Author |
Baethge C, Tondo L, Bratti IM, Bschor T, Bauer M, Viguera AC, Baldessarini RJ |
Title |
Prophylaxis latency and outcome in bipolar disorders. |
Journal |
Can J Psychiatry |
Abstract |
OBJECTIVE: To analyze new and reviewed findings to evaluate relations between treatment response and latency from onset of bipolar disorder (BD) to the start of mood-stabilizer prophylaxis. METHOD: We analyzed our own new data and added findings from research reports identified by computerized searching. RESULTS: We found 11 relevant studies, involving 1485 adult patients diagnosed primarily with BD. Reported latency to prophylaxis averaged 9.6 years (SD 1.3), and follow-up in treatment averaged 5.4 years (SD 3.1). Greater illness intensity and shorter treatment latency were closely associated, resulting in a greater apparent reduction in morbidity with earlier treatment. However, this finding was not sustained after correction for pretreatment morbidity, and treatment latency did not predict morbidity during treatment. Therefore, assessments based on improvement with treatment, or without correction for pretreatment morbidity, can be misleading. CONCLUSIONS: Available evidence does not support the proposal that delayed prophylaxis may limit response to prophylactic treatment in BD and related disorders.
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Year |
2003 |
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Author |
Baldessarini RJ, Tondo L |
Title |
Suicide risk and treatments for patients with bipolar disorder. |
Journal |
JAMA |
Abstract |
(abstract not available) Suicide risk and treatments for patients with bipolar disorder. |
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Year |
2003 |
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Author |
Baldessarini RJ, Tondo L, Hennen J |
Title |
Treatment-latency and previous episodes: relationships to pretreatment morbidity and response to maintenance treatment in bipolar I and II disorders. |
Journal |
Bipolar Disord |
Abstract |
OBJECTIVE: To clarify relationships of treatment delay and pretreatment episode count with pretreatment morbidity and responses to maintenance treatments in bipolar disorders. METHODS: In 450 DSM-IV bipolar I (n = 293) or II (n = 157) patients (280 women, 170 men), we evaluated correlations of latency from illness-onset to starting maintenance treatment and pretreatment episode counts with pretreatment morbidity and treatment response. We considered morbidity measures before and during treatment, and their differences. RESULTS: Latency averaged 7.8 years, with 9.0 episodes per patient, before various maintenance treatments started. Morbidity (percentage of time-ill, episodes per year, first wellness-interval, or proportion of subjects hospitalized or having no recurrences) during maintenance treatment averaging 4.2 years was unrelated to treatment latency or pretreatment episode count. However, pretreatment morbidity was greater with shorter latency, resulting in larger relative reduction of morbidity after earlier treatment. CONCLUSIONS: Greater treatment latency and pretreatment episode count were not followed by greater morbidity during treatment, although longer delay yielded smaller during-versus-before treatment reduction in morbidity. Predictions that longer treatment delay or more pretreatment episodes lead to poorer responses to various maintenance treatments in bipolar I or II disorder were not supported. |
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Year |
2003 |
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Author |
Baldessarini RJ, Tondo L, Hennen J |
Title |
Lithium treatment and suicide risk in major affective disorders: update and new findings |
Journal |
J Clin Psychiatry |
Abstract |
BACKGROUND: Evidence that therapeutic benefits of psychiatric treatments include reduction of suicide risk is remarkably limited and poorly studied. An exception is growing evidence for such suicidal risk reduction with long-term lithium maintenance. This report updates and extends analyses of lithium treatment and suicides and attempts. METHOD: We pooled data from studies providing data on suicidal acts, patients at risk, and average exposure times with or without lithium maintenance therapy, and considered effects of lithium on selected subgroups. RESULTS: Data from 34 reported studies involved 42 groups with lithium maintenance averaging 3.36 years, and 25 groups without lithium followed for 5.88 years, representing 16,221 patients in a total experience of 64,233 person-years. Risks for all suicidal acts/100 person-years averaged 3.10 without lithium versus 0.210 during treatment (93% difference) versus approximately 0.315 for the general population. For attempts, corresponding rates were 4.65 versus 0.312 (93% difference), and for completed suicides, 0.942 versus 0.174 (82% difference). Subjects with bipolar versus various recurrent major affective disorders showed similar benefits (95% vs. 91% sparing of all suicidal acts). Risk reductions for unipolar depressive, bipolar II, and bipolar I cases ranked 100%, 82%, and 67%. Suicide risk without lithium tended to increase from 1970 to 2002, with no loss of effectiveness of lithium treatment. CONCLUSION: The findings indicate major reductions of suicidal risks (attempts > suicides) with lithium maintenance therapy in unipolar >/= bipolar II >/= bipolar I disorder, to overall levels close to general population rates. These major benefits in syndromes mainly involving depression encourage evaluation of other treatments aimed at reducing mortality in the depressive and mixed phases of bipolar disorder and in unipolar major depression.
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Year |
2003 |
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Author |
Tondo L, Hennen J, Baldessarini RJ |
Title |
Rapid-cycling bipolar disorder: effects of long-term treatments. |
Journal |
Acta Psychiatr Scand |
Abstract |
OBJECTIVE: To compare responses to long-term treatment of rapid-cycling (RC) vs. non-RC bipolar disorder patients and assess relative effectiveness of specific agents in RC patients. METHOD: Studies identified by literature searching were analyzed for effects of RC status and treatment-type on clinical outcome (recurrence or non-improvement per exposure-time), using random-effects methods to estimate pooled rates and their 95% CI for quantitative meta-analytic modeling. RESULTS: Data were obtained from 16 reports with 25 trial-arms involving 1856 (905 RC and 951 non-RC) patients treated with carbamazepine, lamotrigine, lithium, topiramate, or valproate, alone or with other agents over an average of 47.5 months (7347 total patient-years). Estimated RC prevalence was 15.4%. Crude rates (%/month) of recurrence (2.31/1.20) and clinical non-improvement (1.93/0.49) averaged 2.9-fold greater in RC vs. non-RC subjects. The pooled RC/non-RC risk ratio (RR) for inferior treatment-response (in 13 direct comparisons) was 1.40 (CI 1.26-1.56; P < 0.0001). Pooled crude recurrence and non-improvement rates suggested no clear advantage for any treatment, nor superiority for anticonvulsants over lithium. However, only lithium vs. carbamazepine could be directly compared (in four treatment-arms) meta-analytically in RC patients (RR = 0.93, CI 0.74-1.18, indicating no difference in effectiveness). CONCLUSION: As expected, RC was associated with lower effectiveness of all treatments evaluated. Direct comparisons of specific treatment alternatives for RC patients were rare, and provided no secure evidence of superiority of any treatment. Additional long-term studies comparing RC/non-RC patients randomized to specific treatments are required.
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Year |
2003 |
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Author |
Tondo L, Isacsson G, Baldessarini R |
Title |
Suicidal behaviour in bipolar disorder: risk and prevention. |
Journal |
CNS Drugs |
Abstract |
Bipolar (manic-depressive) disorder is a common and severe illness. It is also potentially fatal as a result of accidents and increased mortality associated with comorbid substance use and medical illnesses, but its highest lethality results from suicide. Suicide rates, averaging 0.4% per year in men and women diagnosed with bipolar disorder, are >20-fold higher than in the general population. Suicidal acts often occur early in the illness course and in association with severe depressive and dysphoric-agitated mixed phases of illness, especially following repeated, severe depressions.Systematic consideration of risk and protective factors enhances assessment of potentially suicidal patients. Short-term interventions employed empirically to manage acute suicidality include close clinical supervision, rapid hospitalisation and use of electroconvulsive treatment. Several plausible therapeutic interventions have limited evidence of long-term effectiveness against mortality risks associated with any psychiatric disorder, including antidepressant, antimanic, antipsychotic and electroconvulsive, as well as psychosocial, treatments. However, in bipolar disorder and other major affective disorders, lithium maintenance treatment is a notable exception, with strong and consistent evidence that it reduces suicidal risk.The growing range of drugs being introduced to treat acute and long-term phases of bipolar disorder, including antiepileptic drugs, atypical antipsychotics and relatively safe, modern antidepressants, require research assessment for their ability to limit premature mortality from suicide and other causes. For now, however, more can be done to improve treatment in major affective illnesses by application of current knowledge in a systematic fashion, with close and sustained clinical follow-up of patients at risk, hopefully with a resulting reduction of mortality rates.
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Year |
2003 |
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Author |
Baldessarini RJ, Tondo L, Hennen J, Viguera AC |
Title |
Is lithium still worth using? An update of selected recent research. |
Journal |
Harv Rev Psychiatry |
Abstract |
The treatment of bipolar disorder has seen greater innovation in the past decade than at any other time since the introduction of lithium and the neuroleptics a half-century ago. The place of lithium in contemporary psychiatric therapeutics has become controversial, calling for the present overview of research findings pertaining to its use in treating patients with bipolar disorder. Lithium, by itself, typically is inadequate for rapid control of acute mania; antipsychotics, divalproex, or potent sedatives are commonly used, with or without lithium, for this purpose. The special usefulness of lithium lies in long-term prevention of recurrences of mania and bipolar depression and in reducing risk of suicidal behavior. Lithium also may be beneficial in recurrent unipolar depression and is an effective adjunct for treatment-resistant depression. Expectations that prolonged untreated bipolar illness, multiple episodes, rapid cycling, or retreatment following discontinuation might routinely lead to lithium nonresponsiveness, and the belief that lithium is too toxic for use during pregnancy, have not been borne out by research. Lithium retains a substantial share of prescriptions for bipolar disorder and is inexpensive. No other treatment has performed as well as lithium in as many aspects of long-term care of bipolar disorder patients, and despite some risks and limitations, lithium remains the standard against which all proposed alternative are compared. |
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Year |
2002 |
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Author |
Viguera AC, Cohen LJ, Tondo L, Baldessarini RJ |
Title |
Protective effect of pregnancy on the course of lithium-responsive bipolar I disorder. |
Journal |
J Affect Disord |
Abstract |
(abstract not available) Protective effect of pregnancy on the course of lithium-responsive bipolar I disorder. |
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Year |
2002 |
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Author |
Baldessarini RJ, Tondo L |
Title |
Long-term lithium for bipolar disorder. |
Journal |
Am J Psychiatry |
Abstract |
(abstract not available) Long-term lithium for bipolar disorder. |
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Year |
2001 |
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Author |
Baldessarini RJ, Tondo L, Hennen J |
Title |
Treating the suicidal patient with bipolar disorder. Reducing suicide risk with lithium. |
Journal |
Ann N Y Acad Sci |
Abstract |
Bipolar disorder is associated with increased mortality because of complications of commonly comorbid substance use and stress-sensitive medical disorders as well as accidents and very high rates of suicide. Long-term lithium treatment may be associated with reduced suicidal risk. We review and summarize findings that help to qualify relationships between the presence versus the absence of lithium maintenance and suicides or attempts in patients with bipolar or other major affective disorders. Results from 33 studies (1970-2000) yielded 13-fold lower rates of suicide and reported attempts during long-term lithium treatment than without it of after it was discontinued. Although greatly reduced, these rates remain above those estimated for the general population. Evidence for substantial, if incomplete, protection against suicide with lithium is supported by more compelling evidence than that for any other treatment provided for patients with mood disorders. Studies of commonly used, but incompletely evaluated, alternative treatments are required, and further protection against premature mortality can be anticipated with better protection against bipolar depression. |
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Year |
2001 |
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Author |
Faedda GL, Tondo L, Baldessarini RJ |
Title |
Lithium discontinuation: uncovering latent bipolar disorder? |
Journal |
Am J Psychiatry |
Abstract |
(abstract not available) Lithium discontinuation: uncovering latent bipolar disorder? |
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Year |
2001 |
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Author |
Tondo L, Baldessarini RJ, Floris G |
Title |
Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. |
Journal |
Br J Psychiatry Suppl |
Abstract |
BACKGROUND: The effectiveness of lithium is being questioned increasingly and requires clarification. AIMS: To assess the effectiveness of lithium treatment in depression and mania, syndromal types I and II, with predominantly mixed or psychotic episodes or rapid cycling, during treatment resumed following discontinuation, and across three decades. METHOD: The longitudinal course of 360 patients with bipolar disorder compliant with lithium treatment for at least 1 year and without comorbidity for substance use disorder was reviewed. RESULTS: Risk of single-episode recurrences, a common index of treatment failure, was similar to that in other reports. Both episode frequency and 'time ill' improved more in type II than type I cases. Reduced morbidity during treatment was similar in patients with mixed or psychotic episodes, or rapid cycling, and in less complex cases. Retreatment yielded minor decrements in response, and there was no tendency for lesser responses in more recent years. CONCLUSIONS: Based on overall affective morbidity, long-term lithium treatment in compliant patients without comorbid substance use disorder, though imperfect, remains effective, even in subgroups of supposedly poor prognosis.
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Year |
2001 |
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Author |
Tondo L, Ghiani C, Albert M |
Title |
Pharmacologic interventions in suicide prevention. |
Journal |
J Clin Psychiatry |
Abstract |
Suicide rates vary by country and by mental disorder. What does not vary, though, is that the number of suicides per year is not declining and that a person with a mental disorder is more likely to commit suicide than one without such an illness. Although many pharmacologic interventions have been reported to reduce the risk of suicide among mentally ill patients, especially those with bipolar disorder, the effects of such interventions are inconsistent at best. Lithium is the only medication for which the evidence consistently shows an antisuicidal effect. |
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Year |
2001 |
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Author |
Tondo L, Hennen J, Baldessarini RJ |
Title |
Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis |
Journal |
Acta Psychiatr Scand |
Abstract |
OBJECTIVE: To compare suicide rates with vs. without long-term lithium treatment in major affective disorders. METHOD: Broad searching yielded 22 studies providing suicide rates during lithium maintenance; 13 also provide rates without such treatment. Study quality was scored, between-study variance tested, and suicide rates on vs. off lithium examined by meta-analysis using random-effects regression methods to model risk ratios. RESULTS: Among 5647 patients (33,473 patient-years of risk) in 22 studies, suicide was 82% less frequent during lithium-treatment (0.159 vs. 0.875 deaths/100 patient years). The computed risk-ratio in studies with rates on/off lithium was 8.85 (95% CI, 4.12-19.1;P<0.0001). Higher rates off-lithium were not accounted for by treatment-discontinuation. CONCLUSION: Suicide risk was consistently lower during long-term treatment of major affective illnesses with lithium in all studies in the meta-analysis, including the few involving treatment-randomization. |
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Year |
2001 |
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Author |
Tondo L, Tagliamonte A, Ghiani C, Mercenaro S |
Title |
Intensive treatment with lithium carbonate "once a day" in bipolar patients. |
Journal |
Clin Ter |
Abstract |
Lithium carbonate is the treatment of choice in the prevention of recurrences of bipolar mood disorders. The aim of this study is the evaluation of the pharmacokinetics of a new lithium compound to be administered "once a day", with a half-life of 32.4 hours. The present study investigates plasma lithium levels in patients treated with the novel vs. standard preparation of lithium carbonate to assess whether the new preparation may be associated with lithium plasma accumulation. The authors studied twenty-two bipolar patients whose standard lithium treatment was replaced by the new one. The total duration of the new treatment was 57 days. During this period, lithium plasma levels were monitored 7 times, 12 hours post-lithium administration. Lithium plasma level 24 hours following administration was evaluated in seven patients. The average dose of "once a day" lithium was 821 (+/- 250) mg/day, the corresponding plasma level was 0.45 (+/- 0.11) mEq/L, and the dose (g) to plasma level ratio was 1.96 (+/- 0.66). Differences between average lithium plasma levels at time T1 and successive times were not statistically significantly. Moreover, the average lithium level at 12 hours after lithium administration was not different from that after 24 hours (0.45 +/- 0.11 and 0.47 +/- 0.0.29 respectively). These results demonstrate that the new preparation, "once a day", maintains steady lithium plasma levels during our times of observation without accumulation in body fluids and tissues. "Once a day" lithium carbonate appears to be a useful alternative to the standard preparation, and may potentially improve treatment compliance by simplifying patients' medication.
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Year |
2001 |
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Author |
Viguera AC, Baldessarini RJ, Tondo L |
Title |
Response to lithium maintenance treatment in bipolar disorders: comparison of women and men. |
Journal |
Bipolar Disord |
Abstract |
OBJECTIVES: Possible sex differences in responses to mood-stabilizing treatment remain poorly defined. Since women with bipolar disorder reportedly have more features that may predict a poor prognosis (depression and rapid cycling), we tested the hypothesis that women respond less well to lithium maintenance treatment. METHODS: Clinical characteristics of 360 women and men with DSM-IV bipolar I or II disorder were compared before and during clinical lithium maintenance monotherapy in a mood disorders clinic by preliminary bivariate comparisons, multivariate analysis, and survival analysis of time stable during treatment. RESULTS: Women (n = 229) versus men (n = 131) were: more likely to have type II disorder (1.6 times), 3.2 years older at illness onset, more often depressed-before-manic (1.4 times), considered unipolar depressive 1.9 years longer and started maintenance treatment 5.5 years later. However, women differed little from men before treatment in overall morbidity, average episode frequency and risk of suicide attempts. Contrary to prediction, women showed non-significantly superior responses to lithium treatment, and a significant 60% longer median time before a first recurrence during treatment, despite 7% lower average serum lithium concentrations. CONCLUSIONS: Women were diagnosed as bipolar later than men with corresponding delay of lithium maintenance treatment that proved to be at least as effective as in men. |
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Year |
2001 |
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Author |
Baldessarini RJ, Tohen M, Tondo L |
Title |
Maintenance treatment in bipolar disorder. |
Journal |
Arch Gen Psychiatry |
Abstract |
(abstract not available) Maintenance treatment in bipolar disorder. |
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Year |
2000 |
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Author |
Baldessarini RJ, Tondo L |
Title |
Does lithium treatment still work? Evidence of stable responses over three decades. |
Journal |
Arch Gen Psychiatry |
Abstract |
To evaluate whether lithium treatment has been overvalued and may be no longer as effective as formerly, we reviewed published reports on long-term lithium treatment (1970-1996) as well as analyzing its clinical effects on 360 patients with DSM-IV bipolar disorder who entered into lithium maintenance monotherapy after 1970. Neither reported recurrence rates nor average proportions of time ill nor patient improvement of 50% or more during lithium maintenance therapy in a stable clinic setting has changed significantly since the 1970s. Unfavorable results in some settings may reflect accumulation over time of patients with complex, less treatment-responsive illnesses. Lithium is unmatched in research support for long-term clinical effectiveness against morbidity and mortality associated with depression or mania in bipolar I and II disorders Data evaluated herein did not support suggestions that benefits of lithium have been exaggerated in the past or have lost recently. |
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Year |
2000 |
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Author |
Baldessarini RJ, Tondo L, Floris G, Hennen J |
Title |
Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients. |
Journal |
J Affect Disord |
Abstract |
INTRODUCTION: Rapid cycling (RC) in bipolar disorders is widely believe to predict future morbidity and poor treatment response, although empirical testing of its predictive utility remains limited. METHODS: In 360 DSM-IV bipolar I (N=218) and II (N=142) disorder subjects (64% women) followed over an average of 13.3 years, we evaluated factors associated with RC status with bivariate and multivariate techniques, and response to lithium maintenance treatment (recurrence rates, time ill, survival analysis of time to recurrence on lithium). RESULTS: RC risk (15.6% of cases) was 5.1 times greater in bipolar II vs. I subjects (30.3%/6.0%), in minor excess in women vs. men (17.9%/11.5%), and associated with premorbid cyclothymia, depressive first episodes, older onset age, and being employed or married. Before lithium, RC vs. non-RC cases had more mean total (3.9/1.2), manic, and depressive episodes/year, and greater percent time ill (60%/38%). During treatment, prior RC status was unrelated to time to first recurrence and other measures of morbidity and improvement including percent time ill, although depressive episodes were 2.7-times more frequent, and there was 13.7% less chance of full protection from all recurrences in RC cases. Limitation: The study is naturalistic, without random assignment of blind assessment. CONCLUSIONS: The RC bipolar subtype was strongly associated with type II diagnosis, higher average prelithium episode frequency and percent time ill, and weakly with female sex, but not with greater overall morbidity during treatment. |
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Year |
2000 |
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Author |
Tondo L, Baldessarini RJ |
Title |
Reduced suicide risk during lithium maintenance treatment. |
Journal |
J Clin Psychiatry |
Abstract |
BACKGROUND: About 20% of deaths of bipolar disorder patients are suicides associated with depressive or mixed episodes. Long-term lithium treatment may be associated with reduction of suicidal risk. METHOD: We reviewed studies and our previously reported data to quantify relationships of presence versus absence of lithium maintenance and suicides or suicide attempts in bipolar disorder patents. RESULTS: Results from 2 studies (1974-1998) yielded 7-fold lower suicidal rates from patients during long-term lithium treatment than for these patents when they were not receiving such treatment, patients lacking such treatment, or for patients after lithium discontinuation. CONCLUSIONS: Protection against suicide with lithium is incomplete, but rates of suicides plus attempt during lithium treatment may approach general population base rates. Better protection against bipolar depression is essential for limiting suicidal risk: alternatives to lithium require further study for effects on suicidal behavior. |
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Year |
2000 |
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Author |
Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ |
Title |
Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. |
Journal |
Am J Psychiatry |
Abstract |
OBJECTIVE: Pregnancy poses major challenges for the treatment of bipolar disorder, and information to guide clinical care remains very sparse. The authors sought to determine the illness recurrence risk for women with bipolar disorder who discontinue lithium maintenance during pregnancy. METHOD: The authors retrospectively compared recurrence rates and survival functions for 101 women with DSM-IV bipolar disorder (68 type I, 33 type II) during pregnancy and postpartum (N=42) or during equivalent periods (weeks 1-40 and 41-64) for age-matched nonpregnant subjects (N=59) after either rapid (1-14 days) or gradual (15-30 days) discontinuation of lithium. Recurrence rates also were obtained for the year before discontinuing lithium. RESULTS: Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant (52%) and nonpregnant women (58%) but had been much lower for both in the year before treatment was discontinued (21%). Among subjects who remained stable over the first 40 weeks after lithium discontinuation, postpartum recurrences were 2.9 times more frequent than recurrences in nonpregnant women during weeks 41-64 (70% versus 24%). Depressive or dysphoric-mixed episodes were more prevalent in pregnant than nonpregnant women (63% versus 38% of recurrences). Recurrence risk was greater after rapid than after gradual discontinuation, and for patients with more prior affective episodes, but was similar for diagnostic types I and II. CONCLUSIONS: Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant and nonpregnant women but then sharply increased postpartum. Risk was much lower during preceding treatment and less with gradual discontinuation. Treatment planning for potentially pregnant women with bipolar disorder should consider the relative risks of fetal exposure to mood stabilizers versus the high recurrence risks after discontinuing lithium. |
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Year |
2000 |
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Author |
Viguera AC, Tondo L, Baldessarini RJ |
Title |
Sex differences in response to lithium treatment. |
Journal |
Am J Psychiatry |
Abstract |
OBJECTIVE: Although sex differences occur with some psychotropic drug treatments, they are not well defined for mood-stabilizing agents, including lithium. The authors’ goal was to investigate whether there are differences between the sexes in response to lithium. METHOD: Studies identified in a literature search were analyzed for reports of sex differences in clinical response to lithium in major affective syndromes. RESULTS: Data from 17 studies published in 1967-1998, involving 1548 adults treated with lithium for a mean of 38.6 months (SD=30.5), yielded similar weighted response rates to lithium in 1043 women (65%[N=684]) and 505 men (61.0%[N=308). CONCLUSIONS: The results indicate little difference between the sexes in clinical response to lithium treatment of bipolar and related affective disorders. |
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Year |
2000 |
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Author |
Baldessarini RJ, Tondo L, Hennen J |
Title |
Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. |
Journal |
J Clin Psychiatry |
Abstract |
BACKGROUND: Whether mood-altering treatments reduce risk of suicidal behavior remains largely unproved. METHOD: We compared suicidal rates in published studies of patients treated with lithium with those who were not, and in a mood disorders clinic before, during, and after discontinuing lithium. RESULTS: Published reports indicate a 7.0-fold lower rate of suicidal acts with lithium treatment of manic-depressive patients. In new findings in over 300 bipolar patients, latency from illness onset to lithium maintenance averaged 8.3 years (from 11.0 years in women with bipolar II disorder to 6.9 years in men with bipolar I disorder), but half of all suicidal acts occurred in the first 7.5 of 18.3 years at risk. Most acts (89%) occurred during depressive (73%) or dysphoric-mixed (16%) mood states and were associated with previous severe depression, prior attempts, and lower age at onset. Morbidity was reduced 2.7-fold and suicidal acts per year 6.5-fold during lithium treatment, with 8.3-fold cumulative sparing of risk by 15 years on lithium. In the first year off lithium, affective illness recurred in 67% of patients, and suicidal rates rose 20-fold but were much lower thereafter; fatalities were 14 times more frequent after discontinuation of lithium. Early morbidity was 2.5-fold lower, and suicidal risk was 2.0-fold lower after slow versus rapid discontinuation. CONCLUSION: Lithium maintenance is associated with sustained reduction of suicidal acts in manic-depressive disorders. Treatment discontinuation, particularly abruptly, led to early affective morbidity and suicidal behavior. Improved diagnosis and treatment as well as earlier intervention for potentially lethal bipolar depression are urgently needed, as are studies of all mood-altering agents for effects on suicidal behavior. |
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Year |
1999 |
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Author |
Baldessarini RJ, Tondo L, Hennen J, Floris G |
Title |
Latency and episodes before treatment: response to lithium maintenance in bipolar I and II disorders. |
Journal |
Bipolar Disord |
Abstract |
OBJECTIVES: To test whether longer treatment-delays or more pretreatment illness episodes are followed by diminished response to lithium maintenance. METHODS: In 360 DSM-IV bipolar I (n = 220) or II (n = 140) patients, effects of latency from illness onset to starting lithium and number of pretreatment episodes were evaluated by survival analysis based on the number of months stable before a first recurrence on lithium. Factors associated with treatment latency were identified by regression modeling. Relationships of time, episode number, and morbidity before treatment to the overall proportion of time ill on lithium were also tested by nonparametric correlation. RESULTS: Latency to first lifetime lithium maintenance averaged 8.3 years, with 9.3 episodes/subject. Time stable before a first recurrence on lithium averaged 29.6 months and was unrelated to treatment latency (in terciles) or to a high (> or = ten), intermediate (four-nine), or low (< four) number of prior episodes. Overall morbidity during 4.6 years of lithium maintenance was also unrelated to these pretreatment factors. More episodes/year and percentage of time ill before treatment anticipated shorter treatment latency, with greater relative improvement, but were unrelated to morbidity during treatment. CONCLUSIONS: Treatment latency and prelithium episode number were unrelated to morbidity during treatment. Although multiple untreated episodes can lead to severe disability, lithium evidently can greatly limit morbidity, even after years of delay and multiple episodes of bipolar illness. |
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Year |
1999 |
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Author |
Baldessarini RJ, Tondo L, Viguera AC |
Title |
Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications. |
Journal |
Bipolar Disord |
Abstract |
OBJECTIVE: To review research findings on clinical effects of discontinuing lithium maintenance treatment. METHODS: Data from studies reported since 1970 plus our recent findings were updated. RESULTS: Discontinuing lithium maintenance treatment led to marked increases of early affective morbidity and suicidal risk. Gradual discontinuation markedly reduced early recurrences of mania or depression, did so more in bipolar II than I disorder patients, and also tended to reduce suicidal risk. Similar effects were found in pregnant and nonpregnant women after lithium discontinuation. Long-term retreatment with lithium following discontinuation was only slightly less effective than in initial trials. CONCLUSIONS: Recurrences increased sharply soon after discontinuing lithium, but were markedly limited and not merely delayed, by slow discontinuation. Similar reactions may follow discontinuation of other drugs, evidently as responses to long-term pharmacodynamic adaptations. Discontinuing treatment is not equivalent to not-treating. Post-discontinuation relapse risk has implications for the design, management, and interpretation of protocols involving discontinuation of long-term treatments that should be considered in both clinical management and research. |
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Year |
1999 |
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Author |
Baldessarini RJ, Viguera AC, Tondo L |
Title |
Discontinuing psychotropic agents. |
Journal |
J Psychopharmacol |
Abstract |
(abstract not available) Discontinuing psychotropic agents. |
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Year |
1999 |
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Author |
Tondo L, Baldessarini RJ, Hennen J, Minnai GP, Salis P, Scamonatti L, Masia M, Ghiani C, Mannu P |
Title |
Suicide attempts in major affective disorder patients with comorbid substance use disorders. |
Journal |
J Clin Psychiatry |
Abstract |
BACKGROUND: The widely accepted impression that substance abuse and dependence are associated with increased suicidal risk was evaluated by literature review and with new data. METHOD: Previous research on this association was reviewed, and clinical data on suicide attempts and substance use in 504 mood disorder patients hospitalized in 4 psychiatric units in Sardinia affiliated with the Italian mental health system were analyzed. RESULTS: The literature supports associations of alcohol and drug use comorbidity with major affective disorders, and of some substances (polyabuse, alcohol, heroin, cocaine, and even tobacco, but perhaps not marijuana or hallucinogens) with suicidal behavior. Our new findings generally supported these 2-way associations. Suicidal risks were similar in hospitalized men and women but were associated with bipolar II, bipolar I (mainly mixed), and unipolar depressive disorders as well as substance abuse, with little effect of type of agent. Substance abuse was more common in nonmixed bipolar disorders, men, and age below 30. CONCLUSION: The tendency for bipolar I, mainly nonmixed patients, to have a relatively high risk of substance abuse and low risk of suicide attempts indicates that mainly depressive or dysphoric (bipolar II, nonbipolar, and bipolar I, mainly mixed) mood disorders may be especially lethal. Differences in risks of substance abuse and suicidal behavior in men and in bipolar I patients further suggest that substance abuse and mood disorders may contribute to suicidal risk with at least partial independence or additivity. |
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Year |
1999 |
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Author |
Tondo L, Baldessarini RJ |
Title |
Rapid cycling in women and men with bipolar manic-depressive disorders. |
Journal |
Am J Psychiatry |
Abstract |
OBJECTIVE: This study investigated risks for rapid cycling, as defined by DSM-IV, in women and men with bipolar disorders. METHOD: The results of 10 studies with a total of 2,057 bipolar patients were meta-analyzed by pooled contingency methods. RESULTS: The proportions of women and men among rapid-cycling cases averaged 72% and 28%, respectively, but the risk of rapid cycling was inconsistently more frequent among women (29.6%) than among men (16.5%). The mean number of episodes per year was much higher in rapid-cycling patients before and during lithium treatment but was similar in rapid-cycling men and women. CONCLUSIONS: Rapid cycling was only moderately, and inconsistently, more common in bipolar women than men.
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Year |
1998 |
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Author |
Tondo L, Baldessarini RJ, Hennen J, Floris G |
Title |
Lithium maintenance treatment of depression and mania in bipolar I and bipolar II disorders. |
Journal |
Am J Psychiatry |
Abstract |
OBJECTIVE: Effects of long-term lithium treatment for depressive and manic phases of type I and type II bipolar disorders were compared. METHOD: Clinical research records of 317 patients with DSM-IV-defined bipolar disorder (188 with type I and 129 with type II) were analyzed for frequency and duration of affective episodes and hospitalizations before (mean = 8.38 years) versus during (mean = 6.35 years) lithium maintenance treatment. Treatment effects were also assessed by survival analysis of interepisode intervals and by multivariate regression testing for factors associated with response to treatment. RESULTS: Bipolar I and bipolar II patients were ill before treatment a similar percentage of time, but the subtype distinction was supported descriptively. Lithium had superior benefits in type II patients, with significantly greater reduction of episodes per year and of the percentage of time ill. Reduction of depressive morbidity was similarly strong in both diagnostic types. During treatment, bipolar II patients had 5.9-fold longer interepisode intervals and were twice as likely as type I patients to have no new episodes. Starting lithium maintenance earlier predicted greater improvement. CONCLUSIONS: Lithium maintenance yielded striking long-term reductions of depressive as well as manic morbidity in both bipolar disorder subtypes, with greater overall benefits in type II patients and with earlier treatment. |
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Year |
1998 |
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Author |
Tondo L, Baldessarini RJ, Hennen J, Floris G, Silvetti F, Tohen M |
Title |
Lithium treatment and risk of suicidal behavior in bipolar disorder patients. |
Journal |
J Clin Psychiatry |
Abstract |
BACKGROUND: Lithium may exert an antisuicidal effect in bipolar disorder patients, but this hypothesis requires further testing by direct comparison of patients with and without lithium treatment. METHOD: Risk of life-threatening suicidal acts over time and associated factors were analyzed in 310 patients with DSM-IV bipolar I (N = 186) or II (N = 124) disorder evaluated for a mean of 8.3 years before, and prospectively during, a mean of 6.4 years of lithium maintenance in a mood disorder clinic; 185 were also followed for a mean of 3.7 years after clinically discontinuing lithium. RESULTS: In 5233 patient-years of observation, 58 patients made 90 suicide attempts (8 were fatal). Survival analyses with Weibull modeling with adjustments for covariates indicated a highly significant 6.4-fold adjusted hazard ratio during versus before and 7.5-fold ratio after versus during lithium maintenance. Suicidal acts were more common early in the course of illness before lithium and were associated with prior suicide attempts, greater proportion of time depressed, and younger age. After the discontinuation of lithium, suicidal acts were more frequent in the first year than at later times or before start of lithium treatment. Fatalities were 9 times more frequent after versus during treatment. CONCLUSION: Lithium maintenance was associated with marked reduction of life-threatening suicidal acts, the number of which sharply increased after discontinuing lithium. Suicidal behavior was strongly associated with prior suicide attempts, more time depressed, and younger age or recent onset. Greater attention to suicidal risk in patients with bipolar depression and assessment of all proposed mood-stabilizing agents for antisuicidal effects are strongly encouraged. |
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Year |
1998 |
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Author |
Baldessarini RJ, Tondo L, Floris G, Rudas N |
Title |
Reduced morbidity after gradual discontinuation of lithium treatment for bipolar I and II disorders: a replication study. |
Journal |
Am J Psychiatry |
Abstract |
OBJECTIVE: The aim of this study was to verify reduction of early affective morbidity by gradual, rather than rapid, discontinuation of lithium treatment. METHOD: For 78 patients with bipolar disorders, lithium treatment was discontinued either rapidly (over 1-14 days) or gradually (over 15-30 days). The effects of the two schedules were compared by survival analysis of time to first recurrence. RESULTS: Median time to recurrence was 5.6 times as long for gradual discontinuation (14.0 months) as for rapid discontinuation (2.5 months). The ratios of the median survival times for gradual and rapid discontinuation were similar in I and II subtypes and in depression and mania (4-6:1). The polarities of the episodes at onset and at first recurrence after lithium discontinuation were 83.6% concordant. CONCLUSIONS: These results independently confirm a reduction in morbid risk from slow discontinuation of lithium treatment for bipolar disorders. |
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Year |
1997 |
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Author |
Poland RE, McCracken JT, Lutchmansingh P, Lesser IM, Tondo L, Edwards C, Boone KB, Lin KM |
Title |
Differential response of rapid eye movement sleep to cholinergic blockade by scopolamine in currently depressed, remitted, and normal control subjects. |
Journal |
Biol Psychiatry |
Abstract |
The degree of cholinergic dysregulation of sleep in adult depression was evaluated using scopolamine. On separate sessions, placebo and scopolamine (4.5 micrograms/kg, IM) were administered to 14 patients with unipolar major depression, 16 recovered/remitted patients, and 18 normal controls. Scopolamine increased rapid eye movement (REM) latency (RL), reduced REM activity (RA), REM density (RD), and REM duration, and increased the percentage of stage 4 sleep in all groups. There was a differential effect of scopolamine on RL, RA, and REM duration for the first REM period, and on percentage of stage 4 sleep. Whereas a primary cholinergic hyperactivity could account for the RA and RD responses, the response profile for RL was more compatible with reduced aminergic tone as the proximal cause of the cholinergic hyperactivity. Whether the sleep abnormalities observed in remitted patients reflect an underlying vulnerability for development or recurrence of depression, and/or a scar, remains to be determined.
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Year |
1997 |
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Author |
Suppes T, Baldessarini RJ, Motohashi N, Tondo L, Viguera AC |
Title |
Special treatment issues: maintaining and discontinuing psychotropic medications. |
Journal |
Mod Probl Pharmacopsychiatry |
Abstract |
(abstract not available) Special treatment issues: maintaining and discontinuing psychotropic medications. |
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Year |
1997 |
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Author |
Tondo L, Baldessarini RJ, Floris G, Rudas N |
Title |
Effectiveness of restarting lithium treatment after its discontinuation in bipolar I and bipolar II disorders. |
Journal |
Am J Psychiatry |
Abstract |
OBJECTIVE: This study tested the hypothesis that resumption of lithium treatment of bipolar disorders may be less effective after maintenance treatment has been discontinued. METHOD: Eighty-six patients with type I or II bipolar disorder, not selected according to response to treatment, were followed prospectively during two periods of lithium maintenance treatment averaging 4.6 and 4.4 years. Morbidity (illness episodes per year, hospitalizations per year, percentage of time ill) was assessed, and use of adjunctive medication was rated. RESULTS: Morbidity was similar in the first and second treatment periods (mean number of episodes = 0.83 and 0.94 per year, respectively; mean percentage of time ill = 18.0% and 24.2%), with no differences in numbers of manic and depressive episodes or differences by gender, diagnostic type, length of first treatment, interval between treatments, or discontinuation rate. There was 12.8% more use of adjunctive medication in the second period. CONCLUSIONS: The efficacy of lithium did not differ significantly between the first and second treatment periods.
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Year |
1997 |
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Author |
Tondo L, Jamison KR, Baldessarini RJ |
Title |
Effect of lithium maintenance on suicidal behavior in major mood disorders. |
Journal |
Ann N Y Acad Sci |
Abstract |
We reviewed evidence of a possible antisuicide action of lithium maintenance treatment in mood disorders. Of 28 published studies involving over 17,000 patients with major affective illnesses, most yielded supportive evidence: risk of suicides and attempts averaged 3.2 versus 0.37 per 100 patient-years without versus with lithium (8.6-fold difference). In a new study of 284 bipolar I- and II-disordered patients, corresponding rates (2.2 vs. 0.39/100 patient-years) differed by 5.6-fold (p < 0.001); moreover, after discontinuing lithium, rates of suicidal acts rose by 7-fold (16-fold within the first year), and fatalities increased by nearly 9-fold. Lithium maintenance treatment in recurring major mood disorders has strong evidence of antisuicide effects not demonstrated with any other mood stabilizer. Close association of suicide and depression in bipolar disorder emphasizes the need for improved identification and treatment of bipolar depression. |
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Year |
1997 |
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Author |
Baldessarini RJ, Suppes T, Tondo L |
Title |
Lithium Withdrawal in Bipolar Disorder: Implications for Clinical Practice and Experimental Therapeutics Research. |
Journal |
Am J Ther |
Abstract |
Recent clinical research strongly suggests that there is a period of elevated risk of morbidity in the several months following abrupt discontinuation or reduction of doses in maintenance treatments commonly used in the contemporary management of chronic or recurring major psychiatric disorders. This risk is best quantified for the discontinuation of lithium therapy in bipolar disorders, in which risk of mania, depression, and suicidal behavior may rise. Similar symptomatic risks are well known after stopping antianxiety agents, and probably also follow rapid removal of oral neuroleptics in schizophenia and antidepressants in major depression. Morbid risk probably can be limited by slowing the rate of removal of medication. Such responses probably reflect interactions of individual illness diatheses with physiological adaptations to long-term drug treatments. The findings appear to have broad scientific, clinical, and ethical implications for clinical pharmacology in psychiatry as well as in general medicine.
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Year |
1996 |
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Author |
Baldessarini RJ, Tondo L, Faedda GL, Suppes TR, Floris G, Rudas N |
Title |
Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. |
Journal |
J Clin Psychiatry |
Abstract |
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. |
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Year |
1996 |
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Author |
Faedda GL, Baldessarini RJ, Suppes T, Tondo L, Becker I, Lipschitz DS |
Title |
Pediatric-onset bipolar disorder: a neglected clinical and public health problem. |
Journal |
Harv Rev Psychiatry |
Abstract |
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.
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Year |
1995 |
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Author |
Martinelli I, Moia M, Panzeri D, Tondo L, Mannucci PM |
Title |
Prognostic value of the activated partial thromboplastin time after orthotopic liver transplantation: a prospective study. |
Journal |
J Hepatol |
Abstract |
(abstract not available) Prognostic value of the activated partial thromboplastin time after orthotopic liver transplantation: a prospective study. |
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Year |
1994 |
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Author |
Faedda GL, Tondo L, Baldessarini RJ, Suppes T, Tohen M |
Title |
Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. |
Journal |
Arch Gen Psychiatry |
Abstract |
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. |
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Year |
1993 |
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Author |
Faedda GL, Tondo L, Teicher MH, Baldessarini RJ, Gelbard HA, Floris GF |
Title |
Seasonal mood disorders. Patterns of seasonal recurrence in mania and depression. |
Journal |
Arch Gen Psychiatry |
Abstract |
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. |
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Year |
1993 |
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Author |
Poland RE, McCracken JT, Lutchmansingh P, Tondo L |
Title |
Effects of low-dose dexamethasone on sleep EEG patterns, plasma cortisol, and the TSH response to TRH in major depression. |
Journal |
Pharmacopsychiatry |
Abstract |
Dexamethasone (DEX) (0.5 mg, P.O.) and placebo were administered at 2300 h in randomized design to 19 patients with major depression and the effects on the sleep electroencephalogram (EEG) were studied. In addition, the thyroid stimulating hormone (TSH) response to thyrotropin releasing hormone (TRH) and basal plasma cortisol concentrations were assessed the following morning. DEX did not affect sleep architecture or continuity variables, including rapid eye movement (REM) latency, REM activity and REM density. Similarly, DEX did not significantly influence the TSH response to TRH (delta max TSH). In contrast, plasma cortisol concentrations were significantly suppressed by DEX. The results indicate that, as opposed to higher dosages of glucocorticoids, 0.5 mg DEX had minimal effects on the sleep EEG or delta max TSH in depressed patients.
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Year |
1993 |
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Author |
Suppes T, Baldessarini RJ, Faedda GL, Tondo L, Tohen M |
Title |
Discontinuation of maintenance treatment in bipolar disorder: risks and implications. |
Journal |
Harv Rev Psychiatry |
Abstract |
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. |
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Year |
1993 |
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Author |
Poland RE, McCracken JT, Lutchmansingh P, Tondo L |
Title |
Relationship between REM sleep latency and nocturnal cortisol concentrations in depressed patients. |
Journal |
J Sleep Res |
Abstract |
Due to conflicting reports on the possible association between shortening of rapid eye movement (REM) latency and increased cortisol secretion in patients with severe depression, this study examined the relationship between REM sleep latency and nocturnal cortisol concentration in 12 outpatients with major depression. The results showed a significant inverse correlation (r = -0.71, P < 0.01) between REM sleep latency and mean (23.00 hours-03.00 hours) plasma cortisol concentration. Age and severity of depression did not contribute to the inverse relationship. REM activity and density during the first REM period showed no significant correlations with the cortisol measures. A review of the literature suggests that this relationship might be unique to subjects with major depression, and again raises the possibility that these biological disruptions may have a common neurochemical basis. |
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Year |
1992 |
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Author |
McCracken JT, Poland RE, Rubin RT, Tondo L |
Title |
Dose-dependent effects of scopolamine on nocturnal growth hormone secretion in normal adult men: relation to delta-sleep changes. |
Journal |
J Clin Endocrinol Metab |
Abstract |
To explore the sensitivity of nocturnal GH secretion to different degrees of cholinergic blockade, we investigated the effects of two doses of the muscarinic receptor antagonist scopolamine (SCOP; 3.0 and 6.0 micrograms/kg, im) and placebo, administered in a randomized fashion at 2300 h on three nights to eight normal male volunteers. Both doses of SCOP produced significant reductions in mean nocturnal GH concentration compared to the effects of the placebo; the higher dose of SCOP reduced GH to a greater degree than the lower dose, but this difference was not statistically significant (mean, 2.3 micrograms/L after 6 micrograms/kg vs. 3.0 micrograms/L after 3 micrograms/kg). Both SCOP doses significantly shifted GH secretion into later portions of the night, with a significantly greater delay observed after the larger dose. Similarly, a significant delay in the time of the GH rise was produced by SCOP. In contrast, the effects of both doses of SCOP on delta-sleep or sleep onset were small. These data confirm earlier reports demonstrating that cholinergic muscarinic input represents a potentially important source of regulation of nocturnal GH release and suggest that the magnitude of the reduction in GH and the extent of delay in the GH rise time may reflect quantitative differences in the degree of cholinergic blockade. These data are in agreement with recent studies suggesting that the timing of GH release need not be associated with delta-sleep per se. |
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Year |
1991 |
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Author |
Rudas N, Tondo L, Musio A, Masia M |
Title |
Unemployment and depression. Results of a psychometric evaluation. (Italian) |
Journal |
Minerva Psichiatr |
Abstract |
The Authors evaluate the issue about the search of first employment and the depressive effects possibly linked to it. The research includes two groups of unemployed and two control groups of workers. Sex difference has been taken into account. After a preliminary semi-structured interview, all subjects have been evaluated by the means of psychological tests. The psychometric values considered include the D and Ma scales of MMPI and their difference as proposed by Diamond, and the Beck Depression Rating Scale. The results do not show a significant correlation between the search for first employment and the presence of depressive traits.
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Year |
1991 |
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Author |
Rudas N, Tondo L, Musio A, Spada S |
Title |
Depressive features in unemployed individuals. (Italian) |
Journal |
Minerva Psichiatr |
Abstract |
The present research deals with a psychometric evaluation of depressive features in a group of laid-off compared with a control group of full-time workers. Sex differences has been taken into account in the comparison. (The laid-off workers belong to a group under an unemployment fund, Cassa Integrazione Guadagni, which continues paying about 80% of the ex-employee's last wage for an undetermined period of time). The psychometric elements considered include the D and Ma scales of MMPI and their difference as proposed by Diamond, and the Beck Depression Rating Scale. The results, still preliminary, show that work deprivation, even with the financial subsidy from the unemployment fund, can be considered a life event able to provoke a depressive symptomatology. |
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Year |
1991 |
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Author |
Tondo L, Cantone M, Carta M, Laddomada A, Mosticoni R, Rudas N |
Title |
An MMPI evaluation of male sexual dysfunction. |
Journal |
J Clin Psychol |
Abstract |
The present study concerned the evaluation of personality traits associated with sexual dysfunctions. The MMPI was used as a psychodiagnostic tool in male subjects (N = 37) with erectile disorder or premature ejaculation. The results tend to support some clinical observations based upon the cognitive-behavioral approach and some neurophysiological data.
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Year |
1991 |
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Author |
Tondo L, Rudas N |
Title |
The course of a seasonal bipolar disorder influenced by caffeine. |
Journal |
J Affect Disord |
Abstract |
A longitudinal case report shows a sudden remission of the severe course of a seasonal bipolar disorder after 10 years of psychopharmacological treatments. The discontinuation of heavy caffeine intake appears to have contributed to the outcome. |
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Year |
1991 |
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Author |
Tondo L, Rudas N |
Title |
Discontinuation of chronic treatment with lithium salts. (Italian) |
Journal |
Minerva Psichiatr |
Abstract |
The present research reports some results concerning the discontinuation of a long-term treatment with lithium in two groups of bipolar patients, BPI and BPII. The aim of the research is the evaluation of the causes leading to the discontinuation of the treatment and its effects. In all subjects the treatment, not combined with other medications, was effective for at least two years before discontinuation. The results show a percentage of recurrences similar to that reported by other Authors, with significant differences that point out a greater risk of recurrences after an abrupt discontinuation. The hypotheses concerning early recurrences are discussed, taking into account the different features of the recurrences in the two groups.
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Year |
1991 |
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Author |
Baldessarini RJ, Tondo L, Hennen J |
Title |
Treatment delays in bipolar disorders. |
Journal |
Am J Psychiatry |
Abstract |
(abstact not available) Treatment delays in bipolar disorders. |
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Year |
1990 |
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Author |
Poland RE, Tondo L, Rubin RT, Trelease RB, Lesser IM |
Title |
Differential effects of scopolamine on nocturnal cortisol secretion, sleep architecture, and REM latency in normal volunteers: relation to sleep and cortisol abnormalities in depression. |
Journal |
Biol Psychiatry |
Abstract |
Scopolamine (SCOP) (3.0 mu/kg and 6.0 micrograms/kg) and saline were administered intramuscularly at 11:00 PM to eight normal male volunteers in a randomized design, and the effects on the sleep electroencephalogram (EEG) and nocturnal cortisol secretion (via blood sampling every 15 min) were evaluated. Compared to saline, SCOP produced a significant dose-related delay in rapid eye movement (REM) latency. In contrast, neither dose of SCOP significantly affected nocturnal plasma cortisol concentrations. These results suggest that the central cholinergic system that regulates the onset of REM sleep is more sensitive to dysregulation than the cholinergic system that controls the degree of nocturnal cortisol secretion. If central cholinergic overactivity is responsible for both the REM sleep latency and cortisol abnormalities in depressed patients, then our findings with SCOP might help explain why the incidences of these abnormalities are different. |
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Year |
1989 |
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Author |
Tondo L, Burrai C, Scamonatti L, Toccafondi F, Poddighe A, Minnai G, Tundo A, Floris G |
Title |
Carbamazepine in panic disorder. |
Journal |
Am J Psychiatry |
Abstract |
(abstract not available) Carbamazepine in panic disorder. |
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Year |
1989 |
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Author |
Tondo L, Burrai C, Scamonatti L, Weissenburger J, Rush J |
Title |
Comparison between clinician-rated and self-reported depressive symptoms in Italian psychiatric patients. |
Journal |
Neuropsychobiology |
Abstract |
The Inventory for Depressive Symptomatology is a new scale for measuring depressive symptoms. The reliability, validity and correlations between self-report and clinician-rated versions of the scale were examined in 86 Italian psychiatric patients. Results confirmed the validity and internal consistency of the scales. Self-ratings and clinician ratings were highly correlated. Total score on the self-rating scale was generally higher than the corresponding clinician scale score. Item analysis revealed that most items were rated slightly higher by self-report, with the items contributing most to this discrepancy being psychomotor agitation and retardation, self-outlook, and irritable mood. Both quality of mood and psychomotor agitation were more frequently endorsed by self-report than by clinician rating.
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Year |
1988 |
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Author |
Rudas N, Tondo L, Musio A, Schiavo C, Galisai C, Dinelli U, Carta MG |
Title |
Deprivation of work and psychopathologic risk. (Italian) |
Journal |
Minerva Psichiatr |
Abstract |
(abstract not available) Deprivation of work and psychopathologic risk. (Italian) |
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Year |
1987 |
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Author |
Tondo L, Conway PG, Brunswick DJ |
Title |
Labeling in vivo of beta adrenergic receptors in the central nervous system of the rat after administration of [125I] iodopindolol. |
Journal |
J Pharmacol Exp Ther |
Abstract |
The amount of radioactivity in vivo in the central nervous system (CNS) of the rat has been studied after tail-vein injections of (-)- [125I] iodopindolol (IPIN). The content of radioactivity in cortex and cerebellum 1 to 4 hr after IPIN administration was significantly reduced in rats pretreated with I-propranolol (1 mg/kg) given i.v. 5 min before IPIN; only a small effect of I-propranolol was seen in brainstem and spinal cord. The maximum reduction in radioactivity caused by I-propranolol was approximately the same in cortex and cerebellum (about 60-65%) and occurred 2 hr after IPIN administration. I-Propranolol was approximately 1500-fold more potent than d-propranolol in reducing radioactivity. Pretreatment of rats with other lipophilic drugs that act at beta receptors was able to reduce the binding of IPIN in vivo; in contrast, pretreatment of rats with drugs which do not have direct agonist or antagonist activity at beta adrenergic receptors (desmethylimipramine, metergoline, diazepam, fluoxetine, phentolamine and haloperidol) had no effect. Experiments using ICI 118, 551, a beta-2 antagonist and betaxolol, a beta-1 antagonist, indicated that the majority of radioactivity in the cortex in vivo was bound specifically to the beta-1 subtype of the receptor whereas in the cerebellum the majority of specific binding was to the beta-2-subtype. When the specific binding of IPIN to beta adrenergic receptors was measured in vitro in seven regions of the CNS, at a ligand concentration of 30 pM, a high correlation was found with the I-propranolol displaceable radioactivity measured in vivo (r = 0.97, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS) |
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Year |
1985 |
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Author |
Kukopulos A, Caliari B, Tundo A, Minnai G, Floris G, Reginaldi D, Tondo L |
Title |
Rapid cyclers, temperament, and antidepressants. |
Journal |
Compr Psychiatry |
Abstract |
(abstract not available) Rapid cyclers, temperament, and antidepressants. |
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Year |
1983 |
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Author |
Reginaldi D, Tondo L, Caliari B, Minnai GP, Kukopulos A |
Title |
The role of antidepressants in rapid cyclicity. |
Journal |
Adv Biochem Psychopharmacol |
Abstract |
(abstract not available) The role of antidepressants in rapid cyclicity. |
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Year |
1982 |
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Author |
Reginaldi D, Tondo L, Floris G, Pignatelli A, Kukopulos A |
Title |
Poor prophylactic lithium response due to antidepressants. |
Journal |
Int Pharmacopsychiatry |
Abstract |
50 manic-depressive patients with rapid cycles received lithium for more than 1 year, during depression they received antidepressant drugs. Response was poor in 36, partial in 6, and good in 8. 21 of the poor responders were persuaded to endure depression without antidepressants; anxiolytics were allowed, 15 stabilized after the end of the untreated depression or after a few milder, shorter episodes; 4 improved partially; 2 were unchanged. 15 other rapid cycle patients started on lithium and stopped antidepressants at the same time. Response was good in 13, partial in 1, and poor in 1. Patients with a course of depression-hypomania (or mania)-free interval also responded poorly to prophylactic lithium when the depression was treated with antidepressants. They responded well when antidepressants were withdrawn. Antidepressants often cause or accentuate a switch from depression to hypomania or mania, and temporary refractoriness to lithium of the hypomania or mania. In this way lithium fails to prevent depression. |
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Year |
1981 |
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Author |
Tondo L, Laddomada P, Serra G, Minnai G, Kukopulos A |
Title |
Rapid cyclers and antidepressants. |
Journal |
Int Pharmacopsychiatry |
Abstract |
434 bipolar manic-depressive patients were followed longitudinally. The course of the disease changed in many patients over the years. 67 cases became rapid cyclers (two or more cycles per year); in 40 of these cases (12 men and 28 women) the change of the course took place after intense or protracted use of antidepressant drugs. In their previous course these patients had not received antidepressant drugs. The common feature of the transformation of the previous course to a continuous circular one was the appearance for the first time in the course of the disease of hypomanic episodes after the depressions, or the accentuation of hypomanias that had been of milder intensity in previous recurrences. The patients who developed continuous circularity under antidepressant drug treatment were of highly energetic temperament. The hypothesis is advanced that these patients have latent hypomanias, which become clinically manifest under the action of antidepressants. The intensification of an underlying hypomanic process by the antidepressants would precipitate another depression and establish continuous circularity. The change to a rapid cyclical course was more frequent in middle-aged patients and in women. |
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Year |
1981 |
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Author |
Kukopulos A, Reginaldi D, Laddomada P, Floris G, Serra G, Tondo L |
Title |
Course of the manic-depressive cycle and changes caused by treatment. |
Journal |
Pharmakopsychiatr Neuropsychopharmakol |
Abstract |
(abstract not available) Course of the manic-depressive cycle and changes caused by treatment. |
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Year |
1980 |
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Author |
Kukopulos A, Reginaldi D, Tondo L, Bernabei A, Caliari B |
Title |
Spontaneous length of depression and response to ECT. |
Journal |
Psychol Med |
Abstract |
Electro-convulsive treatment (ECT) was therapeutically ineffective in 27 (20%) of 136 depressed patients. Failure to respond occurred in long-lasting depressions and in patients with a history of long-lasting depressions. In these cases the depression lasted at least 6 months. The hyposthesis is proposed that ECT is effective only when given within 6 months of the spontaneous end of the depression. Clinical and nosological implications are discussed. |
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Year |
1977 |
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Author |
Mendels J, Frazer A, Baron J, Kukopulos A, Reginaldi D, Tondo L, Caliari B |
Title |
Letter: Intra-erythrocyte lithium ion concentration and long-term maintenance treatment. |
Journal |
Lancet |
Abstract |
(abstract not available) Letter: Intra-erythrocyte lithium ion concentration and long-term maintenance treatment. |
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Year |
1976 |
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Author |
Kukopulos A, Reginaldi D, Girardi P, Tondo L |
Title |
Course of manic-depressive recurrences under lithium. |
Journal |
Compr Psychiatry |
Abstract |
(abstract not available) Course of manic-depressive recurrences under lithium. |
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Year |
1975 |
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