Functional anatomy of autobiographical memory recall deficits in depression.

BACKGROUND: Major depressive disorder (MDD) is associated with deficits in recalling specific autobiographical memories (AMs). Extensive research has examined the functional anatomical correlates of AM in healthy humans, but no studies have examined the neurophysiological underpinnings of AM deficits in MDD. The goal of the present study was to examine the differences in the hemodynamic response between patients with MDD and controls while they engage in AM recall. METHOD: Participants (12 unmedicated MDD patients; 14 controls) underwent functional magnetic resonance imaging (fMRI) scanning while recalling AMs in response to positive, negative and neutral cue words. The hemodynamic response during memory recall versus performing subtraction problems was compared between MDD patients and controls. Additionally, a parametric linear analysis examined which regions correlated with increasing arousal ratings. RESULTS: Behavioral results showed that relative to controls, the patients with MDD had fewer specific (p=0.013), positive (p=0.030), highly arousing (p=0.036) and recent (p=0.020) AMs, and more categorical (p<0.001) AMs. The blood oxygen level-dependent (BOLD) response in the parahippocampus and hippocampus was higher for memory recall versus subtraction in controls and lower in those with MDD. Activity in the anterior insula was lower for specific AM recall versus subtraction, with the magnitude of the decrement greater in MDD patients. Activity in the anterior cingulate cortex was positively correlated with arousal ratings in controls but not in patients with MDD. CONCLUSIONS: We replicated previous findings of fewer specific and more categorical AMs in patients with MDD versus controls. We found differential activity in medial temporal and prefrontal lobe structures involved in AM retrieval between MDD patients and controls as they engaged in AM recall. These neurophysiological deficits may underlie AM recall impairments seen in MDD.

Three-year outcomes for maintenance therapies in recurrent depression.

We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.

Five-year outcome for maintenance therapies in recurrent depression.

After conducting a randomized, 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy, we asked those individuals who survived the 3-year trial receiving active medication (with or without psychotherapy) to continue in a 2-year additional randomized trial of active medication vs placebo. The question was whether maintaining antidepressant medication at the dosage used to treat the acute episode beyond 3 years would continue to provide a significant prophylactic effect compared with medication discontinuation after the 3 years of effective maintenance treatment. Survival analysis demonstrated a highly significant continued prophylactic effect for active imipramine hydrochloride treatment maintained at an average dose of 200 mg. We conclude that active imipramine treatment is an effective means of preventing recurrence beyond 3 years and that patients with previous episodes less than 2 1/2 years apart, therefore, merit continued prophylaxis for at least 5 years.

Platelet membrane phospholipids in euthymic bipolar disorder patients: are they affected by lithium treatment?

BACKGROUND: Abnormalities in cell membrane processes and intracellular signal transduction pathways may be implicated in the pathophysiology of bipolar disorder. In this study, we attempted to investigate, in euthymic bipolar patients: 1) in vivo signal transduction abnormalities of the phosphatidylinositol pathway in platelets; and 2) possible in vivo effects of lithium treatment on platelet membrane phospholipids. METHODS: We determined the relative absorbances of eight individual classes of platelet membrane phospholipids, using two-dimensional thin-layer chromatography in high-performance plates, followed by scanning laser densitometry, in a group of 10 lithium-treated euthymic bipolar patients and 11 normal controls. RESULTS: The mean relative absorbance of phosphatidyl-inositol-4,5-bisphosphate (PIP2) was lower in the patient group (0.29 +/- 0.08% vs. 0.39 +/- 0.12%; t = 2.35, df = 19, p = .03); no significant differences between patients and controls were found for the other phospholipids. CONCLUSIONS: This study provides in vivo evidence that bipolar patients on lithium treatment exhibit a decreased relative amount of PIP2 in the platelet cell membranes compared to normal controls.

Inducing lifestyle regularity in recovering bipolar disorder patients: results from the maintenance therapies in bipolar disorder protocol.

On the basis of theories we articulated in earlier papers (Ehlers et al 1988: Arch Gen Psychiatry 45:948-952, 1993: Depression 1:285-293), we have developed an adjunctive psychosocial intervention for patients with bipolar 1 disorder. Central to this intervention is the establishment of regularity in daily routines. In this report, we present data from a controlled investigation comparing this new treatment, interpersonal and social rhythm therapy (IPSRT), with a conventional medication clinic approach. Despite comparable changes in symptomatology over a treatment period lasting up to 52 weeks, subjects assigned to IPSRT (n = 18) show significantly greater stability (p = .047) of daily routines with increasing time in treatment, while subjects assigned to the medication clinic condition (n = 20) show essentially no change in their social routines as measured by Social Rhythm Metric (SRM-Monk et al 1990: J Nerv Ment Dis 178(2):120-126) score. We conclude that IPSRT is capable of influencing lifestyle regularity in patients with bipolar 1 disorder, with the possible benefit of protection against future affective episodes.

Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T.

BACKGROUND: This study was conducted to investigate the feasibility of human brain (7)Li MRS investigations at a high magnetic field (3 T), and to further explore the relationship between brain and serum lithium measures in lithium-treated bipolar patients. METHODS: Eight bipolar disorder type I patients (5 males, 3 females; mean age +/- SD = 33 +/- 9 years) were studied. A 3-T scanner, using a dual-tuned ((1)H and (7)Li) echoplanar imaging (EPI) compatible radiofrequency (RF) birdcage coil was used. (7)Li magnetic resonance spectroscopy (MRS) signal was acquired at the frequency of 49.64 MHz using an imaging selective in vivo spectroscopy (ISIS) sequence (TR = 15 sec, 128 averages), and quantitation was obtained in reference to an external standard. RESULTS: The mean +/- SD oral lithium dose was 1265 +/- 442 mg/day, and the mean +/- SD 12-hour serum level was 0.69 +/- 0.19 mEq/L. The measured brain lithium concentrations varied from 0.23 to 0.55 mEq/L (mean +/- SD = 0.35 +/- 0.11 mEq/L). The brain-serum ratios varied from 0.30 to 0.80 (mean +/- SD = 0.52 +/- 0.16). Subjects on single daily doses of lithium at bedtime (n = 5) had higher brain-serum lithium ratios compared with those on twice-a-day schedules (n = 3) (0.61 +/- 0.12 and 0.37 +/- 0.07, respectively; Mann--Whitney U test, Z = -2.24, p =.03). CONCLUSIONS: This study demonstrated for the first time the feasibility of (7)Li MRS human studies at 3 T. Future studies should examine a possible role for this methodology in investigations of lithium refractoriness and prediction of treatment outcome in bipolar patients.

Decreased pituitary volume in patients with bipolar disorder.

BACKGROUND: Neuroendocrinologic investigations in bipolar disorder have suggested abnormalities in pituitary function. However, few imaging studies have evaluated possible anatomical differences in this brain structure in mood disorder patients. Our aim was to examine potential abnormalities in pituitary volume in patients with bipolar and in a comparison group of patients with unipolar disorder. METHODS: We measured the volumes of the pituitary gland in 23 patients with bipolar disorder (mean +/- s.d. = 34.3 +/- 9.9 years) and 13 patients with unipolar disorder (41.2 +/- 9.6 years), and 34 healthy control subjects (36.6 +/- 9.6 years) using 1.5 mm thick T1-weighted coronal 1.5 T MRI images. All measurements were done blindly by a trained rater. RESULTS: Patients with bipolar disorder had significantly smaller pituitary volumes than healthy control subjects (mean volume +/- s.d. = 0.55 +/- 0.15 ml and 0.68 +/- 0.20 ml, respectively; ANCOVA, F = 8.66, p = 0.005), and than patients with unipolar disorder (0.70 +/- 0.12 ml, F = 5.98, p = 0.02). No differences were found between patients with unipolar disorder and healthy control subjects (F = 0.01, p = 0.91). CONCLUSIONS: To our knowledge, this is the first study that reports smaller pituitary volumes in bipolar disorder. Our findings suggest that detectable abnormalities in pituitary size are present in patients with bipolar disorder, which may reflect a dysfunctional HPA axis.

In vitro and in vivo transport of lithium by human erythrocytes.

An in vitro system that can be used to measure both uptake and efflux of lithium by erythrocytes (RBCs) is described. Using this system, RBC lithium accumulation in vitro was compared with in vivo RBC lithium concentrations observed in 6 normal volunteers. A significant correlation was demonstrated between in vitro RBC lithium accumulation after 48-hr incubation and in vivo RBC lithium concentration at 24, 48, 72, and 96 hr following the beginning of lithium ingestion. In addition, when efflux of lithium from RBCs in vitro was studied, a significant correlation was observed between residual lithium in RBCs and in vitro RBC lithium accumulation. Finally, it has been demonstrated that storage of blood in ice for 5 hr prior to incubation with lithium results in increased RBC lithium accumulation. A potential role for this in vitro incubation system as a model for in vivo RBC lithium accumulation is suggested.

Pharmacokinetics of tranylcypromine in patients who are depressed: relationship to cardiovascular effects.

We investigated the pharmacokinetics of tranylcypromine, as well as the relationship between plasma levels of this agent and its effects on blood pressure and pulse rate. Tranylcypromine was absorbed rapidly after oral dosing, with the peak level being attained within 0.67 to 3.50 hours. Absorption was biphasic in seven of nine subjects. Elimination of tranylcypromine also was rapid, with a t 1/2 between 1.54 and 3.15 hours. From 2 to 7 hours after dosing, standing systolic and diastolic blood pressures were lowered and standing pulse was raised, compared with baseline. Onset of the effect on standing systolic blood pressure was correlated with the time of peak plasma tranylcypromine concentration. Maximum orthostatic drop of blood pressure and rise of pulse rate occurred 2 hours after dosing. Mean plasma tranylcypromine concentrations were correlated with mean orthostatic drop of systolic blood pressure and rise of pulse rate. Patients who have clinically significant hypotensive reactions to this agent may benefit from changes in their dose regimen aimed at minimizing peak tranylcypromine levels.

Adjustment of lithium dose during lithium-chlorothiazide therapy.

There has been a long-held belief that lithium salts cannot be used in the presence of thiazide diuretics. Recently, however, thiazides have been demonstrated to be not only safe, but actually indicated in two situations in which lithium salts are used. The first is in the treatment of lithium-induced nephrogenic diabetes insipidus and the second is in severe manic depressive illness in which high doses of lithium do not produce therapeutic serum or intraeythrocytic lithium concentrations. This new information now makes it possible for some manic depressive patients with serious medical illnesses (such as hypertension or congestive heart failure), in whom thiazide diuretics are routinely used, to be treated cautiously with lithium carbonate. This paper analyzes data from 13 patients taking lithium carbonate and varying doses of chlorothiazide in order to indicate the approximate magnitude of downward adjustment of daily lithium dose which the clinician must make to safely give 500, 750, and 1,000 mg/day of chlorothiazide.

Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate in bipolar mania.

Membrane phospholipids were measured in platelets of seven medication-free patients in the manic phase of bipolar affective disorder and seven healthy comparison subjects. The relative percentage of platelet membrane phosphatidylinositol-4,5-bisphosphate was significantly higher in the manic patients than in the comparison subjects. These results are consistent with an enhanced neuronal second messenger response after 5-hydroxytryptamine receptor stimulation followed by neurotransmitter release.

Tranylcypromine versus imipramine in anergic bipolar depression.

OBJECTIVE: This investigation compared the efficacy of the monoamine oxidase inhibitor (MAOI) tranylcypromine with that of the tricyclic imipramine in the treatment of anergic bipolar depressive illness. METHOD: A controlled, double-blind comparison was used to study 56 outpatients who met operationalized criteria for anergic bipolar depression. Patients with bipolar I and II depression were equally distributed between comparison groups. Outcome was measured by the patient-rated Beck Depression Inventory and the clinician-rated Hamilton Rating Scale for Depression, Raskin Mania and Depression Scales, Clinical Global Impression Scale, and the Pittsburgh Reversed Vegetative Symptom Scale. Twenty-eight patients were treated with tranylcypromine and 28 with imipramine. Seventy-three percent of bipolar depressive patients screened for the study met criteria for anergic depression, consistent with previous findings from studies in bipolar illness that stretch back over 100 years. RESULTS: Tranylcypromine produced statistically significant superior outcome in terms of lower attrition, greater symptomatic improvement, and higher global response without increased risk of treatment-emergent hypomania or mania. CONCLUSIONS: The authors propose that the apparently superior efficacy of tranylcypromine in bipolar depression is specifically linked to anergia and reversed neurovegetative symptoms. Bipolar I and bipolar II patients had comparable outcomes, but bipolar I patients had a significantly greater risk of treatment-emergent mood swings. Although the relatively poor showing of imipramine warrants close scrutiny, these findings provide further documentation of the utility of MAOIs in patients presenting with anergia, motor retardation, hyperphagia, and/or hypersomnia.

Treatment of imipramine-resistant recurrent depression, IV: A double-blind crossover study of tranylcypromine for anergic bipolar depression.

OBJECTIVE: Few trials of monoamine oxidase inhibitors (MAOIs) in tricyclic-resistant depression have had double-blind conditions. In the authors' previous double-blind comparison of tranylcypromine and imipramine in anergic bipolar depression, tranylcypromine was significantly more effective. This investigation was a crossover study of nonresponders in the initial study. METHOD: The subjects were 16 outpatients with anergic bipolar depression. Fourteen had not responded to 4 weeks of treatment with at least 30 mg/day of tranylcypromine or 150 mg/day of imipramine, and two patients were crossed over because of intolerable side effects from the initial drug. The crossover medication was prescribed as in the initial double-blind study. RESULTS: Twelve patients were crossed over from imipramine to tranylcypromine; nine of them responded to tranylcypromine. Highly significant improvements were documented on the Hamilton, Beck, and Pittsburgh Reversed Vegetative Symptom Scales. Four patients were switched from tranylcypromine to imipramine, but only one responded. CONCLUSIONS: The high rates of response to tranylcypromine in both the initial and crossover double-blind studies document the efficacy of MAOI treatment for anergic bipolar depression. Moreover, the results further illustrate the utility of MAOIs in tricyclic-resistant depressions.

Sleep EEG and DST findings in anergic bipolar depression.

The authors report sleep EEG and dexamethasone suppression test (DST) findings for a homogeneous sample of anergic bipolar depressed outpatients (bipolar I, N = 7; bipolar II, N = 19) characterized by motor retardation, volitional inhibition, hypersomnia, or weight gain and sleep EEG findings for 26 age- and sex-matched normal control subjects. Sleep architecture was abnormal in bipolar depression, particularly with respect to little stage 1 sleep. The biological profile of an anergic episode of bipolar depression did not include a shorter than normal mean REM latency, poor sleep continuity, or abnormally low amounts of stages 3 and 4 sleep, and only three (13%) of 23 patients manifested cortisol nonsuppression.

Anxiety as a correlate of response to the acute treatment of bipolar I disorder.

OBJECTIVE: Given the adverse impact of anxiety on treatment outcome in unipolar depression and the paucity of data on the role of anxiety in bipolar disorder, the authors sought to determine the effect of anxiety on the acute treatment response of patients with bipolar I disorder. METHOD: The authors examined the correlates of response to the acute treatment of 124 consecutively treated patients with bipolar I disorder. Measures of anxiety included history of panic attacks and a composite variable reflecting current or past anxiety symptoms. RESULTS: History of panic attacks proved to be a significant correlate of nonremission. Anxiety, as assessed with the composite variable, was associated with longer time to remission, as was the treatment of depressive versus manic symptoms and mixed versus manic symptoms. Patients with anxiety as assessed with the composite variable and patients with a history of panic attacks reported more severe medication side effects. They also required a greater number of medications, either sequentially or in combination, in order to achieve remission. CONCLUSIONS: The findings suggest that anxiety is a clinically meaningful correlate of poor outcome in the acute treatment of bipolar I disorder.

Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles.

OBJECTIVE: The authors tested the hypothesis that patients whose episodes of major depression evidenced more neurobiological disturbance would be less responsive to psychotherapy. METHOD: The study subjects were outpatients who were given a diagnosis of recurrent major depressive disorder (unipolar or bipolar II), according to the Research Diagnostic Criteria, following an interview with the Schedule for Affective Disorders and Schizophrenia. They were classified into a group with normal sleep profiles (N = 50) and a group with abnormal sleep profiles (N = 41) on the basis of a validated index score derived from three EEG sleep variables monitored for 2 nights: sleep efficiency, REM latency, and REM density. The groups' responses to short-term interpersonal psychotherapy were compared by means of chi-square tests and life table and random effects model analyses. Responses to the addition of pharmacotherapy for subjects who did not respond to interpersonal psychotherapy were also compared. RESULTS: The patients with abnormal sleep profiles had significantly poorer clinical outcomes with respect to symptom ratings, attrition rates, and remission rates than the patients with more normal sleep profiles. Seventy-five percent of the patients who did not respond to interpersonal psychotherapy had remissions during subsequent pharmacotherapy. CONCLUSIONS: These findings help to define further a neurobiological "boundary" that may limit response to psychotherapy in depression. An abnormal sleep profile may reflect a more marked disturbance of CNS arousal that warrants pharmacotherapy.

Low rate of membrane lithium transport during treatment correlates with outcome of maintenance pharmacotherapy in bipolar disorder.

Lithium is transported across cell membranes by an exchange diffusion process (Na(+)-Li+ countertransport) that is inhibited during lithium treatment. We hypothesized that low rates of lithium efflux (a potential manifestation of strong transport inhibition) would be associated with better clinical outcome of maintenance pharmacotherapy. We measured the erythrocyte (RBC) apparent rate constant for lithium efflux (kexch) in 22 patients with bipolar disorder who had been euthymic on lithium for 1 month. Subsequently, clinical mood ratings and in vivo RBC: plasma lithium ratios (LiR) were determined monthly. Outcome was categorized according to whether subjects completed 1 year of successful maintenance treatment (n = 10), experienced a recurrent affective episode (n = 8), or dropped out (n = 4). The kexch at the outset of the study was significantly lower (potentially because of greater transport inhibition) in 1-year completers than in patients with recurrences or those who dropped out (median kexch = 0.09, 0.24, and 0.27 h-1, respectively; P < .03). Moreover, 77% of patients with a kexch of 0.11 h-1 or lower were successfully maintained on lithium for 1 year, whereas only 23% of those with a kexch greater than or equal to 0.12 h-1 had a successful treatment outcome. LiR measured during the course of maintenance treatment was significantly higher (suggesting greater transport inhibition) in 1-year completers than in noncompleters (recurrences and dropouts). Measurement of kexch at an early point in treatment may provide a means for prospectively identifying those bipolar patients at greater risk for failure of maintenance lithium therapy.

Variability of erythrocyte and serum lithium levels correlates with therapist treatment adherence efforts and maintenance treatment outcome.

This study investigated the relationship between psychotherapeutic interventions and pharmacologic measures of pharmacotherapy treatment adherence in patients with bipolar I disorder, as well as the relationship between these measures and treatment outcome. Subjects were participating in an ongoing maintenance treatment study. Audiotaped therapy sessions were rated for frequency of psychotherapeutic interventions related to pharmacotherapy treatment adherence. Pharmacologic measures of medication adherence were compared to the tape ratings as well as to treatment outcome. Variability in log erythrocyte (RBC) lithium-a marker of probable nonadherence to the pharmacotherapy regimen-for individual patients correlated significantly with treatment adherence interventions scale ratings. This marker of nonadherence was significantly related to maintenance treatment outcome, as was variability of the serum lithium level/dose (L/D) ratio; however, no relationship was found between treatment adherence interventions scale ratings and outcome.

Red blood cell sodium-lithium countertransport and cardiovascular risk factors in black and white college students.

Whites with essential hypertension have high activity of cell membrane sodium-lithium (Na+-Li+) countertransport when compared with normotensives. To determine whether elevated Na+-Li+ countertransport is related to the twofold higher risk of hypertension in US blacks, maximal rates of red blood cell (RBC) Na+-Li+ countertransport were measured in 34 black and 21 white male college students. The race groups were similar in social and physical measurements. Mean Na+-Li+ countertransport activity (mmol Li/RBC per h) was significantly lower in blacks than in whites (0.214 +/- 0.083 versus 0.295 +/- 0.083, P less than 0.001). Countertransport activity was positively correlated with Type A behaviour among whites (r = 0.45, P = 0.039). Other within race correlations between Na+-Li+ countertransport activity and blood pressure and cardiovascular risk factors were generally positive though not significant in whites, whereas they were small or negative in blacks. If Na+-Li+ countertransport has a role in the aetiology of hypertension, it would appear to differ between blacks and whites.

Anergic depression accompanied by increased intracellular sodium and lithium.

This report describes a patient who experienced chronic retarded depression punctuated by precipitous worsening of mood with hyperphagia or by intermittent euphoric episodes. Ratings of depressive symptom severity changed in close association with intracellular sodium content. Intracellular sodium was highly correlated with intracellular lithium. Difficulties that were encountered in the clinical management of this patient are discussed.