Laszlo Gyulai

Maintenance efficacy of divalproex in the prevention of bipolar depression

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2u2009:u20091u2009:u20091 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.

Testing definitions of dysphoric mania and hypomania: prevalence, clinical characteristics and inter-episode stability

37 outpatients with at least one prospectively observed manic or hypomanic episode comprised a sample for comparison of five definitions of dysphoric (hypo)mania. Dysphoric symptoms were continuously rather than bimodally distributed. Prevalence of dysphoria varied from 5 to 73% depending on the definition used. Female gender was associated with dysphoria under two of the five definitions. Inter-episode stability in patients with at least two prospectively observed episodes (n = 15) was not significantly different from chance. These data do not indicate that (hypo)mania can be dichotomized on the basis of dysphoria. Advantages and disadvantages of dimensional and categorical approaches to specifying mood in mania or hypomania are discussed.

Phosphorylethanolamine - the major constituent of the phosphomonoester peak observed by 31P-NMR on developing dog brain

31P‐NMR spectra of newborn dog brains exhibit a prominent phosphomonoester (PME) peak (6.78 ± SD. 0.05 ppm from phosphocreatine peak), similar to those of human neonates. Studies were undertaken to identify the chemical constituents of this peak. Brains of puppies were funnel frozen for methanol‐HCl‐perchloric acid extraction after in vivo 31P‐NMR spectra were taken. The pK of the major component of the PME region in the NMR spectrum of extract was 5.4, corresponding to that of phosphorylethanolamine (PEt). Addition of PEt increased the major peak on the PME region over a wide range of pH, while addition of phosphorylcholine or ribose 5‐phosphate yielded distinct peaks. We suggest that the major constituent of phosphomonoester peak of 31P‐NMR spectra of newborn dog brain is phosphorylethanolamine. Biochemical mechanisms relevant to changes of phosphorylethanolamine during brain development are discussed.

In vivo Time-Resolved Brain Phosphorus Nuclear Magnetic Resonance

Methods used to obtain and quantify high-quality time-resolved dog brain phosphorus nuclear magnetic resonance (31P NMR) spectra are described. In eight animals the normoxic dog brain spectra showed 10% of total phosphorus in ATP, 14% in phosphocreatine (PCr), and 38% in brain phospholipids containing phosphodiesters. The chemical shift between PCr and inorganic phosphate, 5.09, corresponded to an intracellular brain pH of 7.2. During hypoxia, PCr declined to 0.5 ± 0.3 (n = 8) of starting levels, prior to any changes in brain ATP. Simultaneous recording of the EEG was obtained in two animals. During hypoxia, progressive PCr depletion was associated with progressive slowing of the EEG, which was essentially silent before significant changes occurred in brain ATP. Finally, the brain 31P NMR spectrum and pH were measured at 90-s intervals, and the sequential changes that followed respiratory arrest were monitored in one dog until high-energy phosphate depletion was complete.

Simultaneous 31P- and 1H-nuclear magnetic resonance studies of hypoxia and ischemia in the cat brain

The objective of this study was to evaluate simultaneous 31P/1H nuclear magnetic resonance (NMR) spectroscopy as a technique for monitoring and correlating changes in brain energy metabolism during hypoxia and ischemia. Five cats were studied with a protocol that involved 20 min of hypoxia (Pao2 20 mm), 60 min of recovery, 10 min of hypoxia with relative ischemia (bilateral carotid occlusion, PaO2 20 mm), and 60 min of recovery. Bifrontal and biparietal electrocorticograms (ECoG) were monitored continuously during the entire protocol. The results demonstrate that the degree of metabolic response is different in individual cats, but a number of quantitative relationships between metabolic parameters are consistently observed for all cats. First, there is agreement between increases in lactate and changes in intracellular pH; the observed relationship corresponds to an in vivo cerebral buffer capacity of 29 μmol/g/pH unit. Second, the delayed recovery of PCr is due to the effect of metabolic acidosis on the creatine kinase equilibrium and not to a delayed recovery of the ATP/ADP ratio. Third, the observed rate of lactate clearance from the cell is zero-order (k = 0.36 μmol/g/min) for lactate levels >5 μm/g and may be composed of both lactate efflux from the cell and lactate oxidation.

Measurement of tissue lithium concentration by lithium magnetic resonance spectroscopy in patients with bipolar disorder

Measurements of the lithium concentration in the occipital pole of the head and calf muscle of nine patients with bipolar disorder in remission were performed using in vivo lithium-7 nuclear magnetic resonance spectroscopy (7Li NMR). 7Li NMR measurements were performed on a 1-m-bore, 1.85-T, superconducting magnet supplemented with a multinuclear spectrometer, using 11.5-cm-diameter surface coils. The average lithium concentration in the occipital pole was 0.36 +/- 0.10 mEq/L, whereas in the muscle it was 0.50 +/- 0.17 mEq/L, both lower than the average serum lithium concentration (0.79 +/- 0.23 mEq/L). The average brain/serum lithium concentration ratio was 0.47 +/- 0.12 whereas the average muscle/serum lithium concentration ratio was 0.66 +/- 0.20. There was a positive correlation between the brain versus serum and brain versus muscle lithium concentrations. The hypothesis is advanced that the minimal effective concentration of brain lithium concentration for maintenance treatment of bipolar disorder is around 0.2-0.3 mEq/L.

Telephone versus in-person clinical and health status assessment interviews in patients with bipolar disorder.

&NA; We evaluated the correspondence between in‐person‐ and telephone interview‐derived data on affective symptoms, health‐related quality of life, disability days, and medication compliance in patients with bipolar disorder. Twenty‐eight outpatients with DSM‐III‐R‐documented bipolar disorder were randomly assigned to an initial in‐person or telephone interview. An average of 4.0 days later, they were reassessed by the other interview method. Results indicate good to excellent agreement between telephone and in‐person interviews on measures of mania (intraclass correlation coefficient (ICC) = 0.92) and depression symptoms (ICC = 0.90), suicide risk (k = 0.80), and alcohol use (k = 0.61), scores on the Medical Outcomes Study 36‐Item Short‐Form Health Survey (ICCs = 0.66–0.92), and medication compliance (ICCs = 0.50–0.66). Measures of bed disability days (ICC = 0.34) and restricted activity days (ICC = 0.66) showed less agreement. Telephone interviews are feasible and reliable for collecting data on psychiatric and other health‐related outcomes in bipolar disorder patients.

I-123 iofetamine single-photon computed emission tomography in rapid cycling bipolar disorder : A clinical study

The regional distribution of I-123 iofetamine (IMP) in the brain of 12 patients with rapid cycling bipolar disorder was studied by single-photon computed emission tomography imaging. Patients who were either medication free (n = 4) or on lithium monotherapy (n = 8) were assessed serially in depressed/dysphoric, manic/hypomanic, or euthymic states. In 23 imaging studies, IMP images of the brain were taken on a GE Starcam system 20 min after injection of 3-4 mCi of I-123 labeled IMP. The I-123 IMP distribution in the anterior part of the temporal lobes was asymmetric in both depression/dysphoria and mania/hypomania but not in euthymia. Images taken sequentially on the same patient showed temporal lobe asymmetry in the pathological mood states that diminished or disappeared in the euthymic state. The observed changes most likely reflect an altered cerebral blood flow and changes in high-affinity IMP binding to amine receptors in the temporal lobes. This pilot study suggests the presence of a state-dependent temporal dysfunction in bipolar disorder.

Thyroid hypofunction in patients with rapid-cycling bipolar disorder after lithium challenge.

BACKGROUNDnThere is debate whether patients with rapid-cycling bipolar disorder (BD) are predisposed to thyroid axis abnormalities and whether this may contribute to development of rapid mood shifts. Using lithium carbonate as a challenge to the hypothalamic-pituitary-thyroid (HPT) system, we determined whether patients with rapid-cycling BD are sensitive to the antithyroid properties of lithium.nnnMETHODSnWe studied the response to thyrotropin-releasing hormone (TRH) of HPT system hormones in 20 medication-free patients with rapid-cycling BD and compared these measurements with those of 20 healthy age- and gender-matched control subjects. The same measurements were repeated after both groups had received lithium carbonate for 4 weeks in sufficient doses to maintain blood levels between.7-1.2 mEq/L.nnnRESULTSnAt baseline, the results of thyroid function tests, including the TRH challenge test, did not differ between patients and control subjects. After treatment with lithium, serum concentrations of thyroxine significantly decreased, whereas basal thyrotropin (TSH) and DeltaTSH(max) significantly increased in both patients and control subjects; however, patients had significantly higher DeltaTSH(max) after TRH stimulation. More patients than control subjects developed laboratory evidence consistent with grade III hypothyroidism after lithium treatment.nnnCONCLUSIONSnRapid-cycling BD is associated with a latent hypofunction of the HPT system. This dysfunction becomes manifest with short-term lithium challenge.

Validity of the distinction between primary and secondary substance use disorder in patients with bipolar disorder: data from the first 1000 STEP-BD participants.

The validity of a primary/secondary substance use disorder (SUD) distinction was evaluated in the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder. Patients with primary SUD (n = 116) were compared with those with secondary SUD (n = 275) on clinical course variables. Patients with secondary SUD had fewer days of euthymia, more episodes of mania and depression, and a greater history of suicide attempts. These findings were fully explained by variations in age of onset of bipolar disorder. The order of onset of SUDs was not linked to bipolar outcomes when age of onset of bipolar disorder was statistically controlled. The primary/secondary distinction for SUD is not valid when variations in the age of onset of the non-SUD are linked to course characteristics.