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The implantation of the left ventricular assist device Abbott HeartMate 3TM is being increasingly performed for management of end-stage heart failure. LVAD implantation might be associated with early or late right ventricular dysfunction. When severe, a temporary right ventricular support device may need to be implanted. However, these situations are associated with higher mortality. We report a successful case of temporary right ventricular support following HeartMate 3 implantation.

Background: To review and meta-analyse the evidence about the prevalence of barriers to evidence-based practice (EBP) reported in physiotherapy., Methods: Two independent investigators conducted an extensive electronic search in EMBASE, PubMed, Scopus, Web of Science and CINAHL databases from their inception to July 2020 and included the retrieved articles if they investigated barriers to EBP among physiotherapy professionals. Subsequently, they extracted data and assessed the methodological quality using a scale described in a similar previous study. The outcome for meta-analysis was frequency of each reported barrier. Sub-analyses were performed grouping studies based on countries where surveys were performed, classified as either developed or developing countries., Results: Twenty-nine articles were included in the systematic reviews and meta-analysis. Risk of bias assessment of included studies showed a median score: 4 points (interquartile range: 3-4). The findings of meta-analysis revealed that lack of time was the most frequently reported barrier (53.0% [95% confidence interval, 95%CI, 44.0-62.0]), followed by language (36.0% [95%CI 16.0-62.0]), lack of access (34.0% [95%CI 23.0.27]) and lack of statistical skills (31.0% [95%CI 20.0-44.0]). Lack of skills and lack of generalizability were declared as barriers by 27.0% [95%CI 18.0-38.0] and 23.0% [95%CI 15.0-33.0] of responders, respectively. Lack of support and lack of interest are less frequent, with 16.0% [95%CI 11.0-24.0] and 9.0% [95%CI 6.0-15.0] of responses, respectively. Barriers reported in investigations performed in developed countries were less frequent when compared to those performed in developing countries., Conclusion: Organizational issues and methodological skills seem key issues to allow the implementation of EBP, suggesting the need to adopt or enhance organizational and training strategies to facilitate the implementation of the EBP. Quantitative synthesis showed high heterogeneity for all analyses, and therefore, pooled data should be interpreted with caution., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Background: Better and earlier predictive differentiation of bipolar (BD) vs. unipolar major depressive disorder (UD) diagnoses should improve long-term clinical planning., Methods: We reviewed randomly selected clinical records of 334 adults diagnosed with DSM-IV-TR BD-I (n=109), BD-II (n=106), and UD (n=119) and compared features preceding major affective episodes or diagnoses, using bivariate, multivariate, and Bayesian methods., Results: We identified antecedents selectively associated with later BD vs. UD in 52.6% vs. 31.1% of subjects in childhood, starting at age 7.4 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than UD cases (10.3 vs. 4.64/100 person-years; p<0.001). In multivariate modeling, BD-selective factors were: younger at first clinical event > male sex > family BD-history > cyclothymic or hyperthymic temperament > antecedents/person-year. Nonaffective (anxiety, eating, or substance-use) disorders preceded BD vs. UD in 41.4% vs. 28.6% of subjects (p=0.02). By ROC analysis, differential prediction of BD vs. UD was optimal with any ≥ 3 factors/person., Limitations: The validity and timing of antecedent events and factors identified retrospectively from clinical records could not be verified independently, but information was recorded systematically and consistently by a single mood-disorder expert prior to diagnosis, and extracted by two independent observers., Comment: Early clinical features distinguished later BD from UD, often by years. Such prediction should improve treatment-planning and limit risk of mood-switching., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Psychotic affective disorders are the most prevalent idiopathic psychoses, but their outcome from onset has rarely been studied. In this study, the authors determined the rate and latency of syndromal recovery and rates of functional recovery after first lifetime hospitalization in patients with first-episode psychotic affective disorders., Method: From first lifetime hospitalization in 1989-1996, 219 patients with a DSM-IV psychotic affective illness were assessed at intervals over 24 months. Time to syndromal recovery (no longer meeting DSM-IV episode criteria) was assessed by survival analysis, and functional recovery (regaining baseline vocational and residential status) was rated. Factors associated with recovery were identified by bivariate and multivariate methods., Results: By 3, 6, 12, and 24 months after first hospitalization, syndromal recovery was attained by 65.1%, 83.7%, 91.1%, and 97.5%, respectively, of subjects. Time to syndromal recovery (6.1 weeks to 50% of subjects recovered) was shorter for patients who had bipolar disorder, were married, were age 30 or older at onset, lacked comorbidity, required relatively brief hospitalization, and received fewer medicines. Functional recovery by 6 (30.4%) and 24 months (37. 6% of patients) was 2.6-2.7 times less likely than syndromal recovery; 63.1% of those recovering syndromally did not recover functionally by 2 years. Functional recovery was associated with older age at onset and shorter hospitalization. Annual recovery rates remained stable as mean hospital length of stay decreased 3. 6-fold over the 8-year study period., Conclusions: Syndromal recovery was attained by most psychotic affective disorder patients soon after hospitalization, but only one-third recovered functionally by 24 months. The findings suggest that these very common psychotic illnesses can carry a grave functional prognosis from the initial episode and first hospitalization.

Objective: Depressive personality disorder was introduced into DSM-IV's appendix amid controversy. While that disorder appears to be a reliable and valid one, the authors offer new data about its relationship to major depression, dysthymic disorder, and other personality disorders., Method: The authors assessed 54 subjects with early-onset, long-standing mild depressive features for depressive personality disorder, axis I and axis II disorders, family history, and treatment history; they conducted follow-up interviews 1 year after the baseline assessment. Subjects with (N=30) and without (N=24) depressive personality disorder were characterized and compared in terms of those variables., Results: Although depressive personality disorder and dysthymia co-occurred in some subjects, 63% of subjects with depressive personality disorder did not have dysthymia, and 60% did not have current major depression. Although subjects with depressive personality disorder were more likely than the mood disorder comparison group to have another personality disorder, 40% had no such disorder. Contrary to study hypotheses, mood disorder was not more common in first-degree relatives of subjects with depressive personality disorder than in relatives of the comparison group. Subjects with and without depressive personality disorder had similar rates of past treatment with medication and psychotherapy; however, the duration of psychotherapy was significantly longer for subjects with than for those without depressive personality. The depressive personality diagnosis was relatively stable over the 1-year follow-up period., Conclusions: Depressive personality disorder appears to be a relatively stable condition with incomplete overlap with axis I mood disorders and personality disorders. Further studies are needed to better characterize its treatment response and relationship to axis I mood disorders.

Velo-cardio-facial syndrome (VCFS) is characterized by conotruncal cardiac defects, cleft palate, learning disabilities, and characteristic facial appearance and is associated with hemizygous deletions within 22q11. A newly recognized clinical feature is the presence of psychiatric illness in children and adults with VCFS. To ascertain the relationship between psychiatric illness, VCFS, and chromosome 22 deletions, we evaluated 26 VCFS patients by clinical and molecular biological methods. The VCFS children and adolescents were found to share a set of psychiatric disorders, including bipolar spectrum disorders and attention-deficit disorder with hyperactivity. The adult patients, >18 years of age, were affected with bipolar spectrum disorders. Four of six adult patients had psychotic symptoms manifested as paranoid and grandiose delusions. Loss-of-heterozygosity analysis of all 26 patients revealed that all but 3 had a large 3-Mb common deletion. One patient had a nested distal deletion and two did not have a detectable deletion. Somatic cell hybrids were developed from the two patients who did not have a detectable deletion within 22q11 and were analyzed with a large number of sequence tagged sites. A deletion was not detected among the two patients at a resolution of 21 kb. There was no correlation between the phenotype and the presence of the deletion within 22q11. The remarkably high prevalence of bipolar spectrum disorders, in association with the congenital anomalies of VCFS and its occurrence among nondeleted VCFS patients, suggest a common genetic etiology.

Objective: The purpose of this study was to conduct a systematic assessment of psychiatric illness in patients diagnosed with velo-cardio-facial syndrome, a genetic syndrome that involves over 40 somatic anomalies, learning disabilities, and behavioral disorders and is associated with a microdeletion on chromosome 22q11., Method: Subjects were referred for psychiatric diagnostic evaluation without regard to age or previous psychiatric history. In order to establish DSM-III-R consensus clinical diagnoses for patients who ranged in age from 5 to 34 years, the Diagnostic Interview for Children and Adolescents--Revised or the Structured Clinical Interview for DSM-III-R (SCID) was used. A review of available medical and psychiatric records and a clinical interview performed by two research psychiatrists to validate specific symptoms and syndromes reported in the Diagnostic Interview for Children and Adolescents--Revised and the SCID were used to elucidate the chronological appearance and duration of symptoms., Results: Sixty-four percent (N = 16 of 25) of this unselected series of patients with velo-cardio-facial syndrome met DSM-III-R criteria for a spectrum of bipolar disorders with full syndromal onset in late childhood or early adolescence (mean age at onset = 12 years, SD = 3). In addition, 20% (N = 5) met DSM-III-R criteria for attention deficit hyperactivity disorder (ADHD), while 16% (N = 4) met criteria for attention deficit disorder without hyperactivity. In contrast to previous reports of a high prevalence of schizophrenia, none of the patients was diagnosed with schizophrenia, and only four had psychotic symptoms during a phase of their illness, all in their 20s or 30s., Conclusions: Given that the prevalence of bipolar disorder in the general population is estimated to be 1.5% and that the average age at onset is 24, these findings support an unusually strong association between velo-cardio-facial syndrome and early-onset bipolar disorder and suggest that a gene deleted at the 22q11 chromosomal locus may be involved in its pathogenesis. If confirmed, these findings may provide a new and fruitful line of investigation into the molecular basis of bipolar spectrum disorders.

Background: Gradual discontinuation of lithium may reduce high risk of early morbidity in bipolar disorder patients discontinuing successful long-term maintenance on lithium, but previous small samples have limited analyses of subgroups., Method: DSM-IV bipolar disorder patients (N = 161) were pooled from similar samples maintained on lithium for 4.2 +/- 3.1 years. Effects of discontinuing treatment abruptly (1-14 days) or gradually (15-30 days) were compared by survival analysis in clinically closely similar groups., Results: After gradual versus rapid discontinuation, the overall median time to recurrence +/- SE differed by 5.0-fold (20.0 +/- 5.8 vs. 4.0 +/- 0.7 months; p < .0001). After rapid discontinuation, the median time in remission was 2.3 times shorter than the mean cycling interval before lithium (6.3 vs. 14.6 months; p < .0001). The proportion of subjects falling ill/month (recurrence rate) was much higher in the first year after rapid discontinuation (6.5% vs. 2.3%), but similar thereafter (0.4% vs. 0.6%); patients remained stable for 3 years when off lithium treatment 20 times more frequently after gradual than rapid discontinuation (37% vs. 1.8%; p < .0001). Ratios of median survival times after gradual/rapid lithium discontinuation were similar for a first recurrence of mania and depression (4.4 vs. 3.4-fold), insignificantly higher (34%) with rapid or continuous cycling before lithium, and greater in Type II than Type I disorder (9.8- vs. 4.0-fold). The polarity of first off-lithium and first lifetime episodes matched in 70% of cases., Conclusion: These pooled results strengthen the concept or a pharmacodynamic stress factor in early relapse after stopping lithium maintenance and support the conclusion that early recurrence risk can be minimized by discontinuing maintenance treatment gradually in both Type I and II bipolar disorders.

Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploin-sufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methyltransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine-->methionine substitution at amino acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158met leads to a 3-4-fold reduction in enzymatic activity, compared with homozygotes for COMT158val. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158met, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form.

Eighty-six female and 34 male psychiatric outpatients completed a self-report questionnaire that retrospectively assessed their history of physical and sexual abuse and assault. Seventy percent reported an abusive experience in childhood or adulthood. Female subjects were more likely than male subjects to report childhood sexual abuse and adult physical and sexual assaults. For all subjects, childhood sexual abuse was associated with adult sexual and physical assault. The charts of several patients who reported abuse histories did not include any record of abuse.

Bipolar disorder (BPD), probably the most prevalent psychotic disorder in adults, has been relatively neglected or controversial in children and adolescents over the past century. We reviewed the literature on early-onset BPD. Estimates of prevalence, particularly before puberty, are limited by historical biases against pediatric mood disorders and by formidable diagnostic complexity and comorbidity. Although clinical features of pediatric and adult BPD have similarities, pediatric cases probably cannot be defined solely by features characteristic of adult cases. Onset was before age 20 years in at least 25% of reported BPD cases, with some increase in this incidence over the past century. Pediatric BPD is familial more often than is adult-onset BPD, may be associated with a premorbid cyclothymic or hyperthymic temperament, and can be precipitated by antidepressant treatment. Pediatric BPD episodes frequently include irritability, dysphoria, or psychotic symptoms; they are commonly chronic and carry high risks of substance abuse and suicide. BPD is often recognized in adolescents, but the syndrome or its antecedents are almost certainly underrecognized and undertreated in children. Controlled studies of short- and long-term treatment, course, and outcome in this disorder remain strikingly limited, and the syndrome urgently requires increased clinical and scientific interest.

Forty adolescent inpatients with histories of frequent interpersonal violent behavior were compared with 36 hospitalized adolescents without histories of overt violence using self-report questionnaires that measured violence risk, depression, impulsivity, and suicide risk. The two groups did not differ in terms of their demographic characteristics, but the violent patients had a higher prevalence of substance abuse and borderline personality disorder diagnoses. Violent adolescents were more impulsive and at higher suicide risk than nonviolent adolescents. In addition, violent adolescents had more positive histories of suicide attempts and had significantly higher family histories of attempted and completed suicide. In the total sample of adolescents, violence risk was significantly correlated with impulsivity and suicide risk, but not with depression.

There is abundant evidence for substantial long-term prophylactic efficacy of lithium in bipolar manic-depressive disorders. Interruption of such treatment carries an extraordinarily high risk of recurrence within several months, even after several years of stability. Even a sharp reduction in dose may carry some risk. Gradual discontinuation of lithium was accompanied by markedly reduced risk of early recurrence. There is suggestive evidence that the phenomenon of high risk of recurrence after abrupt interruption of maintenance treatment may occur with other disorders and treatments, including neuroleptics in schizophrenia and possibly antidepressants in recurrent depression. The phenomenon of discontinuation-associated iatrogenic risk of early recurrence of major psychiatric illness has clear clinical implications. These include the need to evaluate safer methods of interrupting long-term maintenance treatment, particularly when clinical indications for rapid cessation are compelling and gradual discontinuation is not feasible. Questions also arise concerning interpretation of existing experimental studies of maintenance treatments that require interruption of treatment, reduction of dose, or crossover to a placebo, as well as the ethical and scientifically unambiguous design of future studies of this kind.

Objective: Withdrawal of bipolar mood disorder (BP-I) patients from prolonged, stable lithium maintenance has a high risk of early recurrence, particularly of mania. We thus compared risks of stopping lithium rapidly vs gradually., Design: Outpatients undergoing clinically determined discontinuation of lithium treatment at different rates were followed up prospectively to 5 years. Risks and timing of new episodes were analyzed., Patients: Subjects (N = 64) with a DSM-III-R BP disorder, previously stable on lithium monotherapy for 18 to 120 months (mean, 3.6 years) were followed up clinically after discontinuing lithium (elected in prolonged wellbeing in 67%). None was unavailable for follow-up, and subtyping (BP-I or BP-II) remained stable., Results: Within 5 years, 75% had a recurrent episode; BP-I patients were 1.5-times less likely than BP-II to remain in remission. Polarity of first-recurrent and onset episodes was 80.8% concordant. Overall risk of a new episode of mania was significantly greater after rapid (< 2) than gradual (2 to 4 weeks discontinuation (5-year hazard ratio = 2.8); the difference in risk of depression was even greater hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 4.3) than at later times (2 to 5 years), when courses of "survival" over time were nearly parallel in both discontinuation groups., Conclusions: Risk of early recurrence of BP disorder following discontinuation of lithium maintenance is elevated, but may be both predictable (timing and polarity) and modifiable by gradual discontinuation.

Objective: The authors sought to determine the prevalence and effects of medical and psychiatric comorbidity on initial outcome in a group of patients experiencing a first episode of psychosis., Method: Patients with a first episode of psychosis who were consecutively admitted to a hospital (N = 102) were examined for the presence of psychiatric and medical disorders. Patients were given psychiatric diagnoses with the use of the Structured Clinical Interview for DSM-III-R and were rated weekly on symptom rating scales. Outcome variables at discharge were final symptom rating scale scores, length of hospitalization, and recovery on the basis of operationalized criteria., Results: Comorbid diagnoses were present in 52.0% (N = 53) of the patients, and 37.7% (N = 20) had multiple comorbid diagnoses. The most common comorbid diagnosis was substance abuse. Patients with affected psychoses were significantly more likely than those with nonaffective psychoses to have a comorbid substance abuse diagnosis. Patients with psychiatric comorbidity had poorer initial outcomes, while those with medical comorbidity had fewer symptoms at discharge., Conclusions: Comorbidity is common and may be a useful predictor of the outcome of a first episode of psychosis.

DSM-III-R criteria, applied retrospectively in a research-oriented psychiatric clinic, identified patients (N = 146) with a mood disorder and a seasonal pattern of recurrence (seasonal mood disorder). The seasonal mood disorder syndrome was not rare (10% of all mood disorders); diagnostic distribution was as follows: recurrent depression, 51%, and bipolar disorder, 49%, with 30% of the latter having mania (bipolar disorder type I) and 19% having hypomania (bipolar disorder type II). Most patients were women (71%); onset age averaged 29 years, with a mean of eight cycles in 12 years of illness; mean episode duration was 5.0 months. Mood disorder was found in a high proportion (68%) of the families. All but one patient followed one of two seasonal patterns in equal frequency: type A, fall-winter depression with or without spring-summer mania or hypomania; and type B, spring-summer depression with or without fall-winter mania or hypomania. Both types showed consistent times of onset and remission. These results emphasize that DSM-III-R seasonal mood disorder includes severe cases of recurrent depression and bipolar disorder and support a distinction between two seasonal subtypes.

Objective: The authors reviewed available evidence regarding the status of dysphoric or mixed mania as a distinct clinical state and formulated operational criteria for its diagnosis., Method: Studies of dysphoric mania or hypomania in patients with bipolar disorder were analyzed with regard to clinical characteristics, prevalence, demographic features, course of illness, outcome, family history, associated conditions, biological tests, and response to biological treatment., Results: Although some studies suggest that dysphoric and nondysphoric mania are similar conditions, others suggest that, compared with nondysphoric mania, dysphoric mania may be more severe; more likely to occur in women; more likely to be associated with suicidality, a younger age at onset, a longer duration of illness, higher rates of personal and familial depression, concomitant alcohol or sedative-hypnotic abuse, neuropsychiatric abnormalities, and poorer outcome; more frequently associated with cortisol nonsuppression; and less likely to respond adequately to lithium but perhaps more likely to respond to ECT or anticonvulsants., Conclusions: Substantial evidence suggests that dysphoric mania may be a distinct affective state. Contrary evidence, however, suggests that dysphoric mania may be a form of typical mania, a stage-related or severe form of mania, or a transitional state between mania and depression. Because the evidence may be inconsistent because of varying definitions of dysphoric mania among studies, the authors propose preliminary operational diagnostic criteria for the future study of dysphoric mania.

Comorbidity was studied in 41 manic and mixed-state bipolar patients at first hospitalization. The lifetime prevalence of comorbidity was high; 21 subjects (51.2%) had at least one other psychiatric diagnosis (N = 16, 39.0%) or medical disorder (N = 9, 22.0%). Nine subjects had multiple comorbid diagnoses. Women were 2.7 times more likely to have a comorbid diagnosis. The presence of comorbidity was not associated with differences in outcome measures.

The authors administered the Tridimensional Personality Questionnaire (TPQ) to 61 patients with first-episode psychosis. Subjects were classified into affective states according to DSM-III-R diagnoses. TPQ scores were compared among these states and correlated with two affective symptom subscales: "mania" and "depression." Manic subjects demonstrated little variation from normative TPQ scores. Compared with findings in manic subjects, the dimensional score for Harm Avoidance was elevated in all affective groups, "worry and pessimism" was elevated in mixed-state subjects, "shyness with strangers" was elevated in depressed and nonaffective subjects, and "attachment" was lower in depressed and nonaffective subjects. The Harm Avoidance dimensional score and two subdimensional scores were positively correlated with the "depression" subscale. The Harm Avoidance dimensional and subdimensional scores showed possible affective-state dependence that may limit the utility of this instrument as a personality measure in first-episode psychosis.

For a period of six months (april to october 1990) 361 manic-depressive in-patients or out-patients were examined and treated. 178 patients (119 females and 69 males) were suffering from depression at examination time. Among them, 34 women and 11 men had mixed mood disorders with a symptomatology near that of typical depression (major depression, according to the DSM III-R criteria) but not of mixed bipolar disorder. The main symptoms were: dysphoric mood with irritability; internal tension, psychic and sometimes physical agitation; emotional lability; head crowded with thoughouts or thoughts that vanish too quickly; sleep disorders with initial insomnia or with frequent night awakenings; suicidal thoughts or attempted suicide with impulsiveness. These patients sustained severe suffering. They were in no way slow-minded but rather talkative and expressive. Antidepressant drugs increased agitation and insomnia, and in some cases, suicidal impulses. BZDs had limited efficacy but neuroleptics given in small doses, anticonvulsants and lithium gave very effective results. A limited number of electroshocks provided rapid improvement. In many respects, depression with delirium seems a more severe form of the above-described combined depressive syndrome and responds to the same treatments. We think that this mood disorder includes excitement as an important component, although this was not clearly evident. However, it is not easy to conceive this syndrome as a mixture of depressive and manic symptoms; it should rather be regarded as another specific mood condition, either permanent or transient, situated between the two other conditions.

Episode recurrence in bipolar disorder following discontinuation of stable maintenance treatment with lithium salts was analyzed from 14 studies involving 257 patients with bipolar I disorder. More than 50% of new episodes of illness occurred within 10 weeks of stopping an average of 30 months of treatment. By survival analysis of 124 cases in which the time to a new episode was known, the computed time to 50% failure of remission was 5.0 months after stopping therapy; the time to 25% recurrence of mania was 5.2 times earlier than for depression (2.7 vs 14 months). In 16 patients with a mean cycle length before treatment of 11.6 months, the time to a new episode when off lithium therapy was only 1.7 months. Risk of early recurrence of bipolar illness, especially of mania, evidently is increased following discontinuation of lithium use and may exceed that predicted by the course of the untreated disorder. The basis and management of risks associated with discontinuing effective long-term mood-stabilizing treatment require further study.

Profound depletion of forebrain dopamine by 6-hydroxydopamine in neonatal rats (day 3) was associated with up to 82% loss of D1 receptor sites labeled with [3H]SCH-23390 at day 21. Administration of the selective D1 agonist SKF-38393 (days 6-18) abolished the correlation between D1 receptor density and DA concentrations, even with greater than 99% depletion of DA. In intact control animals, there was an inverse correlation between spontaneous variation in levels of DA and D1 receptor site density in forebrain tissue (r = -0.79) which also was abolished by treatment with the D1 agonist. Thus, D1 receptor density may be regulated by reciprocal regulatory processes during normal development, but may fail to develop in the absence of an adequate level of stimulation.

3H-SCH-23390, a selective antagonist of D-1 dopamine (DA) receptors, was used in a radioreceptor assay with rat brain striatal tissue, optimized biochemically, and extensively characterized pharmacologically with striatal membranes. Nonspecific binding, defined with excess cis(Z)-flupenthixol (300 nM), averaged 20-25% of total counts bound. Specific binding was linearly dependent on the amount of original striatal tissue (0-4 mg) or protein (0-250 micrograms), temperature dependent, saturable and reversible, and appeared to involve a single site at ligand concentrations limited to less than 10 nM. Binding in rat brain regions ranked as: striatum greater than accumbens greater than prefrontal cortex greater than posterior cerebral cortex greater than cerebellum. Association was virtually complete within 30 min at 30 degrees, and the rate of dissociation at 30 degrees was 0.0377 min-1 (half-time = 18.4 min). Affinity (Ka or Kd) determined from association and dissociation rate constants and from concentration isotherms averaged 0.349 and 0.340 nM respectively. Including Na+ at 150 mM increased apparent maximum specific binding (Bmax) by 19%, with a 29% increase in affinity; other monovalent cations alone had small effects on specific binding; Ca2+ and Mg2+ reduced binding by 42%. Agents (N = 85) were tested for potency (Ki or IC50) in competition with the ligand (at 0.30 nM). Those known to have selective effects at D-1 receptors, generally, were most potent and stereoselective. Na+ (150 mM) had little effect on the affinity of cis-thioxanthenes but decreased that of most other agents tested with high D-1 affinity. For antipsychotic agents, the correlation of typical clinical daily doses versus Ki at D-1 sites (r = 0.06) was much lower than at D-2 sites (r = 0.94). (-)Thioridazine was discovered to be D-1 selective, whereas the (+) enantiomer was selective for D-2 sites labeled with 3H-spiperone. Relatively sedating antidepressants had greater D-1 affinity than their less-sedating, secondary amine congeners.

Tissue was obtained from corpus striatum of maturing rats at representative postnatal ages of 8-120 days for evaluation of D1 and D2 dopamine (DA) receptor sites in radioreceptor assays based on use of 0.05-2.5 nM concentrations of [3H]SCH-23390 or [3H]domperidone, respectively. Pharmacologic selectivity was verified by high rank-correlations (rs greater than 0.90) of Ki values for representative test agents in both assays (vs 0.3 nM ligand), using striatal tissue obtained at ages 20 and 120 days. Data from repeated (3-5x) six-concentration isotherm experiments involving a wide range of D1 or D2 radioligand concentrations were analyzed by linear regression of specific binding (B) vs free ligand concentration (F) in linearized form (B/F vs B) for each replicate assay and for pooled values, as well as by curve-fitting all available raw data (B vs F) using the LIGAND program adapted to microcomputer. Values for apparent ligand affinity (Kd = 0.15-0.35 nM) failed to show a consistent change with age, while values for apparent receptor site density (Bmax) followed a similar developmental course with both methods of analysis (between methods: r = 0.99 and 0.89 for D1 and D2 assays, respectively, across all ages tested).(ABSTRACT TRUNCATED AT 250 WORDS)