Volumetric study of brain MRI in a cohort of patients with neurotransmitter disorders.

PURPOSE: Inborn errors of neurotransmitters are rare monogenic diseases. In general, conventional neuroimaging is not useful for diagnosis. Nevertheless, advanced neuroimaging techniques could provide novel diagnosis and prognosis biomarkers. We aim to describe cerebral volumetric findings in a group of Spanish patients with neurotransmitter disorders. METHODS: Fifteen 3D T1-weighted brain images from the International Working Group on Neurotransmitter related Disorders Spanish cohort were assessed (eight with monoamine and seven with amino acid disorders). Volumes of cortical and subcortical brain structures were obtained for each patient and then compared with those of two healthy individuals matched by sex and age. RESULTS: Regardless of the underlying disease, patients showed a smaller total cerebral tissue volume, which was apparently associated with clinical severity. A characteristic volumetric deficit pattern, including the right Heschl gyrus and the bilateral occipital gyrus, was identified. In severe cases, a distinctive pattern comprised the middle and posterior portions of the right cingulate, the left superior motor area and the cerebellum. In succinate semialdehyde dehydrogenase deficiency, volumetric affection seems to worsen over life. CONCLUSION: Despite the heterogeneity and limited size of our cohort, we found novel and relevant data. Total volume deficit appears to be a marker of severity, regardless of the specific neurotransmitter disease and irrespective of the information obtained from conventional neuroimaging. Volumetric assessment of individual brain structures could provide a deeper knowledge about pathophysiology, disease severity and specific clinical traits.

Comparison of psychodrug prescription patterns in patients diagnosed with bipolar disorder and addiction.

OBJECTIVE: To describe if there are differences in the prescription of psychodrug at discharge between bipolar disorder patients with or without addiction. METHODS: We review all the psychotropic drugs dispensed to inpatients of a brief hospitalization psychiatric unit diagnosed as having bipolar disorder at time of discharge. We recluted 225 patients over 18 years old on their last manic episode, between the year 2000 and 2010. We classify them according to the comorbid presence or not of a substance abuse or dependence disorder. RESULTS: Prevalence of addiction was 24%. We found no differences between groups in the number of psychotropic drugs prescribed at discharge. The prescription pattern of mood stabilizers and benzodiazepines was similar in both groups. We detect differences in the total daily dose of antipsychotic, expressed as risperidone equivalents (5.86 ± 4.62 mg in addictions group versus 4.67 ± 3.20 mg in control group, p=0.042) and in the total daily dose of biperideno (4.80 ± 1.78 mg in addictions group versus 3.20 ± 1.03 mg in the control group, p=0.044). CONCLUSIONS: Contrary to our expectations, both groups were similar in psychopharmacological prescription patterns at discharge. However, those patients with substance abuse disorder had higher doses of antipsychotics and higher dose biperiden at discharge.

Mitochondrial Variation of Bottlenose Dolphins (Tursiops truncatus) from the Canary Islands Suggests a Key Population for Conservation with High Connectivity within the North-East Atlantic Ocean.

In recent decades, worldwide cetacean species have been protected, but they are still threatened. The bottlenose dolphin (Tursiops truncatus) is a vulnerable keystone species and a useful bioindicator of the health and balance of marine ecosystems in oceans all over the world. The genetic structure of the species is shaped by their niche specialization (along with other factors), leading to the classification of two ecotypes: coastal and pelagic. In this study, the genetic diversity, population structure, and ecotypes of bottlenose dolphins from the Canary Islands were assessed through the analysis of 49 new samples from biopsies and from stranded animals using the 636 bp portion of the mitochondrial control region and 343 individuals from databases (n = 392). The results reveal high genetic diversity in Canarian bottlenose dolphins (Hd = 0.969 and π = 0.0165) and the apparent lack of population genetic structure within this archipelago. High genetic structure (Fst, Φst) was found between the Canary Islands and coastal populations, while little to no structure was found with the pelagic populations. These results suggest that Canarian bottlenose dolphins are part of pelagic ecotype populations in the North Atlantic. The studied Special Areas of Conservation in the Canary Islands may correspond to a hotspot of genetic diversity of the species and could be a strategic area for the conservation of the oceanic ecotype of bottlenose dolphins.

Use of marine debris as nest material by ospreys.

The use of anthropogenic debris as nest-building materials may affect nest function. We study ospreys (Pandion haliaetus) on an island with scarce vegetation and high availability of beached marine debris. We describe the anthropogenic debris in osprey nests, evaluate the factors affecting its prevalence and abundance, and test its potential effects on breeding parameters. We also quantify plastic entanglements among adults and nestlings. Of the 36 studied nests, 92 % included non-natural items, with plastic being the most frequent material (88.9 %). Nests that were bigger and closer to the coast had more anthropogenic items. The abundance of anthropogenic items in nests did not correlate with osprey breeding parameters. We recorded two live entangled adult females, which represent 3.9 % of the adult population. Monitoring the abundance of anthropogenic debris and its effects on wildlife is necessary to guarantee long-term viability of coastal wildlife.

[Diabetes mellitus and Friedreich´s ataxia in a child: a complicated coexistence]. / Diabetes mellitus y ataxia de Friedreich en un niño: una difícil coexistencia.

Friedreich's ataxia is an autosomal recessive disease caused by trinucleotide repeat expansion, presenting among other systemic complications, diabetes mellitus. The appearance of motor clumsiness, with running and jumping difficulties in a 6-year-old boy prompted the genetic study of Friedreich's ataxia, confirming his diagnosis. After diagnosis, it was evaluated by Pediatric Cardiology, detecting the presence of non-obstructive hypertrophic cardiomyopathy, and by Pediatric Endocrinology, due to overweight. At 9 years of age, he was diagnosed with diabetes mellitus, a regimen of insulin treatment was initiated. During follow-up, he presented significant neurological deterioration, reaching the use of a wheelchair, which hinders adequate metabolic control. This is a report of a pediatric patient with Friedrich ataxia and diabetes mellitus.

La ataxia de Friedreich, de herencia autosómica recesiva causada por una expansión repetida de trinucleótidos se asocia, entre otras complicaciones sistémicas, con diabetes mellitus. La aparición de torpeza motriz, con dificultad en la carrera y el salto en un varón de 6 años motivaron el estudio genético para ataxia de Friedrich y permitieron confirmar el diagnóstico. Tres años más tarde, se diagnosticó diabetes mellitus y se inició el tratamiento con insulina. Durante el seguimiento, presentó un importante deterioro neurológico, con necesidad de usar silla de ruedas, lo que dificultó un adecuado control metabólico. Se presenta el manejo y la evolución de un paciente con ataxia de Friedreich y diabetes mellitus.

Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients.

BACKGROUND: Different factors may influence cognitive functioning in bipolar disorder such as the effect of subsyndromal symptoms, the history of psychotic symptomatology or substance abuse, negative symptomatology, chronicity, sleep disturbances, and hormonal factors. The effect of pharmacologic treatment on cognition is still uncertain because of an insufficient number of studies examining this issue. OBJECTIVE: The aims of this study were to compare neuropsychologic performance of treated bipolar patients with that of controls, including unmedicated patients and healthy subjects, as well as to evaluate possible neurocognitive differences among 3 different atypical antipsychotics. RESEARCH DESIGN AND METHODS: A total of 119 subjects were included in the study. Of 79 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition euthymic bipolar patients, 68 were treated with one atypical antipsychotic, quetiapine (n = 12), olanzapine (n = 26), or risperidone (n = 30). Sixteen patients were drug-free. The 4 groups were compared with a sample of drug-naïve patients and a healthy control group (n = 35) on several clinical and neuropsychologic variables, especially on the domains of attention, verbal memory, and executive functions. Euthymia was defined by a score of 6 or less at the Young Mania Rating Scale and a score of 8 or less at the Hamilton Depression Rating Scale for at least 6 months. RESULTS: The 5 groups did not differ in age, years of education, sex distribution, or estimated premorbid IQ. The 4 patients groups did not differ in chronicity, age of onset, total number of episodes, and number of hospitalizations. No differences were found regarding antipsychotic dosages between the groups. Bipolar patients performed poorly on most neuropsychologic measures as compared with healthy controls. After controlling for Hamilton Depression Rating Scale symptoms, no significant change in the results was observed. Because many patients with antipsychotic treatment had a history of psychotic symptoms, we performed multivariate analysis of covariance controlling for this variable. Bipolar patients taking 1 of the 3 antipsychotics presented with dose-independent significant deficits in most cognitive tasks compared with healthy controls. After several head-to-head group comparisons, the patients receiving quetiapine showed a better performance in learning task, short-term memory, and recognition task assessed with the California Verbal Learning Test and verbal fluency (P < .05). CONCLUSIONS: Our results confirm the findings of previous studies of cognitive deficits in bipolar disorder. Untreated euthymic patients showed better cognitive performance than did patients on atypical antipsychotics. Some iatrogenic-pharmacologic effect, therefore, cannot be excluded, but quetiapine seemed to be less associated with impairment in measures of verbal memory than olanzapine or risperidone. We suggest to use drugs in bipolar disorder with a lower risk of cognitive adverse effects. However, randomized controlled trials are urgently needed to give a definite answer to this critical problem.

Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis.

Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern atypical antipsychotics in bipolar depression. We systematically reviewed published or registered randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined through meta-analysis using risk ratio as an effect size with a 95% confidence interval (95% CI) and with a level of statistical significance of 5% (p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and one addressed both monotherapy and combination with an antidepressant. The two quetiapine trials analysed the safety and efficacy of two doses: 300 and 600 mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of 5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and 6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials) failed in the primary efficacy measure after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression.

Morbidity in 303 first-episode bipolar I disorder patients.

OBJECTIVES: To test the hypotheses that: (i) depressive-dysthymic-dysphoric (D-type) morbidity is more prevalent than manic-hypomanic-psychotic (M-type) morbidity even from first episodes of bipolar I disorder (BPD-I) and despite treatment; (ii) initial presentations predict later morbidity; (iii) morbidity varies internationally; and (iv) early and later morbidity are similar. METHODS: We followed SCID-based, DSM-IV BPD-I patients (n = 303) systematically and prospectively for two years to estimate the percent of weeks in specific morbid states from first lifetime major episodes. RESULTS: Total morbidity accounted for 44% of the first two years, and D-type exceeded M-type illnesses by 2.1-fold (30%/14%) among morbidities ranking: mixed states (major + minor) >or= dysthymia >or= mania >or= major depression > hypomania > psychosis. In 164 cases, morbidities at 0.5-2.5 and 2.5-4.5 years were very similar. Depressive or mixed initial episodes predicted a 3.6-fold excess of D-type morbidity, and initial M-type episodes predicted a 7.1-fold excess of M-type morbidity over two years. Morbidity in European (EU) sites was nearly half that in the U.S., and 22% greater overall among men than women. In five comparable studies, illness accounted for 54% of follow-up time, and the ratio of D/M morbidity averaged 3.0. CONCLUSIONS: In accord with four midcourse studies, morbidity from BPD-I onset, despite treatment by community standards, averaged 44%, was 68% D-type morbidity, and was strongly predicted by first-episode polarity. Lower morbidity in EU than U.S. sites may reflect differences in healthcare or social systems.

Phenotypically linked dichotomy in sea turtle foraging requires multiple conservation approaches.

Marine turtles undergo dramatic ontogenic changes in body size and behavior, with the loggerhead sea turtle, Caretta caretta, typically switching from an initial oceanic juvenile stage to one in the neritic, where maturation is reached and breeding migrations are subsequently undertaken every 2-3 years. Using satellite tracking, we investigated the migratory movements of adult females from one of the world's largest nesting aggregations at Cape Verde, West Africa. In direct contrast with the accepted life-history model for this species, results reveal two distinct adult foraging strategies that appear to be linked to body size. The larger turtles (n = 3) foraged in coastal waters, whereas smaller individuals (n = 7) foraged oceanically. The conservation implications of these findings are profound, with the population compartmentalized into habitats that may be differentially impacted by fishery threats in what is a global fishing hotspot. Although the protection of discrete areas containing coastal individuals may be attainable, the more numerous pelagic individuals are widely dispersed with individuals roaming over more than half a million square kilometers. Therefore, mitigation of fisheries by-catch for sea turtles in the east Atlantic will likely require complex and regionally tailored actions to account for this dichotomous behavior.

Safety and efficacy of Vagus Nerve Stimulation in treatment-resistant depression. A systematic review.

OBJECTIVE: The main objective of this review of the literature was to evaluate the safety and efficacy of Vagus Nerve Stimulation (VNS) in treatment-resistant depression (TRD) by means of systematic review and meta-analysis. METHODS: A systematic review of the literature was made using the major databases (Medline, Psychological Abstracts, Current Contents), beginning in January 2000 and ending in September 2007. Ninety-eight references were found, but only 18 add-on studies met the required quality criteria and were included in this review. Only one double-blind, randomized study was available and therefore a meta-analysis was not feasible. RESULTS: In a majority of the preliminary open studies selected for this review, VNS was associated with a significant reduction of the depressive symptoms (primary outcome: Hamilton Depression Rating Scale, HDRS) in the short and long term. Unfortunately, the only double-blind study gave rather inconclusive results. Generally, VNS is reported to be a safe and feasible procedure, despite its invasive nature. CONCLUSIONS: VNS seems to be an interesting new approach to treating TRD. However, despite the promising results reported mainly in open studies, further clinical trials are needed to confirm its efficacy in major depression. Moreover, studies on its mechanism of action and cost-effectiveness are also required to better understand and develop VNS therapy for affective disorder.

A long-term prospective study on the outcome of bipolar patients treated with long-acting injectable risperidone.

BACKGROUND: Risperidone is the first atypical antipsychotic to become available in a long-acting, injectable formulation. This is the first prospective study to assess the effectiveness of long-acting risperidone in a cohort of bipolar patients. METHODS: Twenty-nine DSM-IV acutely manic bipolar inpatients with a history of poor or partial adherence to medication entered the mirror-design observational study. They received naturalistic treatment for a manic episode plus long-acting, injectable risperidone for a mean period of 2 years. The following measures were used to assess the effectiveness of risperidone: the number of hospitalizations, the number of manic, mixed, and depressive episodes leading to hospitalization, the mean duration of hospitalizations, time to relapse, treatment adherence, aggression and suicide attempts. The Clinical Global Impressions (CGI) was used for clinical relevance as well. RESULTS: During the follow-up, there was a significant decrease in the number of hospitalizations per patient (Z-2.72 P < 0.006), in the number of manic or mixed episodes leading to hospitalization (Z-2.68 P < 0.007) but not in the hospitalizations due to depressive episodes, a decrease in the average length of hospitalization per patient (Z-3.27 P < 0.001), a significant increase in the time to any new episode (first relapse) (Z-3.28, P < 0.001), and significant improvements in treatment adherence (P < 0.0001) and hetero-aggressive episodes (P < 0.0001), but not suicide attempts (P = NS). At study endpoint 14 patients (48%) were very much improved according to the CGI. DISCUSSION: This observational long-term study provides support to long-acting injectable risperidone being effective for the maintenance treatment of mania and improving treatment adherence, reducing relapses and re-hospitalization rates.

Supplemental feeding and other anthropogenic threats to green turtles (Chelonia mydas) in the Canary Islands.

Green turtles are found in the waters of the Canary Islands but little is known about the ecology and anthropogenic pressures that threaten them. Our results have revealed that juvenile green turtles, ranging in curve carapace length from 26.9-81.0cm, are regularly found in the archipelago and originate from rookeries in both the eastern and western Atlantic. Photo-identification and satellite tracking showed high levels of site fidelity to coastal foraging grounds associated with seagrass meadows, but stable isotope analysis indicated animal-based omnivorous diets after settlement on the continental shelf, with no increase in the consumption of macrophytes as the turtles grew. Most turtles exhibited high levels of some blood biochemical markers associated with a high consumption of proteins and fat. In addition, we determined levels of some organic and inorganic pollutants. Supplemental feeding may also contribute to explain the high prevalence of hooking and boat strikes in the green turtles brought to wildlife rescue centers as compared with loggerhead turtles. Regulatory measures and surveillance should be urgently implemented in order to improve the status of the species in the archipelago.

Diabetes mellitus y ataxia de Friedreich en un niño: una difícil coexistencia / Diabetes mellitus and Friedreich´s ataxia in a child: a complicated coexistence

La ataxia de Friedreich, de herencia autosómica recesiva causada por una expansión repetida de trinucleótidos se asocia, entre otras complicaciones sistémicas, con diabetes mellitus. La aparición de torpeza motriz, con dificultad en la carrera y el salto en un varón de 6 años motivaron el estudio genético para ataxia de Friedrich y permitieron confirmar el diagnóstico. Tres años más tarde, se diagnosticó diabetes mellitus y se inició el tratamiento con insulina. Durante el seguimiento, presentó un importante deterioro neurológico, con necesidad de usar silla de ruedas, lo que dificultó un adecuado control metabólico. Se presenta el manejo y la evolución de un paciente con ataxia de Friedreich y diabetes mellitus

Friedreich's ataxia is an autosomal recessive disease caused by trinucleotide repeat expansion, presenting among other systemic complications, diabetes mellitus. The appearance of motor clumsiness, with running and jumping difficulties in a 6-year-old boy prompted the genetic study of Friedreich's ataxia, confirming his diagnosis. After diagnosis,it was evaluated by Pediatric Cardiology, detecting the presence of non-obstructive hypertrophic cardiomyopathy, and by Pediatric Endocrinology, due to overweight. At 9 years of age, he was diagnosed with diabetes mellitus, a regimen of insulin treatment was initiated. During follow-up, he presented significant neurological deterioration, reaching the use of a wheelchair,which hinders adequate metabolic control. This is a report of a pediatric patient with Friedrich ataxia and diabetes mellitus.

Epilepsia dependiente de piridoxina por deficiencia en el gen PNPO / Pyridoxine-dependent epilepsy due to deficiency in the PNPO gene

No disponible

Desarrollo psicomotor en prematuros tardíos a los dos años de edad: comparación con recién nacidos a término mediante dos herramientas diferentes / Psychomotor development in late preterms at two years of age: a comparison with full-term newborn infants using two different instruments

Introducción. Los prematuros tardíos constituyen actualmente el 70% de los nacimientos prematuros. Presentan mayor comorbilidad, incluyendo las alteraciones del neurodesarrollo, que pueden no manifestarse hasta la escolarización. Objetivo. Identificar dificultades en el desarrollo neurológico a los dos años de edad. Sujetos y métodos. Se valoró el desarrollo psicomotor a los dos años de los prematuros tardíos y del grupo control a término nacidos en nuestro centro entre enero y septiembre del año 2014 mediante la escala de Brunet-Lézine revisada y el cuestionario de edades y etapas para la detección de trastornos del neurodesarrollo Ages & Stages Questionnaires (ASQ-3). Resultados. Se incluyó a 88 niños. Los prematuros tardíos presentaron puntuaciones inferiores en el lenguaje y el desarrollo postural. Las niñas obtuvieron resultados superiores en la edad de desarrollo global, la coordinación oculomotriz, el lenguaje y la sociabilidad. El cuestionario ASQ-3 detectó las diferencias en comunicación y socioindividuales. Se identificaron como factores de riesgo para presentar alteración del desarrollo la prematuridad, para alteración del lenguaje, y el sexo masculino, para menor edad de desarrollo y alteración del lenguaje. La correlación entre la valoración del lenguaje con la escala de Brunet-Lézine revisada y el cuestionario ASQ-3 fue buena, con un coeficiente de correlación de Pearson de 0,7 (p < 0,001), lo que nuestra la utilidad del cuestionario. Conclusiones. Los prematuros tardíos presentan menor desarrollo del lenguaje a los dos años. La prematuridad y el sexo masculino son factores de riesgo para presentar alteración. La valoración del lenguaje con el cuestionario ASQ-3 puede ser útil para detectar alteraciones

Introduction. Late preterm infants currently constitute 70% of preterm infant births. They present greater comorbidity, including neurodevelopment disorders, which may not manifest until the school age. Aim. To identify the existence of difficulties in the neurodevelopment at the age of two years. Subjects and methods. The psychomotor development was performed at two years of age in late preterm infants and term control group born at our center between January and September 2014, with Brunet-Lezine Revised test and Ages & Stages Questionnaires (ASQ-3) questionnaire. Results. 88 children were included. Late preterm infants had lower scores in the language area and postural developmental. Girls achieved better results than males at global developmental age, oculo-motor coordination, language area and sociability. The ASQ-3 questionnaire detected differences in communication and socio-individual. Prematurity and male sex were identified as an independent risk factor to present a developmental disorder, prematurity for language impairment and male sex for younger developmental age and language impairment. The correlation between language assessment with the Brunet-Lezine Revised test and the ASQ-3 questionnaire was good, with a Pearson correlation coefficient of 0.7 (p < 0.001), showing the usefulness of the questionnaire. Conclusions. Late preterm infants have a lower developmental age in the language area at two years. Prematurity and male sex are risk factors for developmental disorder. Language assessment with the ASQ-3 questionnaire may be a useful tool to detect disorders and intervene early

Mutación puntual de novo en el gen KCND3 en un paciente con ataxia crónica de inicio precoz / De novo sporadic mutation in the KCND3 gene in a patient with early onset chronic ataxia

No disponible

Head to head comparisons as an alternative to placebo-controlled trials.

Head to head trials have been proposed as an alternative to the ethical and methodological concerns related to placebo-controlled trials. While those studies may be particularly informative from the clinical and cost-effectiveness point-of-view, avoiding placebo poses several regulatory concerns: for superiority designs, the choice of the trial population, outcomes, dose and escalation of the comparator, as well as the comparator itself may be an issue; for non-inferiority studies, issues related to uncertain assay sensitivity and exposure of large samples to potentially ineffective or unsafe drugs make them inappropriate, in the absence of a previous positive superiority trial, for regulatory purposes. The inclusion of active comparators in regulatory trials should not be seen as an alternative, but as a useful complement to the information that can be obtained from placebo-controlled studies.

Asenapine: a new focus on the treatment of mania.

DEVELOPMENT: Asenapine, recently marketed in United States and ready to be so in Europe, is a multimodal action second-generation antipsychotic, with high affinity for multiple dopaminergic (D2, D3 y D4), serotonergic (5HT2A, 5HT2B, 5HT2C, 5HT6 and 5HT7) and adrenergic (α1A, α2A, α2B and α2C) receptors. Asenapine has to be administered sublingually. After going through succesfully the preliminary phases of development, several clinical trials have been completed in two main indications: schizophrenia and mania. This article summarizes the available evidence on its safety and efficacy in acute mania and provides some prospect on its clinical immediate and future applications. CONCLUSIONS: Asenapine is effective and generally well tolerated in the treatment of moderate-to-severe acute mania associated to bipolar I disorder. The sublingual administration may be a challenge (coadministration with food or other drugs needs to be avoided) but also an opportunity (improved treatment adherence). Due to its multimodal receptor profile, it may cause several side-effects, but most of those are relatively mild, with none being particularly outstanding. In Europe, asenapine is indicated for the treatment of acute mania only, but several trials are being conducted in schizophrenia and bipolar depression.

Andrés Piquer-Arrufat (1711-1772): contributions of an eighteenth-century spanish physician to the concept of manic-depressive illness.

Largely unknown in Anglophonic medicine, eighteenth-century Spanish physician-scholar Andrés Piquer-Arrufat was early to coin a name (affectio melancholico-maníaca, or "melancholic-manic illness") for the syndrome that emerged much later as manic-depressive illness and then bipolar disorder. He considered it a single, independent diagnostic entity, distinct from mania and melancholia, with varying manifestations over time. Piquer recognized mixed states, seasonality, and rapid cycling, and hypothesized "mental or cerebral damage" as underlying the disorder. His formulations evolved from clinical observations of patients over time, including his detailed longitudinal clinical description of Spanish King Ferdinand VI (1759), and as presented in his own medical textbook (1764). Piquer anticipated the often cited nineteenth-century works of Jean Falret and Jules Baillarger in Paris, and later, Emil Kraepelin in Heidelberg, by more than a century.