Abnormalities in thalamo-cortical connections in patients with first-episode schizophrenia: a two-tensor tractography study.

The "cognitive dysmetria" hypothesis suggests that impairments in cognition and behavior in patients with schizophrenia can be explained by disruptions in the cortico-cerebellar-thalamic-cortical circuit. In this study we examine thalamo-cortical connections in patients with first-episode schizophrenia (FESZ). White matter pathways are investigated that connect the thalamus with three frontal cortex regions including the anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), and lateral oribitofrontal cortex (LOFC). We use a novel method of two-tensor tractography in 26 patients with FESZ compared to 31 healthy controls (HC), who did not differ on age, sex, or education. Dependent measures were fractional anisotropy (FA), Axial Diffusivity (AD), and Radial Diffusivity (RD). Subjects were also assessed using clinical functioning measures including the Global Assessment of Functioning (GAF) Scale, the Global Social Functioning Scale (GF: Social), and the Global Role Functioning Scale (GF: Role). FESZ patients showed decreased FA in the right thalamus-right ACC and right-thalamus-right LOFC pathways compared to healthy controls (HCs). In the right thalamus-right VLPFC tract, we found decreased FA and increased RD in the FESZ group compared to HCs. After correcting for multiple comparisons, reductions in FA in the right thalamus- right ACC and the right thalamus- right VLPC tracts remained significant. Moreover, reductions in FA were significantly associated with lower global functioning scores as well as lower social and role functioning scores. We report the first diffusion tensor imaging study of white matter pathways connecting the thalamus to three frontal regions. Findings of white matter alterations and clinical associations in the thalamic-cortical component of the cortico-cerebellar-thalamic-cortical circuit in patients with FESZ support the cognitive dysmetria hypothesis and further suggest the possible involvement of myelin sheath pathology and axonal membrane disruption in the pathogenesis of the disorder.

Amylase secretion by rabbit parotid gland. Role of cyclic AMP and cyclic GMP.

Amylase secretion and changes in the levels of cyclic AMP and GMP were studied in rabbit parotid gland slices incubated in vitro with a variety of neurohumoral transmitters, their analogs and inhibitors. Cyclic GMP levels increased 8-fold 5 min after exposure to carbachol (10(-4) M), without a change in cyclic AMP levels; amylase output also rose. These effects were completely inhibited by muscarinic blockade with atropine, but were unaffected by alpha-adrenergic blockade with phenoxybenzamine. Epinephrine (4 - 10(-5) M) produced a rapid increase in the levels of both cyclic nucleotides and in amylase release. The increase in cyclic GMP level was inhibited by previous exposure of the slices to phenoxybenzamine, while the cyclic AMP rise was prevented by the beta-blocking agent, propranolol. Pure alpha-adrenergic stimulation with methoxamine (4 - 10(-4) M) produced modest elevations in cyclic GMP content and amylase output, effects blocked by pre-treatment of slices with either atropine or phenoxybenzamine. At a concentration of 4 - 10(-6) M, isoproterenol (a beta-agonist) failed to affect cyclic GMP levels, but promptly stimulated increases in cyclic AMP levels, and after a short lag, amylase secretion. At a higher dose (4 - 10(-5) M) isoproterenol produced elevations in the levels of both nucleotides. The carbachol-induced effects on cyclic GMP content and amylase release were greatly potentiated by the addition of isoproterenol (4 - 10(-6) M). These data strongly suggest that cholinergic muscarinic agonists and alpha-adrenergic agonists stimulate amylase output in rabit parotid gland by mechanisms involving cyclic GMP. The atropine-sensitive intracellular events effected by alpha-stimulation may be dependent upon endogenous generation of acetylcholine. Both cyclic nucleotides seem to be required for the early rapid secretion of amylase. The unique responses achieved by the combination of carbachol and isoproterenol suggest that isoproterenol may increase the sensitivity of this tissue to the effects of cholinergic stimuli.

Concurrent validation of schizotaxia: a pilot study.

BACKGROUND: Many first-degree relatives of patients with schizophrenia show deficits in clinical, neuropsychological, neurobiological and social domains, in the absence of psychosis. We recently reformulated Meehl's concept of schizotaxia to conceptualize the liability to schizophrenia, and we proposed preliminary criteria based on the presence of negative symptoms and neuropsychological deficits. Here we investigate the concurrent validity of schizotaxia by comparing a group of subjects who met criteria for schizotaxia with a group who did not on independent measures of clinical function, and on lifetime rates of selected comorbid psychiatric disorders. METHODS: Twenty-seven adults who were first-degree, biological relatives of patients with schizophrenia were evaluated for schizotaxia based on our predetermined criteria involving negative symptoms and neuropsychological deficits. Subjects also received portions of the Diagnostic Interview for Genetic Studies, the Structured Interview for Schizotypy, the Family Interview for Genetic Studies, the DSM-IV Global Assessment of Functioning, the Physical Anhedonia Scale, the Social Adjustment Scale and the Symptom Checklist-90-Revised. Subjects who met criteria for schizotaxia were compared with those who did not on each of the clinical measures, and on their rates of comorbid DSM-IV psychiatric diagnoses. RESULTS: Eight subjects met criteria for schizotaxia, and 19 did not. Subjects with schizotaxia showed significantly lower levels of function on each of the clinical scales. Differences in comorbid psychiatric diagnoses were not significant, although the rate of lifetime substance abuse diagnoses in the schizotaxic group (50%) approached levels that are often seen in schizophrenia. CONCLUSIONS: These findings provide the first evidence of concurrent validation for a proposed syndrome of schizotaxia. They are also consistent with the view that the vulnerability to schizophrenia may be defined, at least partially, although larger studies to assess both the concurrent and predictive validity of schizotaxia will be required to confirm these results.

A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital.

Of 1,470 patients treated with neuroleptics during 1 year at a private psychiatric hospital, only one patient developed neuroleptic malignant syndrome--an annual frequency of 0.07%. Use of low doses of neuroleptics may account for this frequency, which is below recent estimates.

A review of 32 cases of tardive dystonia.

OBJECTIVE: Tardive dystonia, historically combined with tardive dyskinesia, is now viewed as probably having a different pathophysiology, course, outcome, and treatment response than tardive dyskinesia. In addition, patients with tardive dystonia are reported to be younger, and most are men. This study evaluates characteristics of 32 patients with tardive dystonia and compares results to other reports. METHOD: Twenty-four patients had been referred for research purposes and were videotaped, while eight had been followed clinically. Two of the authors reviewed all available videotapes and clinical reports to assess the course of symptoms over time. For global ratings and ratings of affected body parts, two scales were used: the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia and a similar scale for tardive dystonia. The method of case finding does not provide incidence or prevalence data for tardive dystonia. RESULTS: Fifty-nine percent of the patients experienced onset of tardive dystonia symptoms within 6 years of antipsychotic drug exposure; women had a shorter exposure time. No patient had complete remission of tardive dystonia symptoms, and 22 were moderately or severely impaired when their movements were most prominent. CONCLUSIONS: While epidemiological studies of tardive dystonia have yet to be performed, these results support the observations of others that most patients with tardive dystonia are men, have a short history of exposure to antipsychotic drugs, and may initially present with blepharospasm. Tardive dystonia rarely remits completely, can cause notable disability, and may partially respond to anticholinergic agents.

Patients with neuroleptic malignant syndrome histories: what happens when they are rehospitalized?

Among approximately 1450 patients treated with neuroleptics in a short-term psychiatric hospital, there were no cases of the neuroleptic malignant syndrome (NMS). Six patients with histories of NMS were treated, either with nonneuroleptic therapies or with low doses of low-potency antipsychotic agents. No case of NMS developed, but one patient suffered transient subsyndromal signs while treated briefly with loxapine. Staff education, screening for patients with history of NMS, and detection of early signs can lower the incidence of this serious drug toxicity.

Renal function monitoring in patients receiving lithium carbonate.

As a screening test for renal function, urine concentration was measured following a 12-hour overnight fast in 54 outpatients taking lithium carbonate and 19 patients receiving antidepressant drugs. A significantly greater percentage of lithium patients failed to achieve a maximum urine concentration of 600 mOsm/kg (63% versus 33% in the antidepressant group, p less than .001). This level, a compromise between the sensitivity and specificity of the test, is viewed as a cutoff point for further testing. It is concluded that urine concentration testing is a feasible first-line screen for renal function among lithium-treated patients. Other preliminary studies include routine urinalysis, serum creatinine determination, and estimated creatinine clearance. Second-line testing includes a repeated dehydration test and administration of DDAVP.

Double-blind comparison of amoxapine and imipramine in the treatment of depressed patients.

A 5-week double-blind study compared amoxapine to imipramine (2:1 dosage ratio) in the treatment of depressed outpatients. The two agents were similar in anti-depressant efficacy and rapidity of action. The most common adverse reactions to both drugs were anticholinergic effects and sedation; cardiovascular effects were minimal. A few amoxapine-treated patients developed adverse effects typical of neuroleptic drugs: some experienced extrapyramidal signs, one developed galactorrhea, and most showed elevated plasma prolactin concentrations. Amoxapine was associated with significant neuroleptic activity in plasma. No correlation was found between blood levels of either drug and therapeutic response.

A crossover study of lecithin treatment of tardive dyskinesia.

The authors enrolled 21 patients in a random-order, crossover, double-blind trial of phosphatidylcholine (lecithin) 20 g/day and placebo. Fourteen patients completed at least 6 weeks of the second 8-week trial and were used for efficacy analyses. Side effects were minimal. The lecithin treatment effect--about one half of an Abnormal Involuntary Movement Scale point--was seen as a statistical effect of treatment order, based on differences between patients who took the active compound before or after they took the placebo. Clinically, however, the lecithin effect was negligible.

Tyrosine for depression.

The catecholamine hypothesis of affective disorders postulates that depression reflects inadequate norepinephrine activity at unspecified brain centers that regulate mood. In light of experimental data showing that the oral administration of tyrosine, precursor of the catecholamine series of neurotransmitters, can increase brain norepinephrine concentrations and activity, we have conducted preliminary trials of tyrosine in depressed outpatients. Initial results are encouraging, and we are now conducting a double-blind, parallel-group trial comparing tyrosine to the tricyclic antidepressant imipramine and to placebo in non-bipolar outpatients with major depression.

Tyrosine for depression: a double-blind trial.

We treated 65 outpatients with RDC major depression in a randomized, prospective, double-blind comparison of oral L-tyrosine, 100 mg/kg/day, imipramine, 2.5 mg/kg/day, or placebo for 4 weeks. Tyrosine increased and imipramine decreased 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion significantly, but there was no evidence that tyrosine had antidepressant activity. The only side effect to achieve statistical significance was greater dry mouth with imipramine. MHPG excretion and plasma amino acid concentrations failed to predict or correlate with clinical improvement.

Amoxapine for the treatment of psychotically depressed subjects. A pilot study.

The treatment of psychotic depression remains controversial, although most studies suggest that the combination of an antipsychotic and an antidepressant agent is most beneficial. The authors describe an open-label study of the treatment of psychotic depression using amoxapine, an agent with both antidepressant and antipsychotic properties. Of the six patients treated, two improved dramatically within the first week of treatment, whereas for the remaining four treatment had to be discontinued due to lack of efficacy or side effects. Amoxapine appears to be effective in some cases of psychotic depression, but side effects and known risks of treatment diminish its usefulness.

A double-blind comparison of clovoxamine and amitriptyline in the treatment of depressed outpatients.

Forty-two outpatients with major depression were treated in a 4-week double-blind parallel-group comparison of the new antidepressant clovoxamine--a member of oximethers of aralkylketones--with amitriptyline. The two drugs were comparable in efficacy, although because of the small sample size a moderate clinical difference between treatments may not have been detected. The magnitude of unwanted effects also was comparable, but clovoxamine produced fewer "anticholinergic" effects; this was determined by patient complaints of typical anticholinergic symptoms, by decreased salivary flow, and by a new signal detection memory test.

Clovoxamine in the treatment of depressed outpatients: a double-blind, parallel-group comparison against amitriptyline and placebo.

In a double-blind, random-assignment, parallel-group trial, outpatients with major depression received either the new antidepressant clovoxamine, the tricyclic amitriptyline, or placebo for 6 weeks. By an "improvement" criterion of 50% or greater improvement in the Hamilton Depression Scale (HAM-D) total score, 88% of clovoxamine completers improved versus 75% with amitriptyline and 43% with placebo; however, due to small numbers, the differences failed to reach statistical significance. Diminished salivary flow was significantly greater with amitriptyline, as were complaints of dry mouth, somnolence, dizziness, and headache. Nausea and vomiting were more common in the clovoxamine-treated group. With amitriptyline, but not with clovoxamine, memory performance declined over a month. However, psychomotor performance was not affected.

Effects of lithium on the kidney.

We tested kidney function in 268 patients given lithium treatment for an average period of 37.6 months and in 59 manic-depressive patients never given lithium. No patients suffered serious renal damage during the course of our observations. Maximum concentration capacity was lower and serum creatinine concentration higher in the lithium treated patients than in the controls, but the differences did not achieve statistical significance. Females had poorer concentrating ability than males, both among the control subjects and during lithium treatment. Concomitant antipsychotic drug therapy may affect concentrating ability and possibly glomerular function adversely.

Colonoscopy associated bacteremia.

Fifty-two patients undergoing uneventful diagnostic colonoscopy with or without polypectomy and biopsy were evaluated for evidence of bacteremia during and after the procedure. In only two instances was bacteremia noted. Positive findings were noted in patients with carcinomatosis and severe liver involvement. These data suggest that routine prophylactic antibiotic coverage is unnecessary in uncompromised patients. Further studies are warranted when patients have either severe liver involvement or impairment of normal host defense mechanisms.

Anticholinergic effects on memory: benztropine versus amantadine.

To evaluate anticholinergic effects on cognition and other functions, we studied 60 healthy volunteers in a double-blind crossover trial of two antiparkinsonian agents, benztropine and amantadine. Benztropine 4 mg/day, but not amantadine 200 mg/day, impaired free recall and perception of time, and subjects' perception of their own memory impairment was significantly greater with benztropine. Side effects in general were worse with benztropine, particularly such anticholinergic effects as dry mouth and blurred vision, and benztropine decreased measured salivary flow to a significantly greater degree than amantadine. Our findings support the hypothesis that drugs that decrease cholinergic transmission impair storage of new information into long-term memory, but have little effect on retrieval from memory or on tasks involving only immediate memory. Clinically, anticholinergic agents can levy a considerable burden on memory and time perception.