To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure firstname.lastname@example.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Immune system markers may predict affective disorder treatment response, but whether an overall immune system marker predicts bipolar disorder treatment effect is unclear.
Bipolar CHOICE (N = 482) and LiTMUS (N = 283) were similar comparative effectiveness trials treating patients with bipolar disorder for 24 weeks with four different treatment arms (standard-dose lithium, quetiapine, moderate-dose lithium plus optimised personalised treatment (OPT) and OPT without lithium). We performed secondary mixed effects linear regression analyses adjusted for age, gender, smoking and body mass index to investigate relationships between pre-treatment white blood cell (WBC) levels and clinical global impression scale (CGI) response.
Compared to participants with WBC counts of 4.5–10 × 109/l, participants with WBC < 4.5 or WBC ≥ 10 showed similar improvement within each specific treatment arm and in gender-stratified analyses.
An overall immune system marker did not predict differential treatment response to four different treatment approaches for bipolar disorder all lasting 24 weeks.
Evidence continues to mount that anticonvulsants represent broad-spectrum central nervous system agents which are highly efficacious in the treatment of core psychiatric symptoms. The US Food and Drug Administration has extended the use of anticonvulsants beyond the treatment of epilepsy, to include wide-reaching neuropsychiatric illnesses such as mania, migraine, panic disorder, and trigeminal neurologia. From the perspective of psychiatric disorders, the most exciting development about these newer agents is the emergence of persuasive evidence that they are effective in treating mood disorders. Depakote and Tegretol have been joined by Neurontin and Lamictal as agents shown to be useful in the treatment of bipolar, and possibly unipolar, depression.
Recently, both clinical and research attention has focused specifically on the use of Neurontin and Lamictal as alternatives to standard, agents for the treatment of mood and anxiety disorders. Because many patients with bipolar disorder experience continued symptomology despite standard treatment, further study of these novel agents for the treatment of affective disorders is warranted.
A post-hoc, descriptive analysis was undertaken to assess the tolerability of and changes in psychiatric rating scales with lamotrigine (LTG) administered concomitantly with commonly prescribed bipolar medications.
During the 8- to 16-week, open-label, preliminary phase of two large clinical trials of patients (N=1,305) with bipolar I disorder, LTG was added to each patient's existing psychotropic regimen. Medications for acute symptoms could have been added and later discontinued to achieve LTG monotherapy. Data were compared for patients taking LTG with or without concomitant valproate, lithium, any atypical antipsychotic, or any selective serotonin reuptake inhibitor.
The percentages of patients with any reported adverse event and reported adverse events of mood symptoms or rash were comparable between those taking LTG with or without other concomitant bipolar medications. Adverse events in >10% of patients in at least one subgroup were headache, infection, nausea, rash, influenza, diarrhea, dizziness, and somnolence. Baseline scores on psychiatric rating scales improved similarly with LTG co-administered with other bipolar medications, and the pattern of results did not differ by baseline polarity of mood symptoms.
LTG co-administered with valproate, lithium, an atypical antipsychotic, or a selective serotonin reuptake inhibitor in the treatment of bipolar disorder seemed to be well tolerated and was associated with clinical improvement.
To assess the efficacy of lamotrigine combined with either divalproex or lithium for the treatment of bipolar disorder.
Lithium and divalproex seem to be predominantly effective for manic and mixed symptoms of bipolar disorder, whereas lamotrigine may be more effective for bipolar depression than for mania. Combination therapy may provide more efficacious treatment for many patients with bipolar disorder.
Data from charts of adult outpatients with bipolar disorder treated with lamotrigine plus divalproex or lithium during a 3-year period were retrospectively analyzed. The Clinical Global Impressions for Bipolar Disorder scale was used to assess severity of illness at baseline (adjunct-therapy initiation) and improvement after 3 months of treatment. The safety and tolerability of the medication combinations were assessed.
After 3 months of treatment, 26 of 39 patients (67%) receiving lamotrigine plus divalproex had a depression rating of 1 (very much improved) or 2 (much improved) compared with seven of 16 (44%) taking lamotrigine plus lithium. The mania rating was 1 or 2 for 13 of 39 (39%) patients treated with lamotrigine plus divalproex and 7 of 16 (44%) patients receiving lamotrigine plus lithium. For overall illness severity, 26 of 39 (67%) patients given lamotrigine plus divalproex had scores of 1 or 2 compared with 10 of 16 (62%) patients taking lamotrigine plus lithium. Five of 39 patients (13%) taking lamotrigine plus divalproex and 5 of 16 (31%) receiving lamotrigine plus lithium discontinued at least one part of the combination in <3 months due to adverse events.
Combination therapy with lamotrigine plus divalproex or lithium may be a valuable option for managing symptoms of bipolar disorder. The combinations were generally well tolerated and apparently effective in improving depression as well as mania.The percentage of patients showing improvement in depression was somewhat larger. Tolerability was somewhat better for lamotrigine plus divalproex in combination than for lamotrigine plus lithium. Differences in tolerability are consistent with studies indicating poorer tolerability of lithium compared with divalproex.
Bipolar disorder, particularly bipolar type I disorder, is at least as highly comorbid with other psychiatric and behavioral disorders as any Axis I medical disorder (Slide 1). Two iterations of the National Comorbidity Survey study, which is epidemio-logic-based and not anecdotal evidence from clinical offices and hospital emergency rooms, have shown that these data are reflective of the overall population in the United States and potentially for all other countries across the world.
In particular, if the prevalence rates of all anxiety disorders are grouped together, they are almost as prevalent as bipolar disorder itself, and clinicians rarely see a patient with bipolar disorder who does not have an anxiety disorder. This finding raises the question that anxiety may not be a separate entity, but an additional fundamental component of bipolar symptomatology, at least for a substantial number of patients. Regardless, the role of anxiety in bipolar disorder is unique. Perugi and colleagues studied the time sequence of different anxiety disorders in relation to first presence and clinical recognition of bipolar disorder (Slide 2). In contrast to panic disorder/agoraphobia and obsessive-compulsive disorder (OCD), social anxiety or social phobia was shown to be prevalent in 94.7% of patients prior to onset of hypomania and the clinically recognizable problematic school and home situations before the diagnosis of the bipolar disorder. This finding suggests that there may be some fundamental aspect of social anxiety and other anxiety disorders that is a ties. These patients tend to be more unstable symptomatically and have multiple comorbidities.
Prevention of mania and maintenance treatment in bipolar disorder is largely routed in the decision to use monotherapy or combination therapy in the treatment regimen. The ability to weigh efficacy against adverse effects is of particular importance in maintenance of this disorder, as most bipolar patients require lifelong use of medication. This discussion will focus on the above mentioned topics, using a case presentation as an example.
There have been no previous factor analytic studies of the Hamilton Depression Rating Scale (HDRS) in samples with bipolar I depression, and no investigations of the utility of any derived factors in determining treatment response in this condition. This study aimed to identify and compare factors of a 31-item version of the HDRS (HDRS-31) in large samples of patients with bipolar depression and Major Depressive Disorder (MDD), then examine the responsiveness of such factors to lamotrigine compared with placebo in the bipolar depressed sample.
This multivariate analytical study was performed on 2 large depressed samples (one bipolar and the other MDD) that had been recruited for separate, contemporaneous, double-blind placebo-controlled trials of lamotrigine. The 2 studies had similar designs and assessment tools, the major measures being the Montgomery–Asberg Depression Rating Scale (MADRS) and HDRS-31. To identify the constructs underlying the scale, exploratory factor analyses were conducted using HDRS-31 baseline scores. Treatment responsiveness in the bipolar depressed sample—as indicated by improvement in the total MADRS and HDRS-31, as well as HDRS factors—were examined using both a mixed-effects analysis and individual time-point t-tests.
Seven factors of the HDRS-31 were identified: I—“depressive cognitions,” II—“psychomotor retardation,” III—“insomnia,” IV—“hypersomnia,” V—“appetite and weight change,” VI—“anxiety,” and VII—“anergia.” A significant therapeutic effect of lamotrigine in bipolar depression was found for the “depressive cognitions” factor (from week 3) and “psychomotor retardation” (from week 4).
This study has identified 7 factors of the HDRS in a large sample of patients with bipolar depression. The results suggest that that the clinical benefits of lamotrigine in acute bipolar depression are primarily upon depressive cognitions and psychomotor slowing.
Combinations of olanzapine and carbamazepine are often used in clinical practice in the management of mania.
To assess the efficacy and safety of olanzapine plus carbamazepine in mixed and manic bipolar episodes.
Randomised, double-blind, 6-week trial of olanzapine (10–30 mg/day) plus carbamazepine (400–1200 mg/day; n=58) v. placebo plus carbamazepine (n=60) followed by open-label, 20-week olanzapine (10–30 mg/day) plus carbamazepine (400–1200 mg/day, n=86), with change in manic symptoms as main outcome measure. Safety and pharmacokinetics were also evaluated.
There were no significant differences (baseline to endpoint) in efficacy measures between treatment groups, but at 6 weeks triglyceride levels were significantly higher (P=0.008) and potentially clinically significant weight gain (⩾7%) occurred more frequently (24.6% v. 3.4%, P=0.002) in the combined olanzapine and carbamazepine group. Carbamazepine reduced olanzapine concentrations but olanzapine had no effect on carbamazepine concentrations.
The combination of olanzapine and carbamazepine did not have superior efficacy to carbamazepine alone. The increases in weight and triglycerides observed during combination treatment are a matter of concern.
Sub-syndromal symptoms in bipolar disorder impair functioning and
diminish quality of life.
To examine factors associated with time spent with sub-syndromal symptoms
and to characterise how these symptoms influence outcomes.
In a double-blind randomised maintenance trial, patients received either
olanzapine or lithium monotherapy for 1 year. Stepwise logistic
regression models were used to identify factors that were significant
predictors of percentage time spent with sub-syndromal symptoms. The
presence of sub-syndromal symptoms during the first 8 weeks was examined
as a predictor of subsequent relapse.
Presence of sub-syndromal depressive symptoms during the first 8 weeks
significantly increased the likelihood of depressive relapse (relative
risk 4.67, P<0.001). Patients with psychotic features
and those with a greater number of previous depressive episodes were more
likely to experience sub-syndromal depressive symptoms (RR=2.51,
P<0.001 and RR=2.35, P=0.03
These findings help to identify patients at increased risk of affective
relapse and suggest that appropriate therapeutic interventions should be
considered even when syndromal-level symptoms are absent.
Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder.
To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone.
Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6–1.2 mmol/l) or valproate (50–125 μg/ml) received lithium or valproate plus either olanzapine 5–20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months.
The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy42 days; P=0.023).
Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy.
Despite increasing knowledge of the neurochemical bases of the action of the tricyclic drugs, little is known about the sequence of psychological effects which precede recovery in drug-responsive patients. This research was aimed at identifying the specific behavioural effects associated with the therapeutic action of amitriptyline in depression. The design involved measurement (post-hoc) of weekly changes in a severely depressed placebo-resistant group who recovered with drug treatment, compared with a group of similar patients treated for the equivalent four weeks, who showed minimal to no clinical response. The research strategy, in accordance with a dose–response paradigm, was to determine which of the early changes in emotion and behaviour found in treatment responders were systematically associated with plasma concentrations of amitriptyline or its major metabolite. Amitriptyline was found to act within seven days on the components of anxiety and on hostility in the responders, and on sleep disorder in all patients. After 12 to 14 days of treatment these effects increased, with improvements in other significant components distinguishing the responders from the non-responders. At the 12th to 14th treatment days when a steady state concentration of drug in plasma was approached, reductions in anxiety and hostility and in certain somatic components correlated significantly with plasma concentrations of amitriptyline. Implications of the findings for clarifying the specificity of clinical actions of the tricyclic drugs, and for understanding the psychobiological dynamics underlying rapid drug-induced recovery in depression, were explored.
Preliminary data are presented from the NIMH Collaborative Study on the psychobiology of depression, biological studies, dealing with relationships between the pre-treatment levels of the neurotransmitter metabolites 3-methoxy-4-hydrophenethyleneglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and the subsequent therapeutic response of depressed patients to imipramine or amitriptyline. Eighty-seven depressed patients were studied during pre-treatment and treatment periods. It has been found that (1) both low pre-treatment urinary MHPG and low CSF 5-HIAA values are associated with a response to imipramine; these relationships were not artefacts due to sex or age; (2) there were no significant relationships between pre-treatment urinary MHPG, CSF MHPG, 5-HIAA, or HVA values and the subsequent response, or failure of response, to amitriptyline; (3) there was not a bimodal distribution for CSF 5-HIAA. For both males and females, there were positive and statistically significant correlations between CSF MHPG and urinary MHPG; for the females, there were positive and significant correlations between both urinary and CSF MHPG and CSF 5-HIAA. The theoretical and practical implications of these findings are discussed.
There are many reports which suggest that patients with affective illness (mania and/or depression) have abnormalities in the functioning of one or more neurobiological systems. At a conference convened by the Clinical Research Branch, Division of Extramural Research Programs, National Institute of Mental Health, these findings were reviewed and some of the factors impeding movement towards a more complete and integrated view of the functioning of neurobiological systems in patients with mania or depression were identified. As a result, a multi-research centre, collaborative approach to the study of the psychobiology of affective disorders was developed. In this collaborative programme, which has now been underway for several years, the focus has been upon: (a) the assessment of the functioning of several different types of biological systems in the same patient, both before and during treatment; (b) obtaining a reasonably large number of patients and comparison subjects; and (c) the use within and across centres of standardized diagnostic categories and behavioural rating methodologies. In this paper the history, background, and rationale for this collaborative effort are reviewed. Those biological systems chosen for study are noted, and issues such as reliability and validity of diagnoses, measurement of state variables, assessment of change with treatment, and logistical and coordinating problems are discussed.
Email your librarian or administrator to recommend adding this to your organisation's collection.