Lithium-induced hypothyroidism and thyroiditis.

Patients with a preexisting thyroiditis may be particularly susceptible to a rapid onset of lithium-induced hypothyroidism. The evidence for this hypothesis is reviewed and a case report illustrating this phenomena is presented.

Sodium lactate infusions after treatment with tricyclic antidepressants: behavioral and physiological findings.

Fourteen patients with panic disorder were infused with sodium lactate both before and after treatment with tricyclic antidepressants. All patients had panic attacks before treatment, and only five after treatment. There was a significant decrease in measures of anxiety prior to and during infusions after treatment. The patients were able to tolerate more lactate during reinfusions. The comparison of reinfusion panickers and nonpanickers revealed that the reinfusion panickers had higher levels of anxiety, as measured by psychological symptoms on the Panic Description Scale, during both their pretreatment and posttreatment infusions. Tricyclic antidepressants appear to increase the threshold for lactate-induced panic attacks.

Isoproterenol-induced panic attacks.

Eighty-six panic disorder patients and 45 nonpsychiatric controls were infused with isoproterenol at a rate of 1 microgram/min for up to 20 min in a placebo-controlled, double-blind study. Sixty-six percent of panic disorder patients experienced panic attacks during isoproterenol infusions, compared to 16% during placebo infusions. Nine percent of control subjects panicked with isoproterenol, but none panicked with placebo. Patients were more sensitive than controls to the anxiogenic effects of isoproterenol, as measured by subject self-ratings on a panic description scale. The frequency of panic attacks induced in patients was related to the dosage of isoproterenol; 79% of the patients who received a mean of 18.5 ng/min/kg of isoproterenol panicked. The panic attacks experienced by patients during isoproterenol infusions were similar to those experienced during placebo infusions.

Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine.

A study was performed to determine if the pharmacokinetics of bromocriptine is altered by factors that have been shown to interact with other ergot compounds. The effects on bromocriptine plasma concentrations by bromocriptine coadministration with caffeine and erythromycin were evaluated in five male volunteers. Serial blood samples were obtained during a 12-hour period after a single 5 mg oral dose of bromocriptine (alone and after 4-day treatments of either erythromycin estolate, 250 mg four times/day, or caffeine, 200 mg four times/day). There were no significant alterations of bromocriptine pharmacokinetic parameters after caffeine, although statistical power was very low. With the use of erythromycin, the bromocriptine area under the concentration-time curve standardized to body weight increased significantly by 268%, whereas peak bromocriptine plasma concentration (Cmax) increased to 4.6 times the Cmax from bromocriptine alone. Time to achieve Cmax was not altered by erythromycin. We conclude that erythromycin can markedly increase the systemic bioavailability of bromocriptine, which can lead to increased therapeutic or adverse effects, whereas the effects of caffeine require further study.

Allergy to tartrazine in antidepressants.

The authors describe five cases of apparent allergy to tartrazine (FD&C yellow dye number 5) in 170 patients exposed to the dye in antidepressants. The frequency of tartrazine sensitivity was much higher than the reported frequency of six in 1,000 persons.

Lactate sensitivity and cardiac cholinergic function in panic disorder.

Using spectral analysis of the continuous time series signal before and during lactate and placebo infusions, the authors studied heart rate variability in six patients with panic disorder and nine normal comparison subjects. The decrease in high-frequency (0.20-0.50 Hz) power and the increase in sympathovagal ratios (mid-frequency [0.07-0.15 Hz] to high-frequency powers) after the administration of intravenous sodium lactate were significantly greater in the patients than in the normal subjects after correction of the values for the amount of lactate infused. This result suggests an exaggerated cardiac vagal withdrawal in patients with panic disorder during lactate infusions.

Follow-up study of control subjects with lactate- and isoproterenol-induced panic attacks.

Eleven of 45 normal control subjects experienced panic attacks during lactate and/or isoproterenol infusions. Ten of the 11 subjects were followed up for a mean period of 32.5 months. Two subjects reported the development of spontaneous panic attacks during the follow-up period; one related the development of these attacks to the infusion experience. Neither subject met DSM-III criteria for panic disorder either before or after the infusions. Twenty-six healthy control subjects who did not experience panic attacks during the infusion experience did not report any attacks during a follow-up period of 31.1 months.

A laboratory procedure for the induction of flashbacks.

The authors administered infusions of lactate intravenously to seven patients with a DSM-III diagnosis of posttraumatic stress disorder, six of whom also met DSM-III criteria for panic disorder. The lactate infusions resulted in flashbacks in all seven patients and panic attacks in six patients. The authors conclude that with further development intravenous lactate infusion may be used to study flashbacks and other dissociative phenomena and to determine the relationship between flashbacks and panic anxiety.

Dissociation between free and bound phenytoin levels in presence of valproate sodium.

A dissociation of free vs bound phenytoin levels is frequently observed in the presence of therapeutic doses of valproate sodium. This leads at times to symptoms and signs of phenytoin intoxication despite "therapeutic" plasma levels. The importance of supplementing bound levels with free levels is stressed when combined therapy of this type is used in epileptic patients.

Clorazepate therapy for refractory seizures.

We treated 61 patients with seizures refractory to conventional anticonvulsants by adding clorazepate to their regimen. There was some improvement of seizure control, but no overall improvement in the electroencephalogram. Improvement of seizure control was not significantly related to seizure type. No significant side effects, drug interactions, or laboratory abnormalities were noted with doses up to 3 mg per kilogram per day.

Pharmacodynamic modeling of concentration-effect relationships after controlled-release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease.

Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 micrograms/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 micrograms/ml. LD plasma concentrations fluctuating around 0.9 micrograms/ml may result in the "on/off" effects seen in Parkinson's disease.

Controlled-release carbidopa/levodopa (Sinemet 50/200 CR4): clinical and pharmacokinetic studies.

Several controlled-release carbidopa/levodopa preparations have been formulated to achieve a more stable and extended antiparkinsonian action. The most effective is Sinemet CR (Sinemet CR4), with an erodible polymer matrix that retards release of levodopa. In 19 parkinsonians with prominent dose-by-dose fluctuations, double-blind crossover trials comparing 8-week regimens of standard carbidopa/levodopa (25/100) to Sinemet CR (50/200) showed comparable clinical outcomes, with mean daily dosing for optimal control reduced from 10.2 to 5.4 (although mean daily levodopa dosage increased from 1,340 to 1,781 mg/day). Most patients improved on the Sinemet CR regimen in hours "on" and in ratings of clinical state and disability. With pharmacokinetic studies correlated to clinical ratings, plasma levodopa was less variable during Sinemet CR treatment, and clinical responses showed greater uniformity. Compared to standard Sinemet 25/100, time to peak levodopa concentration (2.3 versus 1.1 hrs), onset of maximal clinical improvement (2.2 versus 1.1 hrs), and other indices were significantly delayed with Sinemet CR. Levodopa bioavailability and clearance were similar between formulations. Although onset of clinical response is slower, the Sinemet CR formulation lessens peak-dose and "wearing-off" responses occurring with conventional carbidopa/levodopa and offers substantial improvement for some parkinsonians.

Monosodium glutamate and tranylcypromine administration in healthy subjects.

The authors administered 400 to 1600 mg of monosodium glutamate and placebo to five healthy males while they were medication-free and again while they were receiving the monoamine oxidase inhibitor tranylcypromine, after having received the drug daily for at least 2 weeks. Monosodium glutamate produced no consistent changes in either blood pressure or heart rate in subjects receiving tranylcypromine. Spontaneous hypertensive episodes were observed in two subjects. These blood pressure increases also occurred with tranylcypromine alone and were unrelated to monosodium glutamate administration. Diet was not violated during these episodes.

Preinfusion anxiety and laboratory-induced panic attacks in panic disorder patients.

Seventy panic disorder patients participated in a double-blind, placebo-controlled, randomized infusion study in which sodium lactate and isoproterenol were used to induce panic anxiety. Patients who panicked during lactate, isoproterenol, and placebo infusions generally had higher preinfusion anxiety scores. These findings held true irrespective of the order the infusions were given. Stepwise multiple regression analyses comparing panickers with nonpanickers as the criterion variable revealed that the items "afraid of going crazy," "feeling unsteady," and "feeling paralyzed" on the Panic Description Scale had the highest predicting values.

Increased sensitivity of the elderly to the central depressant effects of diazepam.

The effects of diazepam on memory and psychomotor performance in healthy elderly (N = 12) and young (N = 12) individuals were examined. Diazepam was administered acutely in a single, oral 2.5 mg dose. Diazepam impaired memory, both immediate and delayed recall, and psychomotor performance in the elderly subjects. In addition, the drug caused an increase in self-reported sedation in elderly subjects but not in young subjects. These findings suggest an age-related increase in the sensitivity of elderly individuals to the central depressant effects of diazepam.

Beta-receptor responsiveness after desipramine treatment.

To examine whether a tricyclic antidepressant affects the functional response to a beta-receptor agonist in man, the response of heart rate, blood pressure, and plasma cAMP to isoproterenol was measured in 14 normal controls taking 75 mg desipramine daily. Desipramine significantly increased the bolus dose of isoproterenol needed to increase heart rate by 25 bpm at 14-30 days but not at 3-8 days. During infusions of isoproterenol, the increase in systolic blood pressure was blunted at both 3-8 days and 14-30 days, while the decrease in diastolic blood pressure was unaffected. Blood pressure findings were not affected by preadministration of bethanechol. In ten controls, isoproterenol infusions increased plasma cAMP, but this was unaffected by desipramine treatment. These findings suggest a decrease in the functional response of beta 1, but not beta 2, receptors after treatment with desipramine.

Adverse effects of single therapeutic doses of diazepam on performance in normal geriatric subjects: relationship to plasma concentrations.

Elderly normal volunteers (N = 12, mean age 70.4 years) were administered placebo or diazepam 2.5, 5, 10 mg in four consecutive sessions separated by at least a 1-week interval. Memory and psychomotor performance and plasma diazepam concentrations were assessed at baseline and at 1 and 3 h following drug administration. Significant impairments were found in response to all doses of diazepam. The maximum impairment occurred at 1 h, which coincided with the highest plasma concentration of the drug.

Maximizing the benefit of pharmacotherapy in Parkinson's disease.

Levodopa is one of the principal agents administered to treat patients with Parkinson's disease (PD). Several pharmacologic strategies can limit its side effects and enhance its activity. Although certain exceptions apply, dosage adjustments and drug changes should be instituted slowly. Levodopa is typically introduced in the form of carbidopa-levodopa, with upward dosage titration weekly until symptoms improve. A dopamine agonist may be added when the dosage of levodopa reaches 300-500 mg/day Dopamine agonists are used to control symptoms of PD, decrease or delay motor fluctuations, and allow lower dosages of levodopa to be administered. These agents are also being prescribed early in treatment before carbidopa-levodopa therapy is begun. Addition of a catechol-O-methyltransferase inhibitor can increase the duration of levodopa's effect and may prove especially valuable for patients who experience early wearing off of levodopa. Patients with PD require close monitoring for drug toxicity. Because most of them are treated with several agents to provide maximum improvement and also receive treatment for comorbid conditions, drug-drug interactions are possible. Frequently, clinically significant interactions are associated with agents that block D2 receptors or deplete dopamine stores in the brain.

Pharmacokinetic and pharmacodynamic modeling of L-dopa plasma concentrations and clinical effects in Parkinson's disease after Sinemet.

Eleven parkinsonian patients participated in a pharmacokinetic/pharmacodynamic study in an attempt to model levodopa (L-DOPA) plasma concentrations to clinical effect. Carbidopa 25 mg/L-DOPA 100 mg (Sinemet 25/100) was given orally, and blood samples were obtained before and serially for 4 hours after the dose. Effect measurements were obtained with each blood sample and included tapping score, timed walking, and global assessment of motor function. Mean L-DOPA plasma concentrations were fitted to a one-compartment pharmacokinetic model. A time-wise plot of modeled plasma L-DOPA concentrations versus mean effect measurements revealed a counter-clockwise hysteresis. Effect compartment concentrations were determined by a least squares approach, which determined elimination rate constants by minimizing hysteresis. Half-times for the equilibration between plasma and the effect compartment were 0.39 h for tapping, 0.36 h for walking, and 0.34 h for the global score. Pharmacodynamic data were fit best with an Emax model with baseline effect for tapping (Emax = 53.2 taps/60 s, EC50 = 0.58 microgram/ml) and global score (Emax set at 5.0 by limits of scale, EC50 = 2.53 micrograms/ml). A linear model best described the relationship between predicted effect site concentration and timed walking. L-DOPA plasma concentrations after oral Sinemet did not correlate well with clinical response because clinical response lags behind plasma concentrations. Half-times for equilibration between plasma and the effect site were similar for all of the effects measured.

Somatic and psychological symptoms during isoproterenol-induced panic attacks.

To determine which symptoms characterized isoproterenol-induced panic attacks, we analyzed the presence of panic attacks in 54 panic disorder patients who panicked, 24 patients who did not panic, and 37 controls who did not panic during isoproterenol infusions. The increases over the baseline of the symptoms shortness of breath and fear of going crazy were highly associated with panicking patients when compared to nonpanicking patients and nonpanicking controls. The increases of the symptoms trembling and shaking, generally nervous, and fear of going crazy were highly associated with patients when compared to controls. The possibility of a cognitive theory of panic attacks is discussed.