Alberto Bocchetta

Lithium treatment and thyroid abnormalities

BackgroundAlthough the interactions between lithium treatment and thyroid function have long been recognised, their clinical relevance is still controversial. This paper sets out a review of the literature to date, considering that lithium still represents the gold standard among prophylactic treatments of manic-depression several decades after its introduction.MethodPubMed database was used to search for English-language articles relating to lithium treatment and thyroid function. As the amount of relevant papers totalled several hundreds, this review refers to previous reviews, especially with regard to older literature. Moreover, the authors particularly refer to a series of studies of thyroid function performed in a cohort of patients at different stages of lithium treatment, who were followed up by their group from 1989 onwards.ResultsThe main findings from this review included: a) lithium definitely affects thyroid function as repeatedly shown by studies on cell cultures, experimental animals, volunteers, and patients; b) inhibition of thyroid hormone release is the critical mechanism in the development of hypothyroidism, goitre, and, perhaps, changes in the texture of the gland which are detected by ultrasonic scanning; c) compensatory mechanisms operate and prevent the development of hypothyroidism in the majority of patients; d) when additional risk factors are present, either environmental (such as iodine deficiency) or intrinsic (immunogenetic background), compensatory potential may be reduced and clinically relevant consequences may derive; e) hypothyroidism may develop in particular during the first years of lithium treatment, in middle-aged women, and in the presence of thyroid autoimmunity; f) thyroid autoimmunity is found in excess among patients suffering from affective disorders, irrespective of lithium exposure; g) in patients who have been on lithium for several years, the outcome of hypothyroidism, goitre, and thyroid autoimmunity do not much differ from those observed in the general population; h) hyperthyroidism and thyroid cancer are observed rarely during lithium treatment.RecommendationsThyroid function tests (TSH, free thyroid hormones, specific antibodies, and ultrasonic scanning) should be performed prior to starting lithium prophylaxis. A similar panel should be repeated at one year. Thereafter, annual measurements of TSH may be sufficient to prevent overt hypothyroidism. In the presence of raised TSH or thyroid autoimmunity, shorter intervals between assessments are advisable (4–6 months). Measurement of antibodies and ultrasonic scanning may be repeated at 2-to-3-year intervals. The patient must be referred to the endocrinologist if TSH concentrations are repeatedly abnormal, and/or goitre or nodules are detected. Thyroid function abnormalities should not constitute an outright contraindication to lithium treatment, and lithium should not be stopped if a patient develops thyroid abnormalities. Decisions should be made taking into account the evidence that lithium treatment is perhaps the only efficient means of reducing the excessive mortality which is otherwise associated with affective disorders.

Linkage between X-chromosome markers and manic-depressive illness. Two Sardinian pedigrees.

ABSTRACT– Pedigrees of manic‐depressive patients in treatment at the Lithium Clinic of the Institute of Clinical Pharmacology, University of Cagliari, were evaluated for linkage between major affective illness and the protan‐deulan‐glucose‐6‐phosphatc‐dehydrogenase region of the X‐chromosome. Two informative pedigrees were found, investigated and analyzed for linkage using a multigenerational model and considering age‐dependent penetrance. The results are consistent with the hypothesis of X‐linkage in major affective illness.

A double-blind study of l-sulpiride versus amitriptyline in lithium-maintained bipolar depressives

A double‐blind group comparison study of L‐sulpiride and amitriptyline was carried out in 30 bipolar outpatients on maintenance treatment with lithium suffering from a major depressive recurrence. L‐sulpiride showed equivalent antidepressant activity to amitriptyline at 4 weeks using the Hamilton Rating Scale for Depression. However, the onset of action was faster in the L‐sulpiride group, showing a significant improvement at 1 week in both anxiety‐somatization and specific depression items, including depressed mood, feelings of guilt, work & activities and retardation. The incidence of anticholinergic side effects was significantly higher in the amitriptyline treatment group.

Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in sardinia

Association analysis of candidate genes may represent a strategy for clarifying the genetic components involved in bipolar disorder. Polymorphism at dopamine receptor genes DRD2, DRD4, and dopamine and serotonin transporter genes (DAT, SERT) has been used in previous association studies. Some authors have reported positive association between certain alleles and bipolar disorder, using the case-control design. In this family-based association study of DRD2, DRD4, DAT, and SERT, the distribution of parental nontransmitted alleles was compared with that of alleles transmitted to 53 Sardinian probands suffering from bipolar disorder. The transmission disequilibrium test (TDT) was used to detect any disproportionate transmission of alleles by heterozygous parents to affected children. No differences were found between the allele distribution of polymorphisms at DRD2, DRD4, DAT, and SERT in probands and parental nontransmitted chromosomes. TDT did not reveal any difference between transmitted and nontransmitted alleles. Our results do not support the hypothesis of a role for DRD2, DRD4, DAT, or SERT in bipolar disorder. Previously reported positive associations between DRD2 or SERT and bipolar disorder were conceivably due to stratification dependent on the case-control design, even though our sample might have failed to detect small associations due to limited power.

Ten-year follow-up of thyroid function in lithium patients

The objective of this paper was to study prospectively the course of clinically relevant thyroid dysfunction in a cohort of patients on long-term lithium treatment. Patients (N = 150) who had undergone a cross-sectional evaluation of their thyroid function in 1989, when they were at different stages of lithium treatment, were followed up for the presence of thyroid autoimmunity, hypothyroidism, and goiter during a further period of lithium exposure of up to ten years. The following annual rates of newly developed thyroid dysfunction were observed: autoimmunity (1.4%), subclinical hypothyroidism (1.7%), and goiter (2.1%). Subjects with thyroid autoimmunity had a higher chance of requiring substitution treatment with levothyroxine for subclinical hypothyroidism compared with subjects with no evidence of thyroid autoimmunity (13/32 = 41% versus 7/118 = 6%). Subjects (N = 15) who were prescribed carbamazepine in addition to lithium showed a significant decrease of TSH concentrations. In patients already being treated with lithium for several years, the overall incidence of hypothyroidism, goiter, and thyroid autoimmunity were comparable with those reported for the general population. However, lithium exposure may represent an additional risk factor for hypothyroidism in women and/or in the presence of thyroid autoimmunity.

The course of thyroid abnormalities during lithium treatment: a two-year follow-up study

A total of 116 patients on lithium treatment were followed up for 2 years to determine the course and the clinical relevance of thyroid abnormalities. Elevated thyroid‐stimulating hormone (TSH) concentrations were transitory in most patients, except those with serum antithyroid antibodies. The patients who initially had microsomal antibodies remained positive, with an increase in titre in two‐thirds of cases. Three young patients of both sexes developed thyroid autoimmunity early in the treatment. The risk of developing hypothyroidism was higher in women, especially in the presence of antibodies. TSH concentrations were significantly lower when carbamazepine was combined with lithium.

Fifteen-year follow-up of thyroid function in lithium patients

Objective: To study prospectively the course of clinically relevant thyroid dysfunction in a cohort of patients on long-term lithium treatment. Method: Patients (no.=150) who had undergone a cross-sectional evaluation of their thyroid function in 1989, when they were at different stages of lithium treatment, were followed up for thyroid circulating thyroid antibodies, hypothyroidism, hyperthyroidism, and thyroidectomy, during a further period of lithium exposure of up to 15 yr. Results: Annual rates of newly developed circulating thyroid antibodies and hypothyroidism were 1.7 and 1.5%, respectively. Subjects with thyroid antibodies had a higher chance of requiring substitution treatment with levothyroxine for hypothyroidism compared with subjects with no evidence of thyroid antibodies (6.4% annual rate compared to 0.8%; relative risk: 8.4; 95% confidence interval: 2.9–24.0). One case of hyperthy-roidism was observed over 976 patient-yr. Three patients underwent thyroidectomy during follow-up (two for multinodular goiter and one for multi-centric papillary carcinoma). Conclusions: Lithium may be associated with hypothyroidism in particular in the presence of circulating thyroid antibodies. Incidence of thyroid antibodies is comparable with that reported for the general population. Hyperthyroidism and thyroid cancer are rare.

The Use of Antidepressant Drugs and the Lifetime Prevalence of Major Depressive Disorders in Italy

Background: The increased use of antidepressant drugs (ADs) improved the response to the needs of care although some community surveys have shown that subjects without lifetime psychiatric diagnosis (anxiety/depression) used ADs. Objectives: To evaluate the appropriateness and amount of prescription of psychotropic drugs in people with lifetime diagnosis of Major Depressive Disorder (MDD) by means of community survey with a semi-structured interview as a diagnostic instrument, administered by clinicians. Methods: Study design: community survey. Study population: samples randomly drawn, after stratification from the adult population of municipal records. Sample size: 4.999 people were drawn in 7 centres of 6 Italian regions. Tools: questionnaire on psychotropic drug consumption, prescription, health services utilization; Structured Clinical Interview for DSM-IV modified (ANTAS); Training: interviewers were trained psychologists or medical doctors. Results: 3.398 subjects were interviewed (68% of the recruited sample). The lifetime prevalence of DSM-IV MDD was 4.3% in males and 11.5% in females; antidepressant drugs were taken by 4.7% of subjects, 2.9% male and 5.9% female. 38% of males and 57% of females with lifetime diagnosis of MDD were taking ADs. Conclusions: Compared with studies using lay interviewers and structured tools the prevalence of the MDD was quite lower; ADs use was higher and tallied well with the data regarding antidepressant sales in Italy; the correspondence between lifetime diagnosis of MDD and ADs use was closer.

Association of personal and familial suicide risk with low serum cholesterol concentration in male lithium patients

Objective:  We sought to establish whether low cholesterol concentration may be associated with a personal history of attempted suicide or a family history of completed suicide in psychiatric out‐patients on maintenance lithium treatment, who represent a population at risk for suicide.

1 ‐Methyl‐4‐Phenyl‐ 1,2,3,6‐Tetrahydropyridine: Correspondence of Its Binding Sites to Monoamine Oxidase in Rat Brain, and Inhibition of Dopamine Oxidative Deamination In Vivo and In Vitro

Abstract: A saturable, specific, high‐affinity binding site for [3H] 1 ‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine was found in rat brain homogenates. The CNS regional distribution, the subcellular fractionation, and the displacement by pargyline, clorgyline, and deprenyl suggest that this binding site may correspond to monoamine oxidase. I ‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine inhibited the oxidative deamination of dopamine, both in vivo and in vitro. Striatal levels of 3,4‐dihydroxyphenylacetic acid were significantly reduced shortly after intravenous administration, and returned to normal values after a few hours. The in vitro formation of 3,4‐dihydroxyphenylacetic acid from dopamine was inhibited by concentrations of 1‐methyl‐4‐phenyl‐ 1,2,3,6‐tetrahydropyridine comparable to those of pargyline.