Comparison of bipolar disorder type II and major depressive disorder.

OBJECTIVE: Compare patients diagnosed as DSM-5 type II bipolar disorder (BD2) vs. major depressive disorder (MDD). METHODS: We compared characteristics of 3246 closely and repeatedly evaluated, consenting, adult patient-subjects (n = 706 BD2, 2540 MDD) at a specialty clinic using bivariate methods and multivariable modeling. RESULTS: Factors more associated with BD2 than MDD included: [a] descriptors (more familial psychiatric, mood and bipolar disorders and suicide; younger at onset, diagnosis and first-treatment; more education; more unemployment; fewer marriages and children; higher cyclothymic, hyperthymic and irritable temperament ratings, lower anxious); [b] morbidity (more hypomanic, mixed or panic first episodes; more co-occurring general medical diagnoses, more Cluster B personality disorder diagnoses and ADHD; more alcohol and drug abuse and smoking; shorter depressive episodes and interepisode periods; lower intake ratings of depression and anxiety, higher for hypomania; far more mood-switching with antidepressants; lower %-time depressed; DMI > MDI course-pattern in BD2; more suicide attempts and violent suicidal behavior); [c] item-scores with intake HDRS21 higher for suicidality, paranoia, anhedonia, guilt, and circadian variation; lower somatic anxiety, depressed mood, insight, hypochondriasis, agitation, and insomnia; and [d] treatment (more lithium, mood-stabilizing anticonvulsants and antipsychotics, less antidepressants and benzodiazepines). CONCLUSIONS: BD2 and MDD subjects differed greatly in many descriptive, psychopathological and treatment measures, notably including more familial risk, earlier onset, more frequent recurrences and greater suicidal risk with BD2. Such differences can contribute to improving differentiation of the disorders and planning for their treatment.

Factors associated with onset-age in major affective disorders.

BACKGROUND: Research findings on factors associated with onset-age (OA) with bipolar (BD) and major depressive disorders (MDD) have been inconsistent, but often indicate greater morbidity following early OA. METHODS: We considered factors associated with OA in 1033 carefully evaluated, systematically followed mood disorder subjects with DSM-5 BD (n = 505) or MDD (n = 528), comparing rates of descriptive and clinical characteristics following early (age <18), intermediate (18-40), or later onset (≥40 years), as well as regressing selected measures versus OA. Exposure time (years ill) was matched among these subgroups. RESULTS: As hypothesized, many features were associated with early OA: familial psychiatric illness, including BD, greater maternal age, early sexual abuse, nondepressive first episodes, co-occurring ADHD, suicide attempts and violent suicidal behavior, abuse of alcohol or drugs, smoking, and unemployment. Other features increased consistently with later OA: %-time-depressed (in BD and MDD, women and men), as well as depressions/year and intake ratings of depression, educational levels, co-occurring medical disorders, rates of marriage and number of children. CONCLUSIONS: OA averaged 7.5 years earlier in BD versus MDD (30.7 vs. 38.2). Some OA-associated measures may reflect maturation. Associations with family history and suicidal risk with earlier OA were expected; increases of time-depressed in both BD and MDD with later OA were not. We conclude that associations of OA with later morbidity are complex and not unidirectional but may be clinically useful.

Differences between bipolar disorder types 1 and 2 support the DSM two-syndrome concept.

OBJECTIVE: To compare characteristics of bipolar disorder patients diagnosed as DSM-5 types I (BD-1) vs. II (BD-2). METHODS: We compared descriptive, psychopathological, and treatment characteristics in a sample of 1377 consenting, closely and repeatedly evaluated adult BD patient-subjects from a specialty clinic, using bivariate methods and logistic multivariable modeling. RESULTS: Factors found more among BD-2 > BD-1 cases included: [a] descriptors (more familial affective disorder, older at onset, diagnosis and first-treatment, more education, employment and higher socioeconomic status, more marriage and children, and less obesity); [b] morbidity (more general medical diagnoses, less drug abuse and smoking, more initial depression and less [hypo]mania or psychosis, longer episodes, higher intake depression and anxiety ratings, less mood-switching with antidepressants, less seasonal mood-change, greater %-time depressed and less [hypo]manic, fewer hospitalizations, more depression-predominant polarity, DMI > MDI course-pattern, and less violent suicidal behavior); [c] specific item-scores with initial HDRS21 (higher scores for depression, guilt, suicidality, insomnia, anxiety, agitation, gastrointestinal symptoms, hypochondriasis and weight-loss, with less psychomotor retardation, depersonalization, or paranoia); and [d] treatment (less use of lithium or antipsychotics, more antidepressant and benzodiazepine treatment). CONCLUSIONS: BD-2 was characterized by more prominent and longer depressions with some hypomania and mixed-features but not mania and rarely psychosis. BD-2 subjects had higher socioeconomic and functional status but also high levels of long-term morbidity and suicidal risk. Accordingly, BD-2 is dissimilar to, but not necessarily less severe than BD-1, consistent with being distinct syndromes.

Suicidal risks in rural versus urban populations in Sardinia.

OBJECTIVE: Rural locations have been associated with suicidal risk; low population density may be a relevant factor. Accordingly, we investigated hypothesized associations between suicidal ideation and behavior with selected geographic and population-related measures and other factors. METHODS: Consenting adult patients at a mood disorder center in Cagliari, Sardinia, were assessed for the presence of suicidal ideation and acts and their association with selected demographic and clinical factors as well as indicators of urbanicity and rurality, including distance from the region's main metropolitan area, population density, altitude, and population growth trends. RESULTS: Of 5,668 subjects, 27% had an indication of lifetime suicidal behavior or ideation; 8.6% had at least one suicidal act. Low population density, higher altitude and their interaction, distance from the metropolitan center of the main city (Cagliari), and population decline were associated with greater risk of suicidal ideation or behavior. In addition, and as expected, alcohol or substance abuse, diagnosis of mood disorders, higher depression ratings at intake, being younger at illness-onset, family history of suicide or other psychiatric disorder, being female, unmarried, separated or divorced, currently smoking cigarettes, being unemployed, and having experienced sexual abuse all were more likely in subjects with suicidal ideation or behavior. CONCLUSION: Suicidal ideation and behavior were associated with indicators of social isolation as well as with previously reported clinical and demographic risk factors.

Risk of Depression Associated With Finasteride Treatment.

BACKGROUND: Finasteride is one of several inhibitors of the 5α-reductase that converts testosterone to dihydrotestosterone used to treat hair loss and benign prostatic enlargement. Emerging clinical observations indicate that such treatment may be associated with depression, anxiety, and possibly increased suicidal risks, in addition to sexual dysfunction, even after its discontinuation. METHODS: We carried out a systematic review of reports pertaining to association of finasteride treatment with clinical depression or other adverse psychiatric effects. We analyzed reported risks of depression by pooling of rates and by meta-analysis of comparisons of subjects treated with finasteride or not. FINDINGS: Crude pooled rates of depressive symptoms with versus without finasteride were 3.33% (confidence interval, 3.22%-3.44%) versus 2.54% (2.44%-2.64%); random-effects meta-analysis yielded an odds ratio of 2.14 (1.40-3.27) (both P < 0.0001). In addition, risk of suicidal ideation or behavior was greater with versus without finasteride (21.2% [21.0%-21.5%] vs 14.0% [13.8%-14.2%], P < 0.0001), and risk of sustained sexual dysfunction was high (60.1% [37.3%-82.9%]). CONCLUSIONS: The findings support a growing impression that finasteride is associated with adverse psychiatric effects that can persist in association with sexual dysfunction after discontinuing finasteride treatment.

A novel SCL-90-R six-item factor identifies subjects at risk of early adverse outcomes in public mental health settings.

To increase access to treatment, Italy made assessment at community mental health centers (CMHCs) independent of medical referral, resulting in increased numbers of patients to be triaged efficiently. To support this process, we evaluated SCL-90-R item-ratings to identify factors that best predicted adverse early outcomes among persons seeking first-time CMHC care in a 24-month period in Rome. A psychiatric nurse screened subjects with a brief interview and self-administered SCL-90-R and psychiatrists provided CGI ratings and ICD-9 diagnosis. Of 832 screened subjects, 32 (3.85%) were hospitalized or attempted suicide within 90 days. Six SCL-90 items (15,41,55,57,78,88) scored much higher with than without such adverse outcomes; their sum is proposed as a predictive measure ("SCL-6″). In binary multivariable logistic modeling, this factor, but not age, sex, diagnosis, or other SCL-90-derived subscales strongly predicted adverse outcomes. A ROC curve for SCL-6 reflected a strong separation between subjects with versus without adverse outcomes (AUC = 0.76). This simple screening tool may support timely identification of patients at risk of early adverse clinical outcome who require especially close follow-up.

Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary.

PURPOSE/BACKGROUND: High risks of neural tube defects and other teratogenic effects are associated with exposure in early pregnancy to some anticonvulsants, including in women with bipolar disorder. METHODS/PROCEDURES: Based on a semistructured review of recent literature, we summarized findings pertaining to this topic. FINDINGS/RESULTS: Valproate and carbamazepine are commonly used empirically (off-label) for putative long-term mood-stabilizing effects. Both anticonvulsants have high risks of teratogenic effects during pregnancy. Risks of neural tube defects (especially spina bifida) and other major malformations are especially great with valproate and can arise even before pregnancy is diagnosed. Standard supplementation of folic acid during pregnancy can reduce risk of spontaneous spina bifida, but not that associated with valproate or carbamazepine. In contrast, lamotrigine has regulatory approval for long-term use in bipolar disorder and appears not to have teratogenic effects in humans. IMPLICATIONS/CONCLUSIONS: Lack of protective effects against anticonvulsant-associated neural tube defects by folic acid supplements in anticipation of and during pregnancy is not widely recognized. This limitation and high risks of neural tube and other major teratogenic effects, especially of valproate, indicate the need for great caution in the use of valproate and carbamazepine to treat bipolar disorder in women of child-bearing age.

Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters.

BACKGROUND: Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. METHODS: Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8-48 (mean 18) years and aged 20-89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea-nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. RESULTS: Overall, 29.5% of subjects experienced at least one low value of eGFR (<60 mL/min/1.73 m2), most after ≥15 years of treatment and age > 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m2. By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. LIMITATIONS: Control data for age-matched subjects not exposed to lithium were lacking. CONCLUSIONS: Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age.

Major depression in hospitalized Argentine general medical patients: Prevalence and risk factors.

BACKGROUND: Depression is not uncommon among medically hospitalized patients, though reported prevalence has varied widely, often in samples involving elderly patients with particular illnesses. Accordingly, we evaluated risk of major depression in three metropolitan general hospitals in Buenos Aires, in subjects with a range of medical disorders and ages, comparing several standard screening methods to expert clinical examinations. METHODS: Consecutively hospitalized general medical patients were evaluated over a six-months. Excluded were subjects under age 18 and those unable to participate in assessments because of illness, medication, sensory or speech impairment, or lack of language fluency, or scored <25 on the Mini Mental State Examination (MMSE). Consenting participants were examined for DSM-IV-TR major depression by psychiatrists guided by MINI examinations, compared with other standard screening methods. Risk factors were assessed by preliminary bivariate analyses followed by multivariate logistic regression modeling. RESULTS: Overall prevalence of major depression in 257 subjects was 27% by psychiatric examination. The rate was most similar (25%) with the Hospital Anxiety & Depression Scale (HADS), and much higher with the Beck Depression Inventory-II (BDI, 44%) and Patient Health Questionnaire (PHQ, 56%). Factors associated independently with depression by multivariate modeling included: prior psychotropic-drug treatment, female sex, more children, and heavy smoking. Depression was associated most with neoplastic, urological, and infectious disorders, least with pulmonary, neurological, and hematologic conditions. LIMITATIONS: Modest numbers limited power to test for associations of depression with specific medical conditions. CONCLUSIONS: Major depression was identified in over one-quarter of Argentine, general medical inpatients, with marked differences among screening methods. Several risk factors were identified. The findings encourage assertive identification of depression in hospitalized medical patients using valid, reliable, and cost-effective means of improving their care.

Lithium in Psychiatry / Litio en Psiquiatría

Background: Lithium is a light, metallic element and minerals containing it are most abundant in the Andes. John Cade introduced lithium carbonate for the treatment of mania in 1949, opening the era of modern clinical psychopharmacology. Lithium remains the most extensively studied mood-stabilizing agent. It has had a revolutionary impact in supporting bipolar manic-depressive disorder as a discrete diagnosis, and on psychiatric therapeutics. Methods: We survey the development of lithium treatment in psychiatry, including findings concerning effects on suicide. Results: Lithium is the most extensively studied treatment for bipolar disorder and the prototypical mood-stabilizing agent, despite emergence of anticonvulsants and modern antipsychotics. In addition to limiting recurrences of mania, and some reduction of recurrences of bipolar depression, lithium has demonstrated protective effects against suicide. All treatments for bipolar disorder have notable limitations, including sometimes serious adverse effects, incomplete prevention of recurrences of mania and limited prevention of depression, which accounts for three-quarters of the approximately 50% time-ill in long-term follow-up with standard treatments. Lithium can be toxic in untreated overdoses; safe dosing requires monitoring of serum concentrations. Lithium also may have mild teratogenic effects, but far less than those of anticonvulsants used for bipolar disorder. Conclusions: Lithium opened the era of modern psychopharmacology and continues as the best-established mood-stabilizing treatment for bipolar disorder as well as having strong evidence of suicide-preventing effects.

Antecedentes: Litio es un elemento metálico ligero y los minerales que lo contienen abundan predominantementeen la región andina. John Cade introdujo el uso de carbonato de litio para el tratamiento de manía en 1949, iniciando con ello la era de la moderna psicofarmacología clínica. Litio se mantiene como el más extensamente estudiando agente estabilizador del ánimo. Ha tenido un impacto revolucionario en la preservación del trastorno maniaco-depresivo o bipolar como un diagnóstico discreto y en el campo de la terapéutica psiquiátrica.Métodos: Se examina el desarrollo histórico del tratamiento con litio en psiquiatría, incluyendo hallazgos en relación a su efecto sobreconducta suicida. Hallazgos:Litio es el tipo de tratamiento más extensamente estudiado en el manejo de trastorno bipolar disorder, constituido como el prototipo de agente estabilizador del ánimo, a pesar de la emergencia de agentes anticonvulsivantes y de los antipsicóticos modernos. Además de limitar la recurrencia de episodios maniacos y reducir en algo las recurrencias de depresión bipolar, litio ha demostrado efectos protectores en relación a suicidio y conducta suicida. Todos los tipos de tratamiento de trastorno bipolar tienen limitaciones notables, incluyendo algunas veces serios efectos adversos, prevención incompleta de recurrencias de manía y prevención limitada de depresión, todo lo cual constituye las tres cuartas partes de aproximadamente el 50 % de tiempo con enfermedad en estudios de seguimiento a largo plazo con tratamientos estándar.

Longitudinal neuroimaging and neuropsychological changes in bipolar disorder patients: review of the evidence.

Longitudinal studies of biological domains in bipolar disorder (BD) are crucial in determining if such baseline changes are progressive. We reviewed reported studies of longitudinal brain structural/functional magnetic resonance imaging (MRI) and neuropsychological changes in BD through November 2012. Longitudinal brain structural MRI studies suggest cortical and subcortical abnormalities within networks subserving emotional regulation. There is evidence of neuroprogressive loss of gray matter volume in prefrontal and anterior cingulate cortex and the subgenual region, with less consistent findings in temporal and subcortical regions. Abnormal amygdala neurodevelopment is noted in adolescent onset BD and possible changes in hippocampus require further evaluation. The fewer reported longitudinal functional MRI studies suggest neurobiological changes in activation patterns involving fronto-limbic circuitry which relate to different illness phase and mood states. Early onset pediatric/adolescent BD may signify a more malignant course of illness in which extensive and executive neurocognitive deficits are found early and may persist, with some potential for improvement during remission and perhaps with treatment. Future studies should include larger samples, combine investigational modalities, incorporate genetic profiles, consider standardization of assessments and collaborative ventures across institutions, selection of more homogeneous subgroups and track neurobiological changes longer to clarify trajectories of changes.

Adverse endocrine and metabolic effects of psychotropic drugs: selective clinical review.

The article critically reviews selected, clinically significant, adverse endocrine and metabolic effects associated with psychotropic drug treatments, including hyperprolactinaemia, hyponatraemia, diabetes insipidus, hypothyroidism, hyperparathyroidism, sexual dysfunction and virilization, weight loss, weight gain and metabolic syndrome (type 2 diabetes mellitus, dyslipidaemia and hypertension). Such effects are prevalent and complex, but can be managed clinically when recognized. They encourage continued critical assessment of benefits versus risks of psychotropic drugs and underscore the importance of close coordination of psychiatric and general medical care to improve long-term health of psychiatric patients. Options for management of hyperprolactinaemia include lowering doses, switching to agents such as aripiprazole, clozapine or quetiapine, managing associated osteoporosis, carefully considering the use of dopamine receptor agonists and ruling out stress, oral contraceptive use and hypothyroidism as contributing factors. Disorders of water homeostasis may include syndrome of inappropriate antidiuretic hormone (SIADH), managed by water restriction or slow replacement by hypertonic saline along with drug discontinuation. Safe management of diabetes insipidus, commonly associated with lithium, involves switching mood stabilizer and consideration of potassium-sparing diuretics. Clinical hypothyroidism may be a more useful marker than absolute cut-offs of hormone values, and may be associated with quetiapine, antidepressant and lithium use, and managed by thyroxine replacement. Hyper-parathyroidism requires comprehensive medical evaluation for occult tumours. Hypocalcaemia, along with multiple other psychiatric and medical causes, may result in decreased bone density and require evaluation and management. Strategies for reducing sexual dysfunction with psychotropics remain largely unsatisfactory. Finally, management strategies for obesity and metabolic syndrome are reviewed in light of the recent expert guidelines, including risk assessment and treatments, such as monoamine transport inhibitors, anticonvulsants and cannabinoid receptor antagonists, as well as lifestyle changes.

Coffee and cigarette use: association with suicidal acts in 352 Sardinian bipolar disorder patients.

OBJECTIVE: Abuse of illicit drugs and alcohol is prevalent in bipolar disorder (BPD) patients, and is an adverse prognostic factor. Much less is known about correlates of nicotine and caffeine consumption, but tobacco smoking is tentatively associated with suicidal behavior. METHODS: Retrospective analysis of demographic and clinical factors among 352 longitudinally assessed DSM-IV types I and II BPD patients contrasted patients with versus without consumption of nicotine or caffeine, based on univariate comparisons and multiple regression modeling. RESULTS: Current smoking (46%) and coffee drinking (74% of cases) were common, and significantly and independently associated with suicidal acts [coffee: odds ratio (OR) = 2.42, 95% confidence interval (CI): 1.15-5.09; smoking: OR = 1.79, CI: 1.02-3.15; both p < 0.001]. Risk increased with more smoking (cigarettes/day; r(s) = 0.383; p < 0.0001) and greater coffee consumption (cups/day; r(s) = 0.312; p = 0.008). Neither intake was related to yearly rates of all episodes, depressions, or manias. CONCLUSIONS: This is the first report to associate suicidal acts with coffee consumption in BPD patients, and it confirmed an association with smoking. Pending further evidence, the findings underscore the importance of monitoring use of even legal and mildly psychotropic substances by BPD patients.

Factors associated with treatment nonadherence among US bipolar disorder patients.

OBJECTIVE: Since sustained treatment-adherence is often problematic and may limit clinical outcomes among bipolar disorder (BPD) patients, we sought risk factors to guide clinical prediction of nonadherence. METHODS: Data were from a 2005 US national sample providing questionnaire responses by 131 randomly selected prescribing psychiatrists and their adult BPD patients. We contrasted demographic and clinical factors in treatment-adherent versus nonadherent patients (strictly defined as missing > or =1 dose within 10 days) in univariate analyses followed by multivariate logistic-regression modeling. RESULTS: Of 429 DSM-IV BPD patients (79% type-I; 62% women; 17% minorities), 34% reported missing > or = 1 dose of psychotropic medication within 10 days, 20% missed entire daily doses at least once, and only 2.5% missed all doses for 10 days. However, their prescribing psychiatrists considered only 6% as treatment-nonadherent. Factors significantly associated with nonadherence in multivariate modeling ranked: alcohol-dependence > youth > greater affective morbidity > various side effects > or = comorbid obsessive-compulsive disorder > or = recovering from mania-hypomania. Unrelated were sex, diagnostic subtype, and other comorbidities. Since most patients received > or = 2 psychotropics, potential relationships between treatment-complexity and adherence were obscured. CONCLUSIONS: Prevalent treatment-nonadherence among American BPD patients, and striking underestimation of the problem by prescribing clinicians may encourage increasingly complex treatment-regimens of untested value, but added expense, risk of adverse effects, and uncertain impact on treatment-adherence itself.

Epidemiology of tardive dyskinesia: is risk declining with modern antipsychotics?

Second-generation antipsychotic drugs (APDs), including aripiprazole, clozapine, olanzapine, risperidone, quetiapine, and ziprasidone dominate outpatient and inpatient clinical practice, having largely displaced the older neuroleptics. Modern APDs have relatively low risk for acute extrapyramidal syndromes characteristic of older neuroleptics, particularly acute dystonia and Parkinsonism, with variable risks of akathisia and the rare neuroleptic malignant syndrome. Anticipated reduction in risk of tardive dyskinesia (TD) is less well documented. Nearly 50 years after initial reports on TD, it is appropriate to reexamine the epidemiology of this potentially severe late adverse effect of long-term APD treatment in light of current research and practice. We compared recent estimates of incidence and prevalence of TD identified with some modern APDs to the epidemiology of TD in the earlier neuroleptic era. Such comparisons are confounded by complex modern APD regimens, uncommon exposure limited to a single modern APD, effects of previous exposure to typical neuroleptics, and neurological assessments that are rarely prospective or systematic. Available evidence suggests that the risk of TD may be declining, but longitudinal studies of patients never treated with traditional neuroleptics and exposed to only a single modern APD are required to quantify TD risks with specific drugs. Long-term use of APDs should continue to be based on research-supported indications, with regular specific examination for emerging TD.

Clozapine toxicity associated with smoking cessation: case report.

We report on a 28-year-old white woman with chronic psychotic-affective illness who abruptly stopped her decade-long habit of heavy daily cigarette smoking while maintained on clozapine at 450 mg/d. Within several days, she developed dry mouth, muscle spasms, dizziness, and blurred vision with dilated and sluggish pupils, with worsening sedation and confusion. Her combined serum concentration of clozapine + norclozapine was 2.5 microg/mL, compared with levels of about 600 ng/mL at daily doses of 350 mg at other times while smoking. Reducing the dose of clozapine led to rapid alleviation of these symptoms. Additional experience with and without smoking in this case further documented the effect of smoking to decrease circulating levels of clozapine. These observations add to the conclusion that cigarette smoke can increase clearance of many drugs, calling for special caution during treatment with potentially toxic substances and dose reduction in anticipation of smoking cessation.

Effects of desipramine treatment on tyrosine hydroxylase gene expression in cultured neuroblastoma cells and rat brain tissue.

Activity and expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis, are modified in response to antidepressant-treatment. We examined effects of the selective norepinephrine-transporter (NET) inhibitor antidepressant desipramine (DMI) on expression of TH in human neuroblastoma cells (SK-N-BE[2]M17) and in rat brain regions. TH mRNA levels were determined by Northern blot in vitro, and by in situ hybridization ex vivo; TH protein levels were measured by western blot. Brief exposure of neuroblastoma cells to 0 vs. 5, 50, or 500 nM of DMI had little effect on TH mRNA levels, but exposure to 50 and 500 nM DMI for 14 days increased the mRNA by up to 72%, with a continuous rise from 3 to 14 days of exposure to 500 nM DMI. In contrast, 500 nM DMI led to an initial slight increase, followed by a continuous and sustained decrease in TH protein level by up to 53%, from day 3 to day 14. Daily treatment of rats with DMI (10 mg/kg, i.p.) for 3 or 14 days significantly increased postmortem cerebral TH mRNA in the locus coeruleus (LC) area by 47-68%. Again, TH protein concentrations in LC decreased at 3 and 14 days, by 25-40%, with transient significant reduction in amygdala tissue after 3 days of treatment that were not sustained. These findings indicate that DMI exerts complex, typically opposite and perhaps compensatory, gradually evolving effects on the expression of TH protein (decreases) and its message (increases), possibly in response to increased synaptic availability of NE.