Review: Modelling the pathology and behaviour of frontotemporal dementia.

Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease-causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP-43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide-ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease-relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease-relevance of findings and thus better inform therapeutic development.

Diffusion Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3-K27M Mutation Using Apparent Diffusion Coefficient Histogram Analysis.

BACKGROUND AND PURPOSE: Diffuse midline gliomas with histone H3 K27M mutation are biologically aggressive tumors with poor prognosis defined as a new diagnostic entity in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. There are no qualitative imaging differences (enhancement, border, or central necrosis) between histone H3 wildtype and H3 K27M-mutant diffuse midline gliomas. Herein, we evaluated the utility of diffusion-weighted imaging to distinguish H3 K27M-mutant from histone H3 wildtype diffuse midline gliomas. MATERIALS AND METHODS: We identified 31 pediatric patients (younger than 21 years of age) with diffuse gliomas centered in midline structures that had undergone assessment for histone H3 K27M mutation. We measured ADC within these tumors using a voxel-based 3D whole-tumor measurement method. RESULTS: Our cohort included 18 infratentorial and 13 supratentorial diffuse gliomas centered in midline structures. Twenty-three (74%) tumors carried H3-K27M mutations. There was no difference in ADC histogram parameters (mean, median, minimum, maximum, percentiles) between mutant and wild-type tumors. Subgroup analysis based on tumor location also did not identify a difference in histogram descriptive statistics. Patients who survived <1 year after diagnosis had lower median ADC (1.10 × 10-3mm2/s; 95% CI, 0.90-1.30) compared with patients who survived >1 year (1.46 × 10-3mm2/s; 95% CI, 1.19-1.67; P < .06). Average ADC values for diffuse midline gliomas were 1.28 × 10-3mm2/s (95% CI, 1.21-1.34) and 0.86 × 10-3mm2/s (95% CI, 0.69-1.01) for hemispheric glioblastomas with P < .05. CONCLUSIONS: Although no statistically significant difference in diffusion characteristics was found between H3-K27M mutant and H3 wildtype diffuse midline gliomas, lower diffusivity corresponds to a lower survival rate at 1 year after diagnosis. These findings can have an impact on the anticipated clinical course for this patient population and offer providers and families guidance on clinical outcomes.

Preoperative MR Imaging to Differentiate Chordoid Meningiomas from Other Meningioma Histologic Subtypes.

BACKGROUND AND PURPOSE: Chordoid meningiomas are uncommon WHO grade II primary intracranial neoplasms that possess unique chordoid histology and follow an aggressive clinical course. Our aim was to assess the utility of qualitative MR imaging features and quantitative apparent diffusion coefficient values as distinguishing preoperative MR imaging metrics to identify and differentiate chordoid histology from other meningioma histologic subtypes. MATERIALS AND METHODS: Twenty-one patients with meningiomas with chordoid histology, which included both chordoid meningiomas (>50% chordoid histology) and meningiomas with focal chordoid histology (<50% chordoid histology) with available preoperative MR imaging examinations, including diffusion-weighted imaging, were identified. Qualitative imaging features and quantitative ADC values were compared between meningiomas with chordoid histology and 42 nonchordoid meningiomas (29 WHO grade I, eleven WHO grade II, and 2 WHO grade III). RESULTS: The median ADC (10-3mm2/s) of meningiomas with chordoid histology was significantly higher than nonchordoid meningiomas (1.16 versus 0.92, P < .001), as was the median normalized ADC (1.60 versus 1.19, P < .001). In subgroup analysis, the median and normalized ADC values of chordoid meningiomas (n = 11) were significantly higher than those in meningiomas with focal chordoid histology (n = 10, P < .001 and P < .001, respectively) or nonchordoid meningiomas (n = 42, P < .001 and <0.001, respectively). Median and normalized ADC values were not significantly different between the meningiomas with focal chordoid histology and nonchordoid meningiomas (P = .816 and .301, respectively). Among the qualitative imaging features, only DWI signal intensity was significantly associated with meningiomas with chordoid histology diagnosis. CONCLUSIONS: ADC values are higher in chordoid compared with nonchordoid meningiomas and may be used to discriminate the degree of chordoid histology in meningiomas. While qualitative MR imaging features do not strongly discriminate chordoid from nonchordoid meningiomas, DWI may allow preoperative identification of chordoid meningiomas.

Imaging Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3 K27M Mutation.

BACKGROUND AND PURPOSE: The 2016 World Health Organization Classification of Tumors of the Central Nervous System includes "diffuse midline glioma with histone H3 K27M mutation" as a new diagnostic entity. We describe the MR imaging characteristics of this new tumor entity in pediatric patients. MATERIALS AND METHODS: We retrospectively reviewed imaging features of pediatric patients with midline gliomas with or without the histone H3 K27 mutation. We evaluated the imaging features of these tumors on the basis of location, enhancement pattern, and necrosis. RESULTS: Among 33 patients with diffuse midline gliomas, histone H3 K27M mutation was present in 24 patients (72.7%) and absent in 9 (27.3%). Of the tumors, 27.3% (n = 9) were located in the thalamus; 42.4% (n = 14), in the pons; 15% (n = 5), within the vermis/fourth ventricle; and 6% (n = 2), in the spinal cord. The radiographic features of diffuse midline gliomas with histone H3 K27M mutation were highly variable, ranging from expansile masses without enhancement or necrosis with large areas of surrounding infiltrative growth to peripherally enhancing masses with central necrosis with significant mass effect but little surrounding T2/FLAIR hyperintensity. When we compared diffuse midline gliomas on the basis of the presence or absence of histone H3 K27M mutation, there was no significant correlation between enhancement or border characteristics, infiltrative appearance, or presence of edema. CONCLUSIONS: We describe, for the first time, the MR imaging features of pediatric diffuse midline gliomas with histone H3 K27M mutation. Similar to the heterogeneous histologic features among these tumors, they also have a diverse imaging appearance without distinguishing features from histone H3 wildtype diffuse gliomas.

Recovery from major depression. A 10-year prospective follow-up across multiple episodes.

BACKGROUND: Major depressive disorder is often marked by repeated episodes of depression. We describe recovery from major depression across multiple mood episodes in patients with unipolar major depression at intake and examine the association of sociodemographic and clinical variables with duration of illness. METHODS: A cohort of 258 subjects treated for unipolar major depressive disorder was followed up prospectively for 10 years as part of the Collaborative Depression Study, a multicenter naturalistic study of the mood disorders. Diagnoses were made according to the Research Diagnostic Criteria, and the course of illness was assessed with the Longitudinal Interval Follow-up Evaluation. Survival analyses were used to calculate the duration of illness for the first 5 recurrent mood episodes after recovery from the index episode. RESULTS: Diagnosis remained unipolar major depressive disorder for 235 subjects (91%). The median duration of illness was 22 weeks for the first recurrent mood episode, 20 weeks for the second, 21 weeks for the third, and 19 weeks for the fourth and fifth recurrent mood episodes; the 95% confidence intervals were highly consistent. From one episode to the next, the proportion of subjects who recovered by any one time point was similar. For subjects with 2 or more recoveries, the consistency of duration of illness from one recovery to the next was low to moderate. None of the sociodemographic or clinical variables consistently predicted duration of illness. CONCLUSION: In this sample of patients treated at tertiary care centers for major depressive disorder, the duration of recurrent mood episodes was relatively uniform and averaged approximately 20 weeks.

Recovery after 5 years of unremitting major depressive disorder.

BACKGROUND: The long-term course of depression in patients who present for treatment carries prognostic and therapeutic implications. This study presents prospective data on the time to recovery from an episode of major depressive disorder of 5 years' duration among patients followed up since 1978 in the National Institutes of Mental Health Collaborative Program on the Psychobiology of Depression. METHODS: Survival analysis was used to examine the 10-year course of the 431 probands with major depressive disorder with a specific focus on the 35 probands who were observed to be continuously ill for the first 5 years. Univariate analytic techniques were used to describe the demographic and clinical variables in the group that recovered and the group that did not. By study design, somatic treatment was assessed but not controlled by the investigators. RESULTS: By year 10, 93% (Kaplan-Meier estimate) of probands had recovered from their intake episode of major depressive disorder. In those ill for the first 5 years, 38% had recovered within the next 5 years. Shorter duration of illness prior to intake and being married were associated with the group that recovered. Pharmacological treatment dosages averaged 100 mg of imipramine hydrochloride equivalent in the chronically ill group. CONCLUSIONS: Despite lengthy periods of illness, people continued to recover from major depressive disorder for up to 10 years of prospective follow-up. Few demographic and clinical variables distinguished those who recovered from those who did not. Treatment, as observed in this naturalistic study, was at a low level despite lengthy illness.

Reading the tuberculin skin test. Who, when, and how?

A prospective study of 806 healthy volunteers was carried out to determine the value of induration 24 hours after placement of purified protein derivative, if patients can accurately read their own tests, and if the pen and palpation methods are comparable. Subjects were actively employed health workers between 20 and 64 years of age without active tuberculosis. All subjects were tested using 5 tuberculin units of purified protein derivative via the Mantoux technique. Induration was quantitated by trained readers at 24 hours and at 48 to 72 hours. Patients were asked to read their own tests as well at 48 to 72 hours. The amount of induration at 24 hours was highly predictive of eventual findings at 48 to 72 hours. The patients' abilities to read their own tests were poor. Significant differences were noted between the pen and palpation methods. The degree of induration noted 24 hours after placement of 5 tuberculin units of purified protein derivative is valuable in a screening population. Most decisions, however, should still be based on results measured at 48 to 72 hours. Results with the pen technique must be interpreted with caution in the 5- to 14-mm range. The patients' readings of their own results are inaccurate and should never be relied on to make clinical decisions.

Hepatic hydrothorax. Cause and management.

Significant pleural effusions are infrequently noted in patients with cirrhosis of the liver. A large effusion (hepatic hydrothorax) occasionally appears during the course of the disease. The fluid in the pleural space is believed to be derived from ascitic fluid that may accompany hepatic cirrhosis. Although the exact mechanism is somewhat controversial, it appears that the ascitic fluid is transported directly into the pleural space. A therapeutic thoracentesis, usually accompanied by a paracentesis, may be necessary to relieve acute symptoms. Long-term management, however, centers around eliminating or reducing the formation of ascites. When this is not successful, tube thoracostomy followed by chemical pleurodesis, primary repair of diaphragmatic defects with pleural sclerosis, or peritoneovenous shunting in conjunction with chemical pleurodesis may be attempted. These interventions may or may not be successful. Management of hepatic hydrothorax remains a clinical challenge.

Human adjuvant disease. A new cause of chylous effusions.

Connective-tissue disease occurring after cosmetic surgery with silicone injections or implants has been reported. This disorder has been called human adjuvant disease. One patient is described in whom a chylous effusion and systemic lupus erythematosus-like disorder developed after mammary augmentation with silicone gel-filled prostheses. This patient represents still another example of human adjuvant disease. A brief review of the literature regarding human adjuvant disease is also presented.

Isoniazid chemoprophylaxis. Association with detection and incidence of liver toxicity.

The hepatotoxicity of isoniazid was studied in a double blind fashion in 120 adult patients receiving the drug for chemoprophylaxis. The incidence of abnormal SGOT values was significantly higher in those on the drug, 18.3% having elevated values as compared to 6.7% of those on placebo during the three-month study period. There was no statistical difference in the frequency of symptoms suggestive of liver diseases between the isoniazid and placebo groups. Furthermore, there was no significant relationship between symptoms and elevated SGOTs. Therefore, symptomatology would not appear to be a sensitive method for detecting early isoniazid liver toxicity. From available evidence, biochemical monitoring would appear to detect liver toxicity at an earlier and more reversible stage.

The determination of resectability of lung cancer by fiberoptic bronchoscopy.

The usefulness of flexible fiberoptic bronchoscopy (FFB) in determining resectability of lung cancer in 152 patients was evaluated. Based on clinical and routine chest roentgenographic examinations, 66 patients (43%) had what were considered to be operable lesions greater than 3 cm in diameter or tumors associated with atelectasis or obstructive pneumonitis (but less than an entire lung), without evidence of pleural effusion or chest wall, mediastinal, or extrathoracic involvement. Forty-eight (73%) of the 66 patients were eventually found to have unresectable conditions. With FFB alone, the conditions of 32 (67%) of these 48 patients were staged as unresectable, so that more invasive procedures, eg, mediastinoscopy or thoracotomy, were required in only 12 and four patients, respectively. Early FFB should be done in potentially resectable cases in which these roentgenographic criteria are met. This procedure is easy, safe, and economical and would allow many patients with lung cancer to have the stage of their disease determined and be treated entirely as outpatients.

Direct Cranial Nerve Involvement by Gliomas: Case Series and Review of the Literature.

Malignant gliomas are characterized by infiltrative growth of tumor cells, including along white matter tracts. This may result in clinical cranial neuropathy due to direct involvement of a cranial nerve rather than by leptomeningeal spread along cranial nerves. Gliomas directly involving cranial nerves III-XII are rare, with only 11 cases reported in the literature before 2014, including 8 with imaging. We present 8 additional cases demonstrating direct infiltration of a cranial nerve by a glioma. Asymmetric cisternal nerve expansion compared with the contralateral nerve was noted with a mean length of involvement of 9.4 mm. Based on our case series, the key imaging feature for recognizing direct cranial nerve involvement by a glioma is the detection of an intra-axial mass in the pons or midbrain that is directly associated with expansion, signal abnormality, and/or enhancement of the adjacent cranial nerves.

Does major depression result in lasting personality change?

OBJECTIVE: Individuals with a history of depression are characterized by high levels of certain personality traits, particularly neuroticism, introversion, and interpersonal dependency. The authors examined the "scar hypothesis," i.e., the possibility that episodes of major depression result in lasting personality changes that persist beyond recovery from the depression. METHOD: A large sample of first-degree relatives, spouses, and comparison subjects ascertained in connection with the proband sample from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression were assessed at two points in time separated by an interval of 6 years. Subjects with a prospectively observed first episode of major depression during the interval were compared with subjects remaining well in terms of change from time 1 to time 2 in self-reported personality traits. All subjects studied were well (had no mental disorders) at the time of both assessments. RESULTS: There was no evidence of negative change from premorbid to postmorbid assessment in any of the personality traits for subjects with a prospectively observed first episode of major depression during the interval. The results suggested a possible association of number and length of episodes with increased levels of emotional reliance and introversion, respectively. CONCLUSIONS: The findings suggest that self-reported personality traits do not change after a typical episode of major depression. Future studies are needed to determine whether such change occurs following more severe, chronic, or recurrent episodes of depression.

Serum lithium levels and psychosocial function in patients with bipolar I disorder.

OBJECTIVE: This study compared the effect of two different serum lithium levels on the psychosocial functioning of patients with bipolar I disorder. METHOD: Ninety patients with bipolar I disorder were enrolled in a prospective, double-blind, maintenance trial of lithium. The patients were randomly assigned to treatment with doses of lithium adjusted to achieve a serum lithium concentration of either 0.8 to 1.0 mmol/liter (standard) or 0.4 to 0.6 mmol/liter (low). The Longitudinal Interval Follow-Up Evaluation was used to assess psychosocial functioning in the areas of work, interpersonal relationships, and global functioning. All observed values were analyzed with a mixed-effects analysis of covariance. Independent variables included treatment group (low or standard lithium serum level), relapse status, socioeconomic status, time from random treatment assignment to assessment, termination of protocol before or after relapse, length of remission before random treatment assignment, polarity of the last mood episode before random treatment assignment, and number of mood episodes in the 3 years before random treatment assignment. RESULTS: Relapse was associated with large negative effects on psychosocial functioning. Patients in higher socioeconomic brackets had better psychosocial functioning than did those in lower brackets. Patients receiving lithium doses that achieved standard serum levels had better psychosocial functioning than those receiving doses that achieved low serum levels; this effect was partially but not wholly mediated through relapse prevention. CONCLUSIONS: For patients with bipolar I disorder, standard serum lithium levels may enhance psychosocial functioning, above and beyond the effects of relapse prevention.

Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects.

OBJECTIVE: There has been speculation in the literature about a link between fluoxetine use and suicidal behavior. The authors of this study hypothesized that there is no elevation in risk of suicidal behavior associated with use of fluoxetine. METHOD: The data come from the National Institute of Mental Health Collaborative Depression Study, a prospective, naturalistic follow-up of persons who presented for treatment of affective disorders. The analyses included data on 643 subjects who were followed up after fluoxetine was approved by the Food and Drug Administration in December 1987 for the treatment of depression. RESULTS: Nearly 30% (N = 185) of the study group was treated with fluoxetine at some point during the follow-up period. Relative to the other subjects, those who were subsequently treated with fluoxetine had onset of affective illness at a younger age and, after intake into the study and before 1988, had elevated rates of suicide attempts before fluoxetine treatment. A mixed-effects survival analysis that incorporated treatment exposure time, multiple treatment trials, and multiple suicide attempts per subject showed that relative to no treatment, use of fluoxetine and use of other somatic antidepressants were associated with nonsignificant reductions in the likelihood of suicide attempts or completions. Severity of psychopathology was strongly associated with elevated risk, and each suicide attempt after intake into the Collaborative Depression Study was associated with a marginally significant increase in risk of suicidal behavior. CONCLUSIONS: The results do not support the speculation that fluoxetine increases the risk of suicide. Rather, there was a nonsignificant reduction in risk of suicidal behavior among patients treated with fluoxetine, even though those subjects were more severely ill before treatment with fluoxetine.

Recurrence after recovery from major depressive disorder during 15 years of observational follow-up.

OBJECTIVE: The recurrence of an affective disorder in people who initially recover from major depressive disorder was characterized by using the unique longitudinal prospective follow-up data from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression-Clinical Studies. METHOD: Up to 15 years of prospective follow-up data on the course of major depressive disorder were available for 380 subjects who recovered from an index episode of major depressive disorder and for 105 subjects who subsequently remained well for at least 5 years after recovery. Baseline demographic and clinical characteristics were examined as predictors of recurrence of an affective disorder. The authors also examined naturalistically applied antidepressant therapy. RESULTS: A cumulative proportion of 85% (Kaplan-Meier estimate) of the 380 recovered subjects experienced a recurrence, as did 58% (Kaplan-Meier estimate) of those who remained well for at least 5 years. Female sex, a longer depressive episode before intake, more prior episodes, and never marrying were significant predictors of a recurrence. None of these or any other characteristic persisted as a predictor of recurrence in subjects who recovered and were subsequently well for at least 5 years. Subjects reported receiving low levels of antidepressant treatment during the index episode, which further decreased in amount and extent during the well interval. CONCLUSIONS: Few baseline demographic or clinical characteristics predict who will or will not experience a recurrence of an affective disorder after recovery from an index episode of major depressive disorder, even in persons with lengthy well intervals. Naturalistically applied levels of antidepressant treatment are well below those shown effective in maintenance pharmacotherapy studies.

Multiple recurrences of major depressive disorder.

OBJECTIVE: The authors of this study examined multiple recurrences of unipolar major depressive disorder. METHOD: A total of 318 subjects with unipolar major depressive disorder were prospectively followed for 10 years within a multicenter naturalistic study. Survival analytic techniques were used to examine the probability of recurrence after recovery from the index episode. RESULTS: The mean number of episodes of major depression per year of follow-up was 0. 21, and nearly two-thirds of the subjects suffered at least one recurrence. The number of lifetime episodes of major depression was significantly associated with the probability of recurrence, such that the risk of recurrence increased by 16% with each successive recurrence. The risk of recurrence progressively decreased as the duration of recovery increased. Within subjects, there was very little consistency in the time to recurrence. CONCLUSIONS: Major depressive disorder is a highly recurrent illness. The risk of the recurrence of major depressive disorder progressively increases with each successive episode and decreases as the duration of recovery increases.

Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness?

OBJECTIVE: This study investigated the influence of incomplete recovery from first lifetime major depressive episodes on long-term outcome. METHOD: After their first lifetime major depressive episode, patients were divided into asymptomatic (N=70) and residual subthreshold depressive symptom (N=26) recovery groups and compared on longitudinal course during up to 12 years of prospective naturalistic follow-up. RESULTS: Patients with residual subthreshold depressive symptoms during recovery had significantly more severe and chronic future courses. Those with residual symptoms relapsed to major and minor depressive episodes faster and had more recurrences, shorter well intervals, and fewer symptom-free weeks during follow-up than asymptomatic patients. CONCLUSIONS: Resolution of major depressive episodes with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course. When ongoing subthreshold symptoms continue after major depressive episodes, the illness is still active, and continued treatment is strongly recommended.

Course of illness and maintenance treatments for patients with bipolar disorder.

BACKGROUND: Both naturalistic studies and treatment research on bipolar disorder are reviewed to describe its clinical course, the need for maintenance therapy, the efficacy of current pharmacologic prophylaxis, and the empirical basis for more comprehensive approaches to treatment. METHOD: Articles were identified through computerized literature searches and from bibliographies of published studies, review articles, and textbooks. RESULTS: Bipolar disorder is marked by multiple relapses and recurrences, as well as significant interepisode psychopathology. Within 1 year of recovery from a mood episode, half of all patients will have suffered a second episode. Various clinical and demographic variables have been investigated as risk factors for recurrence. Although lithium represents the single greatest advance in the treatment of this disease, it is clear that a substantial number of patients fail lithium prophylaxis, including those with a high frequency of prior episodes, mixed (dysphoric) mania, comorbid personality disturbance, and rapid cycling. The foremost pharmacologic alternatives to lithium are the anticonvulsants carbamazepine and valproate. Increased recognition of the psychosocial sequelae of bipolar disorder and the limitations of pharmacotherapy alone have led to the investigation of psychosocial interventions. These preliminary studies are small in number and of poor quality for the most part, but have nevertheless yielded positive findings. CONCLUSION: Although lithium often fails to meet the clearly established need for prophylactic treatment, there is little evidence from rigorous clinical trials to support the wide-spread use of anticonvulsants in maintenance therapy. Treatment research should further examine these medications and the use of psychosocial treatments as adjuvants to pharmacotherapy.

A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder.

BACKGROUND: This pilot study compared the efficacy of lithium plus divalproex sodium with the efficacy of lithium alone for the continuation and maintenance treatment of patients with bipolar I disorder. METHOD: Twelve patients with bipolar I disorder as defined by the DSM-III-R were recruited and followed prospectively for up to 1 year. Each subject received lithium at serum levels of 0.8 to 1.0 mmol/L and a management/education session weekly or every 2 weeks. By random assignment, subjects received either divalproex sodium or placebo in conjunction with lithium. Divalproex sodium was adjusted to achieve a serum concentration of 50 to 125 micrograms/mL. Adjunctive medications were used on an as needed basis to treat psychosis, depression, and anxiety. The course of illness was monitored through use of the Longitudinal Interval Follow-up Examination. RESULTS: Subjects treated with the combination of lithium and divalproex were significantly less likely to suffer a relapse or recurrence (p = .014), but were significantly more likely to suffer at least one moderate or severe adverse side effect (p = .041). There was no significant difference between groups in the use of adjunctive medication. CONCLUSION: These results provide preliminary evidence of the risks and benefits of combining lithium with divalproex sodium for the continuation and maintenance treatment of bipolar I disorder.