A critical review of genetic studies of schizophrenia. I. Epidemiological and brain studies

Many patients with chronic posttraumatic stress disorder (PTSD) suffer from comorbid major depression. The present study examines the responsiveness of such dual-diagnosis patients to antidepressant medication. Subjects were enrolled in the PTSD medication clinic at the San Diego Veterans Affairs Medical Center. Inclusion criteria were current diagnoses of PTSD and major depression, at least 6 months of regular participation in the clinic, and treatment with antidepressant medication at therapeutic levels and durations. Exclusion criteria were current drug or alcohol abuse, primary psychotic illness, and poor compliance or frequent missed appointments. Among 72 patients meeting inclusion and exclusion criteria, 50% were estimated to be substantially improved, on the basis of Clinical Global Evaluation (CGE) scores of 2 or 1, after remaining on the same antidepressant treatment regimen at therapeutic doses for at least 1 month. Antidepressant medications affecting predominantly serotonin reuptake (sertraline, fluoxetine) were associated with better outcomes than antidepressants affecting predominantly norepinephrine reuptake (nortriptyline, desipramine).     

Hamilton Rating Scale for Depression: Reliability and validity of judgments of novice raters.

Reliability studies of the Hamilton Rating Scale for Depression (HRSD) in therapy-outcome research require at least 2 clinicians. The present authors hypothesized that a less costly alternative, such as using trained undergraduates as 2nd raters, would produce results comparable to the use of 2 clinicians. Four expert raters provided criterion ratings for the HRSD on 20 depressed women. Three trained undergraduates rated the same Ss. The expert and student raters both made reliable ratings on the HRSD. Estimates of criterion validity for the student raters were also in the satisfactory range. (9 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The impact of patient compliance on drug concentration profile in multiple doses

Physicians commonly prescribe drugs in a multiple dosage regimen for prolonged therapeutic activity. To study the effect of multiple dosing on drug concentration in blood, researchers often use deterministic models with the assumption that drugs are administered at a fixed dosage, with equal or unequal (fixed) dosing intervals. In practice, many patients do not comply with such a rigid schedule. Hence, two possible scenarios might occur: patients might not take the prescribed dosing amount, resulting in erratic dosing sizes; they might not adhere to the dosing schedule, resulting in erratic dosing times. We propose separate statistical models for these two scenarios and study their impact on blood serum/plasma concentration. With non-compliance, some basic concepts such as steady state need new definition. We provide a rigorous formulation for the principle of superposition which enables us to generalize the concept of steady state. Applying the proposed models, we demonstrate that non-compliance causes the drug concentration time curve to exhibit an increase in fluctuation. The increase in fluctuation due to non-compliance cannot be explained with use of the classical deterministic multiple dose model.     

Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness

OBJECTIVE: The authors' first objective was to ascertain whether imipramine is superior to placebo in treating axis I depressive disorders in the context of HIV illness. Supplementary questions were whether severity of immunodeficiency is associated with antidepressant response and whether patients with greater immunodeficiency can tolerate standard doses of imipramine. Second, the authors sought to determine whether imipramine treatment is associated with changes in immune status. METHOD: A double-blind, randomized placebo-controlled trial of imipramine was conducted in a university-affiliated research outpatient clinic. After 6 weeks of treatment, responders were maintained double-blind for another 6 weeks and nonresponders were removed from the study and treated openly. All patients were offered 26 weeks of treatment. Of the 97 patients who were randomly assigned to placebo or imipramine, 80 completed the 6-week phase. Main outcome measures included the Clinical Global Impression, the Hamilton Depression Rating Scale, the Brief Symptom Inventory, and CD4 cell count. RESULTS: Among study completers, 31 (39%) had AIDS. The response rate to imipramine was 74% and the response rate to placebo was 26%. There was no difference in depression response between patients with more or less severe immunodeficiency, nor was there a difference in medication dose or side effects. Neither type nor duration of treatment influenced CD4 cell count during the course of treatment. CONCLUSIONS: Depressed patients with HIV illness respond to imipramine at the same rate as medically healthy depressed patients. Severity of immunosuppression is not associated with imipramine treatment outcome. There is no evidence that imipramine has negative effects on enumerative measures of immune status.     

Effects of phenobarbital and diazepam on imipramine-induced changes in blood pressure, heart rate and rectal temperature of rats

To investigate the safety of anticonvulsants in doses found equipotent in suppressing imipramine induced convulsions, the effects of diazepam (1.8 mg/kg) or phenobarbital (40 mg/kg) following a toxic dose of imipramine (50 mg/kg) on heart rate, blood pressure and body temperature were examined in male Wistar rats. Administration of imipramine alone resulted in significant decreases in blood pressure, heart rate and rectal temperature. Phenobarbital or diazepam alone failed to significantly affect any of these parameters apart from a slight reduction in rectal temperature seen with phenobarbital. Diazepam given after imipramine antagonized the imipramine-induced decrease in heart rate but increased the hypotensive and hypothermic effects. Phenobarbital failed to significantly affect the imipramine-induced changes in any of the physiological parameters studied. The present data suggests that phenobarbital may be preferable to diazepam in treatment of imipramine-induced convulsions.     

Context-processing deficits in schizophrenia: Diagnostic specificity, 4-week course, and relationships to clinical symptoms.

Previous research on schizophrenia suggests that context-processing disturbances are one of the core cognitive deficits present in schizophrenia. However, it is not clear whether such deficits are specific to schizophrenia as compared with other psychotic disorders. To address this question, the authors administered a version of the AX Continuous Performance Test designed to assess context processing in a sample of healthy controls, patients with schizophrenia, and patients with other psychotic disorders. Participants were tested at index (when medication naive and experiencing their first contact with psychiatric services) and 4 weeks later, following medication treatment. At index, patients with schizophrenia and the psychotic comparison group demonstrated similar impairments in context processing. However, context-processing deficits improved in the psychotic comparison group at 4 weeks but did not improve in patients with schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factors involved in noncompliance with drug treatment in non-insulin dependent diabetes mellitus

OBJECTIVE: To find the level of non-compliance with treatment with oral hypoglycemics, its causes and the profile of non-compliant patients. DESIGN: Prospective study. SETTING: Primary Care Centres in the province of Alicante. PATIENTS: 107 diabetics not dependent on insulin on the lists of five General Medicine practices and all receiving pharmacological treatment. MEASUREMENTS AND MAIN RESULTS: The method used to value compliance was a surprise count of pills in the patient's home. Patients achieving 80-110% compliance were considered compliant. The level of non-compliance was 51.5% (C.I. 42.1%-61%), 36.5% being hypocompliers and 15% hypercompliers. Forgetting (40.7%) and lack of knowledge (29.5%) were the most frequent reasons for non-compliance. The factors associated with non-compliance were: over four years evolution of the disease (p = 0.02), the diet not properly observed (p = 0.03), over a year in regular treatment (p = 0.006), poor control of the disease valued by HbA1C (p = 0.003). CONCLUSIONS: A high level of non-compliance with pharmacological treatment was found for patients with Diabetes Mellitus not dependent on insulin. Its causes were identified and factors associated with poor compliance were profiled.     

Doctors in limbo: the United States ''DNR'' debate

The escape behaviour induced in rats by injecting D,L-homocysteic acid (DHL) into the dorsal periaqueductal grey area (DPAG) was used as an animal model of panic attacks to investigate the effect of imipramine, a drug used for the treatment of panic disorder, on the sensitivity of 5-HT1A receptors in the DPAG. Rats given imipramine (10 mg/kg per day SC for 3 weeks or IP for 2-3 days) received 250 nl saline or the 5-HT1A agonist 8-OH-DPAT (8.6 nmol) into the DPAG 10 min before inducing the escape response with DLH. As expected, 8-OH-DPAT produced a marked decrease in the average speed of the DLH-induced flight response. The short-term treatment with imipramine changed neither the DLH-induced escape behaviour nor the effect of prior 8-OH-DPAT administration on this response. In contrast, long-term treatment with imipramine enhanced the 5-HT1A-mediated inhibition, as the decrement in the amplitude of the flight response produced by 8-OH-DPAT was 96% after this treatment compared to 41% in controls. The injection of 8-OH-DPAT also significantly decreased the amplitude of the freezing behaviour observed at the end of the flight response in rats given imipramine for 3 weeks, but not in controls. The long-term imipramine treatment, however, did not significantly decrease the amplitude of DLH-induced flight and freezing behaviours in absence of prior 8-OH-DPAT administration. Finally, 8-OH-DPAT failed to inhibit the DLH-induced flight and freezing behaviours in rats withdrawn from imipramine after long-term treatment (10 mg/kg per day x 21 days). It is suggested that an alteration at the level of the DPAG-5-HT1A receptor system is implicated in the therapeutic and withdrawal effect of imipramine in panic disorder.     

Effect of depressive symptoms on smoking abstinence and treatment adherence among smokers with a history of alcohol dependence.

This study examined the effect of depressive symptoms on smoking abstinence and treatment adherence among smokers with a past history of alcohol dependence. Participants (24 women, 27 men) were randomly assigned to behavioral counseling (BC) or behavioral counseling plus cognitive-behavioral mood management training (CBT). The Hamilton -Rating Scale for Depression (HRSD; A Hamilton, 1967) was administered to assess baseline depressive symptoms. Participants who received CBT and had higher HRSD scores were more likely to achieve short-term abstinence from smoking and attend more treatment sessions than those with lower depression scores, whereas for BC participants the effect of HRSD scores was the opposite. Smokers with a history of alcohol dependence reporting high levels of depressive symptoms may benefit from a mood management intervention. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Promoting compliance with antihypertensive medication

One of the key areas identified for action in 'The Health of the Nation' (Department of Health, 1992) is a reduction in the number of deaths from cerebrovascular accident. The major precursor of stroke is elevated blood pressure, and although efficacious medication exists for the control of hypertension, non-compliance in patients with this condition is notoriously high. This article examines ways to successfully address this problem and reduce morbidity. Consideration of psychosocial variables emphasizes that compliance with antihypertensive medication regimens is a multifactorial problem, but one that can be solved. Nurses, mindful of barriers to compliance, can encourage and support the patient in taking the prescribed antihypertensive medication.     

The severity of major depression and choice of treatment in primary care practice.

The Agency for Health Care Policy and Research Depression Guideline Panel recommended pharmacotherapy as the 1st-line treatment for more severely depressed primary care patients, but research supporting its recommendation has not been conducted with this population. A post hoc analysis was conducted, therefore, with data gathered in a randomized controlled trial about the relationship between initial level of depressive severity and functional ability, treatment with nortriptyline hydrochloride (NT) or interpersonal psychotherapy (IPT), and clinical course over 8 months among primary care patients experiencing major depression. Treatment type was unrelated to clinical course among more severely depressed patients (baseline 17-item Hamilton Rating Scale for Depression [HRSD] score ≥20). However, less severely depressed patients (baseline 17-item HRSD score ≤19) who were prescribed NT improved significantly more rapidly during the initial 3 months of treatment than patients provided with IPT. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treatment of refractory depression with high-dose thyroxine

In an open clinical trial we investigated whether addition of supraphysiological doses of thyroxine (T4) to conventional antidepressant drugs has an antidepressant effect in therapy-resistant depressed patients. Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 +/- 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 +/- 72 micrograms/day. The patients' scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 +/- 4.7 prior to the addition of T4 to 11.6 +/- 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of < or = 9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T4 and followed up for a mean of 27.2 +/- 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T4 augmentation treatment, and one failed to profit from T4 treatment during the follow-up period. Side effects were surprisingly mild, and no complications were observed at all. In conclusion, augmentation of conventional antidepressants with high-dose T4 proved to have excellent antidepressant effects in approximately 50% of severely therapy-resistant depressed patients.     

International Emergency Medicine Reference List

Mirtazapine is a newer antidepressant that exhibits both noradrenergic and serotonergic activity. It is at least as effective as the older antidepressants for treating mild to severe depression. Sedation is the most common side effect. Although agranulocytosis is the most serious side effect, it is rare (approximately one in 1,000) and usually reversible when the medication is stopped. Mirtazapine is relatively safe in overdose. Many clinicians consider mirtazapine a second-line or even third-line antidepressant to be used when older antidepressants are not tolerated or are ineffective. Physicians who are concerned about the risks of elevated lipid levels and agranulocytosis may choose to reserve mirtazapine as a third-line choice. It is particularly useful in patients who experience sexual side effects from other antidepressants. Mirtazapine is also a good choice in depressed patients with significant anxiety or insomnia. Although mirtazapine has been used successfully in Europe for a number of years, its place in the care of patients with depression in the United States has not yet been established.     

Attendance versus compliance with tuberculosis treatment in an occupational setting--a pilot study

AIM: To determine the prevalence of non-compliance with tuberculosis treatment at Freegold Mines. OBJECTIVES: 1. To establish the rates of attendance and collection of anti-tuberculosis drugs. 2. To determine prevalence of non-compliance by means of urine tests. DESIGN: A cross-sectional study conducted over 2 weeks at mine medical stations. METHOD: Urine samples were collected from tuberculosis patients 3 hours after drug ingestion. Non-compliance was established by testing these samples for rifampicin and/or isoniazid (INH) metabolites. Non-compliance was defined as a negative urine test result for these drugs in participants whose treatment regimens included one or both. Daily attendance and collection of drugs statistics are recorded in the medical station tuberculosis register. The patient rate of adherence was calculated as the observed number of days on which medication had been collected over the expected treatment days in a given period. RESULTS: Urine test results showed an overall prevalence of non-compliance of 14.6 +/- 3.3%. The study showed that non-compliance with tuberculosis treatment was underestimated by the surveillance data. The rate of non-adherence with treatment established from the formal surveillance procedure was 0.2%. The poor response rate of patients was found to be a major problem and fewer than 40% per day returned to bring urine specimens. The mean prevalences of non-compliance established by rifampicin and INH tests were 19.5 +/- 5.3% and 9.8 +/- 3.9%, respectively, and these were significantly different (Chi 2 = 7.44; P < 0.05). The proportion of false-positive results for INH and rifampicin urine tests were 21% (11/53) and 35% (17/48), respectively, showing that some patients were taking the wrong treatment. CONCLUSIONS: It is clear that attendance at the clinics does not accurately reflect compliance. Both programme compliance (dispensing of the correct treatment) and patient compliance need to be improved. This has important implications for the new national tuberculosis control policy adopted by the South African government that stresses the importance of directly observed therapy, short-course (DOTS) and a patient-centred approach.     

Faster remission of chronic depression with combined psychotherapy and medication than with each therapy alone.

The main aim of the present novel reanalysis of archival data was to compare the time to remission during 12 weeks of treatment of chronic depression following antidepressant medication (n = 218), psychotherapy (n = 216), and their combination (n = 222). Cox regression survival analyses revealed that the combination of medication and psychotherapy produced full remission from chronic depression more rapidly than either of the single modality treatments, which did not differ from each other. Receiver operating characteristic curve analysis was used to explore predictors (treatment group, demographic, clinical, and psychosocial) of remission. For those receiving the combination treatment, the most likely to succeed were those with low baseline depression (24-item Hamilton Rating Scale for Depression [HRSD; M. Hamilton, 1967] score     

Moclobemide and imipramine in chronic depression (dysthymia): an international double-blind, placebo-controlled trial. International Collaborative Study Group

An international, multicenter, placebo-controlled study was undertaken to determine the safety and antidepressant efficacy of moclobemide, a new reversible inhibitor of monoamine oxidase A, and imipramine in the treatment of dysthymia (DSM-III-R). A total of 315 patients were enrolled and randomly assigned to an 8-week treatment in one of three groups (moclobemide, imipramine and placebo). Patients were male or female outpatients aged between 18 and 65 years meeting DSM-III-R criteria for dysthymia, primary type, with late or early onset. Of the patients in each group 85% completed the 8-week treatment period. The percentage of patients who no longer fulfilled DSM-III-R symptom criteria at treatment endpoint was significantly higher in the moclobemide (60%) and imipramine (49%) treatment groups than in the placebo group (22%). Differences to placebo were also statistically significant both for moclobemide and for imipramine on the other efficacy variables (i.e. Hamilton Rating Scale for Depression, final overall efficacy assessment, Clinical Global Impression and symptom check list self-rating). A significant superiority of moclobemide and imipramine over placebo was found in pure dysthymia and in double-depression, as well as in early and late onset subgroups. In early onset cases, moclobemide was significantly more effective than was imipramine on the Hamilton Rating Scale for Depression. Anticholinergic symptoms and sleepiness were significantly more frequent side effects on imipramine than on moclobemide or on placebo, and the investigators' final overall assessment of tolerability significantly favoured moclobemide over imipramine. This study demonstrates the efficacy of high dose moclobemide (mean dose 675 mg/day) and high dose imipramine (220 mg/day) against placebo in the treatment of dysthymia. Moclobemide was better tolerated than was imipramine.     

The effect of prolonged treatment with imipramine on the biosynthesis and functional characteristics of D2 dopamine receptors in the rat caudate putamen

1. The present study shows the effects of imipramine in a single dose (10 mg kg(-1), p.o.) or following repeated (14 days, twice a day) treatment on the level of mRNA coding for D2 dopamine receptors in the rat caudate putamen (CP). Repeated administration of imipramine resulted in the increase of the level of mRNA coding for D2 dopamine receptors. 2. Radioligand binding studies with the D2 receptor agonist, [3H]-N-0437, indicated, that following imipramine administration, the affinity of the agonist for the D2 dopamine receptor significantly increased, though without any alterations in the Bmax. 3. Pharmacological manipulations (by use of forskolin, GppNHp and quinpirole) of the cyclic AMP generating system, ex vivo following administration of imipramine indicated that an up-regulation of factors inhibiting cyclic GMP formation takes place. 4. Most probably it is the D2 dopamine receptor which undergoes functional up-regulation, resulting from the enhancement of its biosynthesis.