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Attachment style, which has been theorized to be rooted in childhood bonding experiences, influences adult cognitive, emotional and interpersonal functioning. Despite its relationship with early experiences, research indicates that the continuity of attachment style across childhood and adulthood is only partial, being a malleable tendency that is shaped throughout development, with an increasing influence of genetics, as it occurs in other cognitive and behavioral phenotypes. Genetic research indicates that up to 45% of the variability in anxious and 39% in avoidant adult attachment style could be explained by genetic causes, but the precise mechanisms remain unclear. A narrative review is conducted analyzing the existing literature regarding the implication of candidate genes related to oxytocin, dopaminergic pathways, serotonergic pathways and brain-derived neurotrophic factor in adult attachment, with both vulnerability and differential susceptibility approaches, yielding mixed results. We highlight the lack of genome-wide studies and the scarcity of epigenetic investigation. Based on the existing data, we conclude that the genetics of adult attachment is an area that requires further research to clarify its etiological role and that it should be preferably approached as an interaction between nature and nurture.

Insecure attachment has been described as mediating the relationship between childhood trauma and dysfunctional personality traits in different mental disorders. Despite the role insecure attachment and childhood trauma have independently demonstrated to play as determinants of borderline personality disorder, less is known about the mediating mechanisms explaining these associations. For the first time, we assessed adult attachment, childhood trauma and dimensional personality pathology in a sample of outpatients with borderline personality disorder and tested whether the association between childhood trauma and personality dysfunction was at least partially attributable to insecure attachment. The results showed that attachment anxiety fully mediated the relationship between specific types of trauma (emotional abuse and physical neglect) and emotional dysregulation. Further, emotional abuse was both directly associated with dissocial behaviour and indirectly via attachment anxiety (partial mediation). Emotional abuse has been described as an essential environmental factor for the development of borderline personality disorder and emotional dysregulation, on its part, as the core feature of the condition. Our results indicate that attachment anxiety explains the link between these central aspects of borderline personality disorder. Our findings are consistent with previous research and current etiological understanding of the condition and provide support for recommending a careful assessment of childhood traumatic experiences and adult attachment style to gain a more comprehensive insight into the symptoms and its heterogeneity. As a secondary aim, we assessed the effect parental mental illness may have in these mediation models, but no significant influence on childhood trauma, attachment or personality was found. This work was supported by the Health Department of the Basque Government under grant PI2014111034, by Biocruces Bizkaia Health Research Institute and by the Research Unit of Galdakao-Usansolo Hospital. Open access funding was provided by the University of the Basque Country UPV/EHU.

Subacute necrotising encephalopathy or Leigh syndrome is a congenital neuro-metabolic disease that is part of a group of diseases called mitochondrial encephalopathies. The form inherited is variable and it has a multisystemic effect, although with a predominance of lesions in the central nervous system. Prognosis is poor and there is no specific treatment for it. In 2007, we published the case of a 23-year- old patient, with severe psychomotor agitation crises, who responded favourably to lithium1 after the failure of several previous treatments. Here, we describe the follow-up of this patient during the 5 years after discharge from hospital, until her death at 29 years of age. Her improvement was maintained, she was not hospitalised again and the patient#8217;s level of autonomy increased. The possible relationship of this improvement to new data on the neuroprotective and neurotropic effects of lithium are discussed.

Facial emotion recognition (FER) has been described to be impaired in borderline personality disorder (BPD), especially for neutral faces. Genetic modulation of FER has been studied in healthy individuals and some psychiatric conditions, but no genetic association studies have been conducted in BPD hitherto. The main objective of our study was to explore the influence of the serotonin-transporter-linked promoter region (5HTTLPR) and catechol-o-methyltransferase (COMT) Val158Met on facial emotion processing among BPD patients. To that end, seventy-six BPD outpatients were asked to complete a computer-based facial affect recognition task, representing four emotions (neutral, happy, fearful or angry). Accuracy of FER and perceptual biases were calculated. The 5HTTLPR and COMT Val158Met polymorphisms were genotyped using saliva samples. Individuals with the high-activity serotonin-transporter genotype and those with the low-activity COMT genotype had significantly more difficulties identifying neutral faces; the former showed stronger bias to perceive neutral faces as happy, and the latter, neutral faces as fearful. Interestingly, the perceptual biases observed in our patients are similar to previous reports in healthy individuals. The authors propose that the ability to accurately recognize neutral faces might be a possible endophenotype of BPD. Sex-genotype interactions were also observed in relation to angry faces and 5HTTLPR, and neutral faces and COMT Val158Met polymorphisms, in line with sex-related differences previously described for both polymorphisms in relation to FER and other cognitive and behavioral outcomes. The impact of inaccurate FER on psychosocial functioning and potential interventions are also discussed.

Dysfunctional noradrenergic transmission is related to several neuropsychiatric conditions, such as depression. Nowadays, the role of G protein-coupled inwardly rectifying potassium (GIRK)2 subunit containing GIRK channels controlling neuronal intrinsic excitability in vitro is well known. The aim of this study was to investigate the impact of GIRK2 subunit mutation on the central noradrenergic transmission in vivo. For that purpose, single-unit extracellular activity of locus coeruleus (LC) noradrenergic neurons and brain monoamine levels using the HPLC technique were measured in wild-type and GIRK2 mutant mice. Girk2 gene mutation induced significant differences among genotypes regarding burst activity of LC neurons. In fact, the proportion of neurons displaying burst firing was increased in GIRK2 heterozygous mice as compared to that recorded from wild-type mice. Furthermore, this augmentation was even greater in the homozygous genotype. However, neither the basal firing rate nor the coefficient of variation of LC neurons was different among genotypes. Noradrenaline and serotonin basal levels were altered in the dorsal raphe nucleus from GIRK2 heterozygous and homozygous mice, respectively. Furthermore, noradrenaline levels were increased in LC projecting areas such as the hippocampus and amygdale from homozygous mice, although not in the prefrontal cortex. Finally, potency of clonidine and morphine inhibiting LC activity was reduced in GIRK2 mutant mice, although the efficacy remained unchanged. Altogether, the present study supports the role of GIRK2 subunit-containing GIRK channels on the maintenance of tonic noradrenergic activity in vivo. Electric and neurochemical consequences derived from an altered GIRK2-dependent signalling could facilitate the understanding of the neurobiological basis of pathologies related to a dysfunctional monoaminergic transmission.

Aim: We examined the association of COMT haplotypes and plasma metabolites of catecholamines in relation to the clinical response to antipsychotics in schizophrenic and bipolar patients. Patients & methods: We studied 165 patients before and after four weeks of treatment, and 163 healthy controls. We assessed four COMT haplotypes and the plasma concentrations of HVA, DOPAC and MHPG. Results: Bipolar patients: haplotypes are associated with age at onset and clinical evolution. In schizophrenic patients, an haplotype previously associated with increased risk, is related to better response of negative symptoms. Conclusion: Haplotypes would be good indicators of the clinical status and the treatment response in bipolar and schizophrenic patients. Larger studies are required to elucidate the clinical usefulness of these findings.

The objectives of this study were to evaluate the oral health of a group of schizophrenic outpatients and a control group without psychiatric illness. The study also aimed to assess the influence of positive and negative symptomatology on oral health among outpatients with schizophrenia. The DMF-T Index (sum of decayed, missing and filled teeth) and the Community Periodontal Index of Treatment Needs (CPITN) were assessed in both groups. We evaluated the psychopathological state of the patient group using the Positive and Negative Syndrome Scale (PANSS). The schizophrenic patients had higher scores than the control group with respect to decayed teeth (4.39 vs. 0.72), missing teeth (5.66 vs. 1.50), the DMF-T index (13.51 vs. 7.8) and CPITN (2.32 vs. 1.04); and lower scores for filled teeth (3.53 vs. 5.54). The PANSS negative subscale score correlated positively with the oral health variables studied, whereas the PANSS positive subscale score correlated negatively and exclusively with the number of missing teeth. Age and smoking status affected oral health in both groups, but even when the influence of these factors was considered, the oral health of the patients was poorer than that of the control group.

Metabolites of dopamine and norepinephrine measured in the plasma have long been associated with symptomatic severity and response to treatment in schizophrenic, bipolar and other psychiatric patients. Plasma concentrations of catecholamine metabolites are genetically regulated. The genes encoding enzymes that are involved in the synthesis and degradation of these monoamines are candidate targets for this genetic regulation. We have studied the relationship between the Val158Met polymorphism in catechol O-methyltransferase gene, variable tandem repeat polymorphisms in the monoamine oxidase A gene promoter, and plasma concentrations of 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid in healthy control subjects as well as in untreated schizophrenic and bipolar patients. We found that the Val158Met substitution in catechol O-methyltransferase gene influences the plasma concentrations of homovanillic and 3,4-dihydroxyphenylacetic acids. Although higher concentrations of plasma homovanillic acid were found in the high-activity ValVal genotype, this mutation did not affect the plasma concentration of 3-methoxy-4-hydroxyphenylglycol. 3,4-dihydroxyphenylacetic acid concentrations were higher in the low-activity MetMet genotype. Interestingly, plasma values 3-methoxy-4-hydroxyphenylglycol were greater in schizophrenic patients and in bipolar patients than in healthy controls. Our results are compatible with the previously reported effect of the Val158Met polymorphism on catechol O-methyltransferase enzymatic activity. Thus, our results suggest that this polymorphism, alone or associated with other polymorphisms, could have an important role in the genetic control of monoamine concentration and its metabolites.

It has been suggested that the family history of psychotic disorders is useful in defining homogeneous groups of bipolar patients. The plasma homovanillic acid (pHVA) concentrations have been related to the effect of antipsychotic treatment in psychotic patients. We have studied the influence of a positive family history of psychotic disorders both on the variation of pHVA levels and on the relation between pHVA concentrations and the clinical response to treatment. Clinical status and pHVA levels were assessed in 58 medication free patients before and after 4 weeks of treatment with olanzapine and lithium. Clinical improvement correlated positively with pHVA levels on the 28th day of treatment only in the patients having first degree relatives with psychotic disorders. The pHVA levels did not decrease after 28 days of treatment. Our results reinforce the idea that a positive family history of psychosis in psychotic bipolar disorders may constitute a good basis for sub-grouping these patients.

El diagnostico del paciente en el que coexisten sintomas afectivos y sintomas psicoticos entrana cierta dificultad. En primer lugar tenemos que ver si el paciente tiene un trastorno afectivo, y en Segundo lugar, si presenta sintomatologia psicotica, tenemos que decidir si esta es congruente o no con el estado de animo. En este articulo se revisa la situacion actual de este tema, y se contrastan las opiniones de distintos autores. Tambien se reflexiona sobre los puntos donde mas dificultades encontramos a la hora de diagnosticar a estos pacientes, como que presente delirios persecutorios o sintomas de primer rango de Schneider. Se concluye que son necesarias bases mas objetivas para clasificar a estos pacientes.

Several findings suggest that glial cell line-derived neurotrophic factor (GDNF) may be a useful tool to treat parkinsonism by acting as a neuroprotective and neurotrophic factor for dopaminergic neurotransmission systems. In the present study, we implanted alginate-poly-L-lysine-alginate microcapsules containing immobilized Fischer rat 3T3 fibroblasts transfected to produce GDNF in vitro into the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats. Microencapsulated GDNF secreting cells were stable for at least 3 weeks in vitro. Intrastriatal implantation of microencapsulated GDNF secreting cells into 6-OHDA lesioned rats resulted in a decrease in apomorphine-induced rotations by 84%, 64%, 84%, 60% and 52% (2, 5, 8, 16 and 24 weeks, respectively) with respect to the value before implantation and with respect to the value obtained from the empty microcapsule implanted-group at each time point. Six months after transplantation, immunohistochemical detection of GDNF revealed strong immunoreactivity in the striatal tissue surrounding the microcapsules in the absence of tissue damage due to microcapsule implantation. No changes in the levels of dopamine and its metabolites or of tyrosine hydroxylase immunoreactivity were detected in the striatum. In summary, the implantation of microencapsulated GDNF secreting cells allows the delivery of this molecule into the rat striatum for at least 6 months and results in substantial behavioral improvement.

The relation between changes in the levels of plasma homovanillic acid (pHVA) and clinical evolution during neuroleptic treatment of schizophrenic patients has not been satisfactorily characterized, as a number of conflicting findings have been reported. Significant correlations have generally been found using the assessment of positive symptoms as an index of clinical outcome. Nevertheless, attempts to correlate pHVA concentrations with negative symptoms have yielded contradictory results. With a view to evaluating if different responses in negative symptoms are associated with distinct pHVA profiles, we examined the levels of pHVA in 46 neuroleptic-free schizophrenic patients and in these patients after neuroleptic treatment. Negative and positive symptoms were also addressed before and after treatment. Our results reveal that at least two classes of negative symptoms exist; the clinical evolution of the first class of negative symptoms parallels that of positive symptoms, and clinical improvement correlates with reduced dopaminergic activity. In contrast, in the second class, reduced dopaminergic activity is associated with a further deterioration of negative symptoms. These findings corroborate the heterogeneity of negative symptoms and may contribute to a better definition of endophenotypes in the schizophrenic syndrome.

Introduccion Los estudios mas recientes apoyan la idea de que la fisiopatologia del sindrome bipolar se sustenta en diversas interacciones de varios sistemas de neurotransmision. Datos clinicos y preclinicos sugieren tambien que la actividad noradrenergica esta elevada en estos pacientes antes del tratamiento. Metodo En nuestro estudio se ha medido la concentracion plasmatica del 3-metoxi-4-hidroxifenilglicol (MHPG), principal metabolito de la noradrenalina (NA), en 50 pacientes bipolares tipo I, 29 varones y 21 mujeres, diagnosticados segun el Diagnostic and Statistical Manual of Disorders (DSM-IV). Tambien se determinaron los polimorfismos Val108/158Met de la catecol-O-metiltransferasa (COMT). Los pacientes se trataron con olanzapina, a la que posteriormente se anadio litio. Resultados y Conclusiones El tratamiento demostro ser eficaz, tanto en pacientes psicoticos como en no psicoticos; y no se encontro una relacion significativa entre los polimorfismos estudiados de la COMT y la respuesta clinica medida por la escala de Young para la mania. Si se puso de manifiesto una correlacion significativa y positiva entre los valores plasmaticos de MHPG antes del tratamiento y despues de 3 dias de tratamiento con la respuesta a este.

Background The activity of catechol-O-methyltransferase (COMT) may be related to psychosis susceptibility. The Val108/158Met polymorphism of the COMT gene influences its enzymatic activity and may result in altered concentrations of monoamine metabolites and different clinical responses of patients to pharmacological treatments. Methods We examined in a sample of 42 bipolar patients if the Val108/158Met polymorphism influences: (a) the presence of psychosis in type I bipolar patients; (b) the blood plasma concentration of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), which are metabolites of dopamine and noradrenaline respectively and (c) the severity of the clinical characteristics of these patients and their response to pharmacological treatment. Results No significant associations were found between the studied COMT genotypes and the studied parameters. However, a non-significant aggregation of bipolar patients presenting with psychosis was found in the homozygous Val-Val group. Clinical improvement was found to significantly correlate with the levels of plasma MHPG prior to treatment. Moreover, a significant difference was found between the standard deviations of the concentrations of HVA in the three genotypes, but not in their mean values. Significant associations were not detected between COMT polymorphisms and the initial severity of the disorder, or the clinical response to pharmacological treatment. Limitations The size of the studied sample is somewhat small and comparisons have been made with a previously studied control group. Conclusions The Val108/158Met polymorphism does not appear to be a crucial determinant in type I bipolar disorder.

Differentially expressed clones from subtracted cDNA libraries of a pair of monozygotic twins discordant for schizophrenia have been reported in the literature. The clones were expressed in lymphocytes from the healthy twin, but not from the schizophrenic twin. In the current study, we assessed the expression of one of these clones, oksc12b, in 10 normal controls and in 10 patients who met DSM-IV criteria for schizophrenia and had never received neuroleptic medication. We hypothesized that this clone would be differentially expressed in normal controls and in the schizophrenic patients, and that its expression could be a peripheral marker of the disease. Lymphocytes were isolated and total RNA was purified, reverse-transcribed, and quantified by two PCR methods. In the first PCR assay, oksc12b expression was measured relative to beta-actin gene expression. The second PCR assay consisted of a competitive procedure using a heterologous DNA internal standard. Neither method confirmed any difference in oksc12b expression between schizophrenic patients and normal controls. Subtypes of schizophrenia or the general heterogeneity of this syndrome may explain the discrepancy found. It is also possible that the differentially expressed clones are present in discordant monozygotic twins, but not in other patients.

Gene expression in human lymphocytes was assessed using reverse transcription and polymerase chain reaction amplification followed by ion-pair reversed-phase chromatography analysis. Competitive PCR was used to quantitate the desired cDNAs with a polivalent competitor adaptable to multiple novel mRNAs estimations with minor changes. Accuracy was 11.27+/- 11.87% (n = 7), as determined using standards. The coefficients of variation of the assessment of human OK12b were 7% (n = 6), 7.68 attmol/microg of total RNA, and 21% (n = 6), 0.93 attmol/microg of total RNA. Sample-to-sample variation in the reverse transcription and in the quantity and quality of RNA was attenuated by normalising results to beta-actin mRNA expression. The correlation between the OK12b/beta-actin ratio and competitive assessments of OK12b was 0.984, n = 6. The correlation between HPLC results and an independent method based on radionuclide uptake by the product, detected by electrophoretic separation, was 0.848, n = 10.

El trastorno bipolar es una enfermedad cronica, caracterizada por remisiones y exacerbaciones, cuya evolucion puede modificarse favorablemente con un tratamiento apropiado. Aunque el tratamiento de los episodios agudos es importante, la prevencion de recaidas mediante un tratamiento de mantenimiento es el objetivo terapeutico principal. Se ha estimado que aproximadamente el 60% de la poblacion diagnosticada de trastorno bipolar I experimenta de forma cronica dificultades en la actividad sociolaboral. Los sintomas subclinicos entre los episodios agudos son, en un gran numero de pacientes, la causa de esas dificultades. Presentamos el caso de una paciente con subsintomas interepisodicos, a la que instauramos un tratamiento con aripiprazol. Este neuroleptico, de singular mecanismo de accion, ha producido en nuestra paciente sorprendentes consecuencias clinicas de interesante discussion.

Background: Plasma homovanillic acid (HVA) changes in response to a challenge of several days with haloperidol have been found to be predictive of the therapeutic response to haloperidol over a longer period of treatment. Methods: Twenty-six elderly women who gave informed consent were divided into two groups, with or without tardive dyskinesia, and subjected to an 80-day washout, after which both the dyskinetic and nondyskinetic group was divided, and half of each group given haloperidol or clozapine. Conclusions: The nondyskinetic group had a brief rise in plasma HVA, then a decline. The dyskinetic group had no change in plasma HVA. Neither group challenged with clozapine had any change in plasma HVA.

Hyperprolactinemia is a common side effect of antipsychotic treatments. Existing alternatives to resolve this problem include decreasing the antipsychotic dose or switching to a different antipsychotic agent. Nevertheless, said modifications can sometimes lead to decompensation of the patient. We report a clinical case of a female patient in whom the combined treatment of 5 mg/day of aripiprazole (5 mg/day) reversed paliperidoneinduced hyperprolactinemia within four weeks.

Andia, Isabel, Mercedes Zumarraga, Francisco Retuerto, Isabel Zamalloa and Ricardo Davila: Chronic neuroleptic treatment does not suppress the dynamic characteristics of the dopaminergic receptor D2 system. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1994,18(1): 181–191. 1. 1. Rats were treated with either haloperidol(0.5 mg/kg) or haloperidol plus an anticholinergic drug (0.5 and 0.15 mg/kg/day respectively) for 3 days, 7 days and 16 months. 2. 2. Estimates made twenty hours after the last doses showed that haloperidol reduced the concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and the olfactory tubercle. 3. 3. A challenge dose of either haloperidol or haloperidol plus an anticholinergic drug was administered to rats pretreated with haloperidol or haloperidol plus an anticholinergic drug; this challenge dose reversed the reduction in dopamine metabolites caused by neuroleptic administration. 4. 4. After sixteen months of haloperidol administration dopamine levels were reduced, but adding an anticholinergic drug to haloperidol treatment prevented this reduction in dopamine concentration.

In the present study we have measured, on a monthly basis, the concentration of plasma homovanillic acid (pHVA) in schizophrenic patients during 13 months of their pharmacological treatment. The average pHVA values of each patient were within the range of 7.30–17.70 ng/ml and the coefficients of variation for each patient (CV %) were within the range of 13–33%. Half of the patients that showed higher pHVA CV% values also showed higher scores on the Brief Psychiatric Rating Scale at the beginning of the study, and improved more after 6 months, when compared to the remaining 50% with lower CV% values. There was no significant relationship between the scores of the Wisconsin Card Sort Test and the concentration or the CV% of the pHVA of each patient. A greater variability in the pHVA may be associated with a greater plasticity of the dopaminergic system and a better clinical response.

We have determined the plasma (p) concentration of gamma-aminobutyric acid (GABA) and the dopamine metabolite homovanillic acid (HVA), and the pHVA/pGABA ratio in schizophrenic and bipolar patients. The research was undertaken in a geographic area with an ethnically homogeneous population. The HVA plasma concentrations were significantly elevated in the schizophrenic patients compared to the bipolar patients. The levels of pGABA was significantly lower in the two groups of patients compared to the control group, while the pHVA/pGABA ratio was significantly greater in the both groups of patients compared to the controls. As the levels of pHVA and pGABA are partially under genetic control it is better to compare their concentrations within an homogeneous population. The values of the ratio pHVA/pGABA are compatible with the idea of an abnormal dopamine-GABA interaction in schizophrenic and bipolar patients. The pHVA/pGABA ratio may be a good peripheral marker in psychiatric research.

We examined the catechol-O-methyl transferase (COMT) Val108/158Met genotype in 160 type 1 bipolar patients. We also analyzed the plasma concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylenglycol (MHPG) and 3,4-dihydroxyphenylacetic acid in 60 of those patients who had been without mood stabilizers or neuroleptic treatment for at least 8 days. Results: Patients with congruent psychotic symptoms presented a higher plasma concentration of HVA than mood incongruent psychotic patients. The Val/Val genotype was associated with higher plasma concentrations of HVA and MHPG. We detected a larger proportion of patients with psychotic symptoms in the Val/Val genotype group, although this did not reach statistical significance. It was found that the distribution of the COMT genotype was not influenced by the congruent/incongruent nature of the psychotic symptoms. Limitations: The proportion of patients without psychotic symptoms in our sample was low. This fact limits the value of some comparisons. Conclusions: Congruent and incongruent psychotic patients can be distinguished in terms of the concentration of plasma HVA. Based on the presence or absence of mood incongruent symptoms, the Val108/158Met polymorphism of the COMT gene alone does not appear to be a crucial determinant in the division of psychotic bipolar patients. Nevertheless, COMT polymorphisms may influence some of the characteristics of the patients by their effect on monoamine metabolism.

BACKGROUND Changes in the levels of homovanillic acid in blood plasma (pHVA) may reflect changes which occur in the brain. In healthy individuals, this concentration of pHVA is stable over time. METHODS Over the course of one month, we studied 98 acute schizophrenic patients who had not been taking any medication but were administered neuroleptics upon hospital admission, together with 23 chronic schizophrenic patients on long-term treatment from whom medication was withdrawn. Blood samples were taken at regular intervals from each individual and the concentration of plasma homovanillic acid was measured. RESULTS We found relative stable values of pHVA with an intraclass correlation coefficient of 0.363 in acute patients and 0.638 (p

Plasma homovanillic acid concentration was assessed in 60 young schizophrenic patients, with and without first-degree relatives with schizophrenia, before treatment, and 3 days after starting haloperidol treatment. The baseline concentration of homovanillic acid in plasma was no different in the two groups before treatment; it was, however, significantly higher in the patients with relatives than in those without relatives diagnosed of schizophrenia after 3 days of haloperidol treatment. © 1995 Wiley-Liss, Inc.

Plasma concentrations of homovanillic acid were determined in samples obtained at 8.30 a.m. and 12.30 p.m. from 29 untreated schizophrenic patients, 14 males and 15 females. When the earlier samples were compared with the later, a significant decrease in mean plasma homovanillic acid level was observed, but only in the male patients. The morning fall was observed in 10 of 14 male patients and 6 of the 15 female patients. This morning rhythm in plasma homovanillic acid concentration may mask the putative rises in plasma homovanillic acid provoked by neuroleptic administration and may explain some of the observed differences between findings in studies involving the assessment of this metabolite.

We describe a sensitive, simple method for measuring homovanillic acid in human plasma. The method is based on liquid chromatography with electrochemical detection. Sensitivity was 125 pg of homovanillic acid per injection. Samples were deproteinized and extracted with organic solvent before chromatography. Quantification was by the standard-additions technique. Analytical recovery of added HVA was 44.8 (SD 6.2%). We confirmed specificity by using serial amperometric detectors.

Several attempts have been made to relate subtypes of schizophrenia to dopaminergic status. For example, Crow's hypothesis states that Type I schizophrenia is characterised by positive symptoms, increased activity of the dopaminergic system, good response to neuroleptics, and no brain structural changes; and Type II by negative symptoms, reduced dopaminergic activity, poor response to neuroleptics, and brain structural changes. Testing of this hypothesis has, however, been inconclusive, and it seems more likely that both types are inter-related.

• Fourteen schizophrenic subjects were evaluated for degree of psychosis before and after treatment with the antipsychotic drug haloperidol and for plasma homovanillic acid concentration after four and 28 days of treatment. A significant correlation was found between an increase in homovanillic acid concentration on day 4 or a decrease from day 4 to day 28 and the degree of improvement after four weeks of treatment. Thus, those patients who had the greatest change in plasma homovanillic acid in response to neuroleptic blockade showed the greatest improvement. These and other observations have led us to propose that the central dopaminergic system, through adaptive changes in activity, serves as a physiologic buffer system protecting against destabilization of mental function from diverse biologic or psychologic insults.

To the Editor.— The increase in homovanillic acid (HVA) concentration in rat plasma occurring after treatment with neuroleptic drugs has been found to be largely of central nervous system origin, 1 although basal levels derive from both the periphery and the central nervous system. 2 The findings on the effect of neuroleptic drugs on plasma HVA level in humans have not been entirely consistent. Pickar et al 3 failed to demonstrate an acute neuroleptic drug-induced increase in plasma HVA level in schizophrenic patients, and Davis et al 4 originally were unable to detect this effect in subjects studied six hours after treatment. Recently, this latter group reported that an increase did occur 24 hours after treatment. 5 They administered haloperidol intramuscularly at 11 AM (0.2 mg/kg) and later, at 6 PM, orally (10 mg). The level of HVA in plasma was determined before administration of haloperidol and again the next