Effectiveness of ultra-long-term lithium treatment: relevant factors and case series.

BACKGROUND: The phenomenon of preventing the recurrences of mood disorders by the long-term lithium administration was discovered sixty years ago. Such a property of lithium has been unequivocally confirmed in subsequent years, and the procedure makes nowadays the gold standard for the pharmacological prophylaxis of bipolar disorder (BD). The efficacy of lithium prophylaxis surpasses other mood stabilizers, and the drug has the longest record as far as the duration of its administration is concerned. The continuation of lithium administration in case of good response could be a lifetime and last for several decades. The stability of lithium prophylactic efficacy in most patients is pretty steady. However, resuming lithium after its discontinuation may, in some patients, be less efficient. MAIN BODY: In the article, the clinical and biological factors connected with the prophylactic efficacy of long-term lithium administration are listed. Next, the adverse and beneficial side effects of such longitudinal treatment are presented. The main problems of long-term lithium therapy, which could make an obstacle to lithium continuation, are connected with lithium's adverse effects on the kidney and, to lesser extent, on thyroid and parathyroid functions. In the paper, the management of these adversities is proposed. Finally, the case reports of three patients who have completed 50 years of lithium therapy are described. CONCLUSIONS: The authors of the paper reckon that in the case of good response, lithium can be given indefinitely. Given the appropriate candidates for such therapy and successful management of the adverse effects, ultra-long term lithium therapy is possible and beneficial for such patients.

Ultra-long-term lithium therapy: all-important matters and a case of successful 50-year lithium treatment.

This paper discusses essential issues related to long-term lithium therapy and presents a case of successful 50-year lithium treatment. Lithium is currently regarded as the drug of choice for preventing manic and depressive recurrences in bipolar disorder. In 1/3 of patients with bipolar disorder, long-term monotherapy with lithium can completely prevent recurrences of abnormal mood. Numerous clinical and psychosocial factors associated with a good response to lithium have been described. Lithium is more efficacious than other mood stabilizers, and its long-term treatment significantly exceeds them. Lithium also exerts antisuicidal, immunomodulatory, and neuroprotective effects. The main problems associated with long-term lithium treatment include kidney, thyroid, and probably cognitive issues. In this paper, a case of successful continuous lithium treatment for 50 years in a 79-year-old female patient is presented. In this patient, apart from maintaining a euthymic state, long-term lithium treatment also exerted a favorable effect on general health, especially the elimination of viral and other respiratory infections. It is concluded that ultra-long term lithium therapy can enable good professional and psychosocial functioning for many patients, and the possible somatic side effects are manageable.

Electroconvulsive therapy and autobiographical memory in patients with treatment-resistant depression. / Terapia elektrowstrzasowa i pamiec autobiograficzna u pacjentów z depresja lekooporna.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drugresistant depression. In most studies, cognitive functions including working and semantic memory showed only transient impairment after ECT. However, the deficits of episodic (autobiographical) memory were demonstrated to be long-lasting. METHODS: We investigated autobiographical memory in 20 patients (8 male, 12 female), aged 21-64 years, with drug-resistant depression, treated with ECT, using the Polish adaptation of the Autobiographical Memory Interview-Short Form (AMI-SF). The assessments were performed before, immediately after 10-12 ECT sessions, and 3 months thereafter. RESULTS: Before the ECT, the mean severity of depression was 30 ± 6 points on the 17-item Hamilton Depression Rating Scale and the treatment produced a significant clinical improvement in all patients. The indices of autobiographical memory, as assessed by the AMI-SF, were significantly lower immediately after ECT and 3 months thereafter. The impairment in autobiographical memory did not show correlation with clinical improvement and with any other clinical factors. CONCLUSIONS: The results obtained in patients with drug-resistant depression confirm that ECT treatment produces a significant impairment of autobiographical memory persisting also three months after the procedure, suggesting that it may be the most important adverse cognitive effect of the ECT.

Augmentation of Pharmacotherapy by Sleep Deprivation with Sleep Phase Advance in Treatment-Resistant Depression.

INTRODUCTION: The aim was to assess the efficacy of total sleep deprivation (TSD) with sleep phase advance (SPA) in treatment-resistant depression (TRD) and associated biochemical factors. METHODS: We studied nine males and 12 females, aged 49±14 years, with treatment-resistant unipolar or bipolar depression, receiving antidepressant and mood-stabilizing drugs. The four-day schedule included single TSD and three consecutive nights with SPA. Biochemical markers were measured on the day before and on 1st, 7th and 14th day after the TSD. RESULTS: Ten subjects met criteria for response, defined as a reduction of ≥50% in the Hamilton Depression Rating Scale, on the 14th day. Concentrations of cortisol at baseline were lower in responders, and they decreased during therapy in both groups. In responders, there was an increase of interleukin-10 (IL-10) and IL-1ß on the 14th day. DISCUSSION: Our preliminary study demonstrated the efficacy of pharmacotherapy augmentation by TSD and SPA in half of the patients with TRD. The main biochemical factors related to clinical response included status of cortisol and increase in IL-10 and IL-1ß levels.

Kidney, thyroid and other organ functions after 40 years or more of lithium therapy: a case series of five patients.

We present the cases of five patients (two men aged 64 years and 79 years) and three women (aged 64 years, 65 years and 75 years) who have received lithium treatment for 40-45 years, with particular regard to kidney and thyroid functions, hypercalcaemia and cognition, in the context of disease course and overall functioning. Lithium was initiated in the early phase of the illness (in three patients within the first 2 years). In four patients, lithium concentration was between 0.60 and 0.65 mmol/l and in one patient, between 0.7 and 0.8 mmol/l. Four were very good lithium responders. One man had stage 3 chronic kidney disease, and the other stage 2/3 chronic kidney disease. All three women had asymptomatic stage 2 chronic kidney disease. One woman had severe thyroid dysfunction (Hashimoto's disease) with extremely high levels of antithyroid peroxidase antibodies and antithyroglobulin antibodies and was receiving thyroxine. Serum calcium levels were normal or borderline in all five patients, and most cognitive functions were comparable to healthy persons of similar gender, age and years of education. All the patients were professionally active until 55-65 years and their family and social functioning were satisfactory. It was concluded that, in good lithium responders, ultra-long-term treatment with lithium enables good professional and psychosocial functioning, and the possible somatic side effects are manageable.

Ketamine Anesthesia, Efficacy of Electroconvulsive Therapy, and Cognitive Functions in Treatment-Resistant Depression.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drug-resistant depression (DRD). Because a single infusion of ketamine may exert both a rapid antidepressant effect and a quick improvement of cognition, the aim of the present study was to assess whether ketamine, as an anesthetic drug for ECT, can augment the antidepressant activity of the procedure and/or exert a beneficial effect on cognition. METHODS: A total of 11 male and 34 female patients with DRD, aged 21 to 75 years, were included in the study. Fifteen patients (group 1) received only thiopental anesthesia, 15 patients (group 2) had their second and third ECT sessions with ketamine, and 15 patients (group 3) had ketamine for the second, fourth, sixth, eighth, and tenth sessions. Depression intensity was measured by the 17-item Hamilton Depression Rating Scale. Cognitive functions were measured before and after ECT, assessing visual-spatial abilities, verbal auditory memory, working memory, and executive functions. RESULTS: Before the ECT, the mean (SD) intensity of depression was 32 (6) points on the Hamilton Depression Rating Scale and the mean number of ECT sessions was 10.8 (1.5), with no difference between groups. After the last ECT session, the intensity of depression was significantly lower in group 3, compared with group 1. Cognitive assessments after ECT showed a more marked worsening in verbal memory in patients with added ketamine anesthesia. CONCLUSIONS: The addition of ketamine may be connected with better antidepressant efficacy of ECT, compared with only thiopental anesthesia. However, patients with added ketamine had worse results on some of the indices measuring verbal memory.

Renal sonography in bipolar patients on long-term lithium treatment.

PURPOSE: The aim of the study was to analyze sonographic (US) renal findings in lithium-treated bipolar patients and to correlate them with renal function. METHODS: Renal US and renal function tests were performed on 120 patients with bipolar disorder. Ninety patients (30 males, 60 females), aged 36-82 years, had received lithium therapy for an average of 16 years, whereas 30 patients (10 males, 20 females), aged 35-85 years, who had never been exposed to lithium, served as controls. RESULTS: In the lithium-treated group, patients with macrocysts (22%) had poorer renal function with higher creatinine serum concentrations, lower estimated glomerular filtration rates, and lower urine specific gravity, compared with the patients without macrocysts. The US changes characteristic for lithium nephropathy (punctate hyperechoic foci, microcysts < 2 mm, and increased echogenicity) were seen in three patients. These patients had been treated with lithium for more than 20 years and had impaired renal function. Sixteen percent of patients in the control group had macrocysts; however, no correlation between their presence and impaired renal function was found. CONCLUSIONS: The presence of macrocysts in the kidneys of lithium-treated bipolar patients is associated with impaired renal function. The US changes characteristic for lithium nephropathy are rare, and in our study, were only found in patients treated with lithium for 20 years or more. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:354-359, 2016.

Electroconvulsive therapy and cognitive functions in treatment-resistant depression.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drug-resistant depression (DRD). We estimated the short- and long-term effects of ECT on cognitive functions in patients with unipolar and bipolar DRD. METHODS: We investigated 63 patients (18 male, 45 female), aged 34-75 years. Cognitive assessments were performed before, immediately after 6-12 ECT sessions, and 3 months thereafter, using the Benton Visual Retention, Trail Making (TMT), Rey-Osterrieth Complex Figure (ROCF) tests, the Digit Span of the Wechsler Adult Intelligence Scale, and the Rey Auditory Verbal Learning (RAVLT), verbal fluency and Stroop tests. RESULTS: Immediately after ECT, a significant worsening was noted in some indices of memory and verbal fluency. However, 3 months after ECT, the indices of both RAVLT and verbal fluency significantly improved compared to baseline, and those of the Benton and ROCF were significantly better than before ECT. The Digit Span, Stroop and TMT were not affected by the treatment. CONCLUSIONS: The negative effects of ECT on the reported measures of cognition are transient. After 3 months, the indices of memory were significantly better than before the treatment. In addition to its antidepressant effect in DRD, ECT may also exert a long-term favourable influence on some cognitive functions.

A cross-sectional study of thyroid function in 66 patients with bipolar disorder receiving lithium for 10-44 years.

OBJECTIVES: An important side effect of lithium therapy is an influence on thyroid function. It is unclear whether there is a significant association between thyroid function and duration of lithium administration. The aim of the present cross-sectional study was to measure levels of thyroid hormones and antibodies in patients with bipolar disorder receiving lithium for more than ten years. METHODS: The study was performed in 66 patients (21 males, 45 females) with bipolar mood disorder, receiving lithium for 10-44 (21 ± 9; mean ± standard deviation) years. Thyroid-stimulating hormone (TSH), free thyroxine (fT3), and free triiodothyronine (fT4) were measured by the microparticle enzyme immunoassay. Thyroid peroxidase (TPO) antibodies, thyroglobulin (TG) antibodies, and TSH receptor (TSH-R) antibodies were measured by the radioimmunoassay. RESULTS: Some features of hypothyroidism were found in ten (22%) female patients (seven received levothyroxine and three had increased TSH). No abnormality in thyroid hormones was found in male patients. A significant percentage of patients had abnormally high levels of anti-TPO, and anti-TG antibodies, which correlated with TSH and fT3 concentrations. There were no differences in thyroid function between patients receiving lithium for 10-20 years and those taking the drug for more than 20 years. CONCLUSIONS: These results confirm the greater susceptibility of female subjects for disturbances of thyroid hormones during lithium therapy, with one-fifth of them showing some features of hypothyroidism. Abnormally high levels of anti-TPO and anti-TG antibodies were shown in a significant proportion of patients. However, in contrast to the effect of lithium on kidney function, our results do not show an association between the duration of lithium therapy and thyroid dysfunction.

[The effect of lithium on thyroid function in patients with bipolar disorder]. / Wplyw stosowania litu na czynnosc gruczolu tarczowego u pacjentów z choroba afektywna dwubiegunowa.

Since 1963 lithium treatment has been the best proven long-term pharmacotherapy for bipolar disorder (BD), both in the prevention of depressive and manic episodes, along with the reduction of the suicide risk. Thyroid gland and the hypothalamic-pituitary-thyroid (HPT) axis play a role in the pathophysiology, clinical course and treatment of BD. The influence of lithium on the thyroid gland is one of the key side effects in the long-term therapy with this drug. Lithium is accumulated in the thyroid gland at 3 to 4-fold higher concentrations as compared to its plasma levels. Its administration results in the reduced production with release inhibition of thyroid hormones, altering the immune processes of this gland. The most common thyroid side effects associated with long-term lithium treatment are goiter and hypothyroidism. Hyperthyroidism is a rare complication of lithium therapy. Lithium may also induce an increase in the thyroid autoimmunity, especially if such change had been present before lithium treatment producing structural changes in this gland. This paper reviews the management of complications described above as well as recommendations for monitoring of thyroid function in patients receiving long-term lithium treatment are discussed.

[Factors connected with efficacy of single ketamine infusion in bipolar depression]. / Czynniki skutecznosci jednorazowego wlewu ketaminy w depresji w przebiegu choroby afektywnej dwubiegunowej.

AIM: The aim of this study was to evaluate the efficacy of single ketamine infusion and clinical and biochemical factors connected with such efficacy, in patients with bipolar depression, which had not improved on antidepressant treatment. METHODS: The study included 42 patients (32 women, 10 men), aged 22-67 years, with bipolar depression. They received > or = 1 mood-stabilizing medications of first and/or second generation. After discontinuation of antidepressants (> or = 7 days), intravenous infusion of ketamine (0.5 mg/kg body weight) was performed. The assessment of depression by the 17-item Hamilton Depression Rating Scale was made before, and after 1, 3, 7 and 14 days following administration of ketamine. The assumed criterion for clinical improvement was the reduction of > or = 50% score on the Hamilton scale after 7 days. In a subgroup of 20 patients, prior to administration of ketamine, serum concentrations of homocysteine, vitamin B12, folic acid, neurotrophins and inflammatory proteins were measured. RESULTS: In the whole group, the severity of depression on the Hamilton scale decreased significantly 24 hours after administration of ketamine from 22.6 +/- 5.1 to 15.6 +/- 7.4 points. After 7 days it was 13 +/- 7 and after 14 days - 11.8 +/- 7.8 points. Patients showing clinical improvement (n = 22) had significantly higher frequency of alcohol addiction and family history of alcoholism. Biochemical tests in the subset of 20 patients demonstrated that those with clinical improvement (n = 10) had higher serum concentrations of vitamin B12 and receptor-1 Vascular Endothelial Growth Factor before administration of ketamine. Ketamine infusion was well tolerated. CONCLUSIONS: The results confirm a rapid antidepressant effect of ketamine infusion maintaining for 2 weeks, in a considerable proportion of patients with bipolar depression, and good clinical tolerance of such procedure. Also, some clinical and biochemical factors associated with ketamine efficacy were shown.

Hyperhomocysteinemia in bipolar depression: clinical and biochemical correlates.

BACKGROUND: Depression may be associated with elevated homocysteine (HCY) levels. Procedures aiming at its decrease, i.e. supplementation with folic acid or vitamin B12, have antidepressant effect. Both depression and elevated HCY can increase cardiovascular risk. In this study, clinical and biochemical factors, including markers of endothelial function, in relation to hyperhomocysteinemia, in patients with bipolar depression during acute episode were studied. METHOD: One hundred and twelve patients (24 male, 88 female), aged 20-78 (mean 51 ± 14 years), with depressive episode in the course of bipolar mood disorder have been included. The assays were made of serum concentrations of HCY, vitamin B12, folic acid as well as markers of endothelial function such as E-selectin and intracellular adhesion molecule-1 (ICAM-1). RESULTS: Hyperhomocysteinemia (>15 mM) was found in 50 patients (45%), significantly more frequently in male (67%) than in female subjects (39%). Female patients with hyperhomocysteinemia were significantly older than the remaining ones. A significant inverse correlation between HCY level and concentration of folic acid and vitamin B12 as well as with E-selectin and ICAM-1 was observed. CONCLUSION: The results point to a significant prevalence of hyperhomocysteinemia in bipolar depressed patients during an acute episode. They also corroborate the correlation between increased concentration of HCY and lower level of vitamin B12 and folic acid. An unexpected finding of negative correlation of HCY level with markers of endothelial functions in such patients is discussed in view of current concepts of the role of HCY in various conditions.

Novel markers of kidney injury in bipolar patients on long-term lithium treatment.

OBJECTIVES: We assessed kidney function in long-term lithium-treated bipolar patients compared with age-matched patients not taking lithium, including novel markers of kidney injury such as plasma neutrophil gelatinase-associated lipocalin (NGAL) and urinary beta-2 microglobulin (ß2-MG) METHODS: The study comprised 120 patients with bipolar disorder of which 90 (30 males and 60 females) have been receiving lithium for 5-38 (mean 16) years, and 30 (10 males and 20 females) have never been exposed to lithium. RESULTS: Lithium-treated patients, both men and women, showed significantly higher plasma NGAL and urinary ß2-MG and lower urine specific gravity and estimated glomerular filtration rate (eGFR), compared with patients not taking lithium. In these patients, serum NGAL did not correlate with any clinical feature or other parameter of kidney function. Urinary ß2-MG correlated with serum creatinine and eGFR in the whole group of lithium-treated patients and in addition, in males, with duration of illness, duration of lithium treatment, and urine specific gravity. CONCLUSIONS: Lithium treatment causes an impairment of kidney function reflected also by abnormal levels of novel markers of kidney injury. Of these, urinary ß2-MG, as a marker of tubular function seems to be better predictor than serum NGAL in lithium-treated patients because it shows multiple clinical and biochemical correlations, especially in men.

[The effect of long-term lithium treatment on kidney function]. / Wplyw dlugotrwalego podawania litu na czynnosc nerek.

In 1963 it was first demonstrated that long-term lithium administration exerts a "mood-stabilising" effect, preventing recurrences of mania and depression in bipolar affective disorder. Despite the introduction of many other drugs having mood-stabilising effect, lithium still remains the first choice drug for the prophylaxis of affective episodes in mood disorder. Lithium is eliminated nearly exclusively by the kidneys: lithium clearance is proportional to creatinine clearance and is influenced by natriuretic and antinatriuretic factors. Nowadays, nearly 40-year experience with long-term lithium treatment point to a possibility of nephrotoxic effects of this ion. Impaired urinary concentrating ability, which, in a few patients can reach an intensity of diabetes insipidus, can occur after several weeks of lithium administration. Favourable results in the treatment of diabetes insipidus have been obtained with amiloride, the drug which block epithelial sodium channel. However, after 10-20 years of treatment, lithium-induced interstitial nephropathy may be demonstrated in some patients, which, in small proportion of the latter may lead to end-stage renal disease. Lithium-induced hipercalcemia and nephrotic syndrome are rare complications of lithium therapy. In patients on long-term lithium therapy periodic monitoring of kidney function by measuring serum creatinine concentration and glomerular filtration rate is necessary. In case of detecting nephropathy, a discontinuation of lithium sho uld be considered. The patient in whom lithium was discontinued due to nephropathy should remain in nephrological treatment.

Screening for the markers of kidney damage in men and women on long-term lithium treatment.

BACKGROUND: Lithium is the most effective therapeutic modality for the prevention of recurrences in bipolar disorder. An important adverse effect of lithium, especially with long-term treatment, is a possibility of a toxic effect on kidney function. Therefore, the aim of the study was to assess kidney function in a group of long-term lithium-treated patients. MATERIAL/METHODS: The study comprised 80 patients with bipolar mood disorder (26 male, 54 female), aged 60 ± 11 years. They had been receiving lithium for 5-38 (16 ± 9) years. Random urine sample was examined for albumin and creatinine excretion, and urinary albumin to creatinine ratio (UACR) was calculated. Specific gravity of the urine sample was recorded. Serum concentration of creatinine was measured and estimated glomerular filtration rate (eGFR) was calculated. Serum concentration of albumin was also measured. RESULTS: Decreased eGFR values <60 ml/min/1.73 m² were found in 23% of patients, significantly more frequently in men that in women (38% vs. 16%, p=0.04). Elevated UACR values (>30 mg/g) were found in 25% of men and 12% of women, respectively. Serum albumin concentration >52 g/l was detected in 19% of patients (17% of men and 20% of women). Specific gravity of the urine, equal to or below 1.005, was recorded in 21% of men and 14% of women. CONCLUSIONS: The results confirm the opinion that screening for the markers of kidney damage should be performed in long-term lithium-treated patients for identification of persons with impaired kidney function. Male sex seems to be the risk factor for the development of kidney damage during long-term lithium treatment.

[Depression, its therapy and venous thromboembolism: three cases of pulmonary embolism]. / Depresja i jej leczenie a zylna choroba zakrzepowo-zatorowa: trzy przypadki zatorowosci plucnej.

The associations between depression and coronary heart disease, especially via platelet hyperactivity, have been widely described. The relationships between depression and venous thromboembolism are less clear. We present three cases of pulmonary embolism (PE) in patients with previously diagnosed depression and discuss possible, depression-related prothrombotic factors, including the impact of psychotropic drugs. A 69 year-old woman, treated with different antidepressants and also antipsychotics, died two months after recurrent PE. Another woman, at the same age, on mirtazapine therapy, developed segmental PE. In a 39 year-old man, taking paroxetine, severe PE required thrombolysis.

[Long-term lithium prophylaxis in the bipolar affective disorder]. / Dlugotrwala profilaktyka litem w chorobie afektywnej dwubiegunowej.

The purpose of the study was to evaluate the efficacy of lithium prophylaxis in patients with bipolar affective disorder and to determine clinical differences between lithium responders and non-responders. Clinical and demographic data of 103 patients treated with lithium for at least 10 years were analysed. 24 patients had no episodes on lithium (excellent responders--ER), in 48--at least 50% reduction of episode index (number of episodes/year) was observed, and the remaining 31 did not benefit from lithium treatment. Duration of illness before lithium introduction was significantly longer in lithium non-responders. Lithium responders had significantly higher episode index before lithium. Percentage of excellent responders diminished during treatment. The trend toward higher lithium plasma level in excellent responders was observed. Non-responders had significantly more depressions during first year of lithium prophylaxis. Depressive episodes during first year of treatment may be a predictor of non-response.