were accompanied by an intense, confusional agitated state that required admission, in the first episode, in a psychiatric unit.