Comparison of acute behavioral effects of sustained-release and immediate-release methylphenidate.

The rate of onset of a drug's effect is an important determinant of its abuse potential. This experiment examined the acute behavioral effects of orally administered sustained-release methylphenidate (SR; 20-40 mg), immediate-release methylphenidate (IR; 20-40 mg), and placebo in 10 healthy volunteers. Drug effects were assessed before drug administration and periodically afterwards for 6 hr using drug-effect questionnaires and performance measures that are sensitive to the acute effects of stimulants. The IR formulation produced stimulant-like drug effects (e.g., increased ratings of "good effects") that generally varied as a function of dose and time. The SR formulation produced only transient effects on these measures. These findings are consistent with previous research on the influence of rate of onset using other drugs and suggest that the abuse potential of IR methylphenidate may be greater than that of SR methylphenidate.

Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness.

Of 30 patients with treatment-refractory affective illness, 10 showed a moderate to marked response to blind nimodipine monotherapy compared with placebo on the Clinical Global Impressions Scale. Fourteen inadequately responsive patients (3 unipolar [UP], 11 bipolar [BP]) were treated with the blind addition of carbamazepine. Carbamazepine augmentation of nimodipine converted four (29%) of the partial responders to more robust responders. Patients who showed an excellent response to the nimodipine-carbamazepine combination included individual patients with patterns of rapid cycling, ultradian cycling, UP recurrent brief depression, and one with BP type II depression. When verapamil was blindly substituted for nimodipine, two BP patients failed to maintain improvement but responded again to nimodipine and remained well with a blind transition to another dihydropyridine L-type calcium channel blocker (CCB), isradipine. Mechanistic implications of the response to the dihydropyridine L-type CCB nimodipine alone and in combination with carbamazepine are discussed.

Pretreatment with isradipine, a calcium-channel blocker, does not attenuate the acute behavioral effects of ethanol in humans.

The acute subject-rated, performance-impairing, and physiological effects of ethanol (0, 0.5, and 1 g/kg) were examined after pretreatment with isradipine (0, 5, and 10 mg) in nine healthy volunteers. Volunteers received 1 of the 9 ethanol-isradipine combinations during each of nine experimental sessions. Ethanol alone produced prototypical subject-rated drug effects (e.g., increased ratings of "Drunk," "Good effects," and "Like drug") and impaired performance. Isradipine alone also produced significant subject-rated drug effects (e.g., increased ratings of "Drug effect," "Bad effects," "High," and "Stimulated"), but did not impair performance. Isradipine pretreatment generally did not significantly alter the subject-rated or performance-impairing effects of ethanol. Isradipine alone, but not ethanol alone, significantly decreased systolic and diastolic blood pressure. The ethanol-isradipine combinations generally produced significantly greater decreases in blood pressure than were observed with isradipine alone. Breath-alcohol levels were significantly lower after isradipine pretreatment, which suggests isradipine altered the bioavailability of ethanol. The present findings extend previous studies with humans that examined the behavioral effects of ethanol after pretreatment with other calcium-channel blockers, including nifedipine, nimodipine, and verapamil. Whereas the available studies suggest that calcium-channel blockers would not be useful pharmacological adjuncts in the management of ethanol abuse, more research is needed. Future studies should use self-administration and drug discrimination procedures adapted for use with humans to determine if calcium-channel blockers can attenuate any of the behavioral effects of ethanol.

Benzodiazepine-receptor ligands in humans: acute performance-impairing, subject-rated and observer-rated effects.

The study presented here compared the acute performance-impairing, subject-rated, and observer-rated effects of quazepam (15, 30, and 45 mg), triazolam (0.1875, 0.375, and 0.5625 mg), zolpidem (7.5, 15, and 22.5 mg), and placebo in nine healthy, non-drug-abusing humans. Quazepam, a trifluoroethylbenzodiazepine, was chosen for study because, when compared with triazolam, a triazolobenzodiazepine, it is a relatively weak benzodiazepine-receptor ligand, and it may bind selectively to the BZ1 benzodiazepine-receptor subtype. Zolpidem, an imidazopyridine, is the most commonly prescribed hypnotic and was chosen for study because it is biochemically distinct from benzodiazepine hypnotics and also purportedly binds selectively to the BZ1 benzodiazepine-receptor subtype. Triazolam was chosen as the reference compound because it binds nonselectively to BZ1 and BZ2 benzodiazepine-receptor subtypes. Triazolam, zolpidem, quazepam, and placebo were administered orally in a double-blind, crossover design. Triazolam and zolpidem produced orderly dose- and time-related impairment of learning, performance, and recall, and produced sedative-like subject- and observer-rated drug effects. The behavioral pharmacologic profile of zolpidem and triazolam was indistinguishable in that at peak effect, the absolute magnitude of drug effect was comparable across the various measures. Quazepam, by contrast, did not impair performance on any task to a statistically significant degree, nor did it produce significant sedation as measured by subject- and observer-rated drug-effect questionnaires. Whether these effects are a result of the unique benzodiazepine-receptor binding profile of quazepam or the testing of insufficient dosages is unknown. Future research could extend the findings presented here by testing higher dosages of quazepam.

Discriminative-stimulus and participant-rated effects of methylphenidate, bupropion, and triazolam in d-amphetamine-trained humans.

The discriminative-stimulus and participate-rated effects of a range of doses of d-amphetamine (2.5-20 mg), methylphenidate (5-40 mg), bupropion (50-400 mg), and triazolam (0.0625-0.5 mg) were tested in 5 humans trained to discriminate between oral d-amphetamine (20 mg) and placebo. d-Amphetamine and methylphenidate generally dose dependently increased drug-appropriate responding. Bupropion and triazolam on average occasioned less than or equal to 40% drug-appropriate responding. d-Amphetamine, methylphenidate, and bupropion produced stimulant-like participant-rated effects, while triazolam produced sedative-like effects. These results further demonstrate that the acute behavioral effects of d-amphetamine and methylphenidate overlap extensively in humans, which is concordant with preclinical studies. Bupropion produced some d-amphetamine-like, participant-rated drug effects but did not occasion significant levels of d-amphetamine-appropriate responding. These findings are concordant with previous findings of a dissociation between the discriminative-stimulus and participant-rated effects of drugs.

Trazodone and triazolam: acute subject-rated and performance-impairing effects in healthy volunteers.

The present study compared the acute subject-rated and performance-impairing effects of trazodone and triazolam in seven healthy humans. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured approximately 30 min before drug administration and repeatedly afterwards for 6 h. Trazodone and triazolam produced dose-related increases in subject-ratings of drug effect and sedation. The absolute magnitude of trazodone's and triazolam's effects was comparable across these measures, which suggests the doses tested were equivalent on some behavioral dimension. By contrast, triazolam, but not trazodone, increased subject ratings of "dizzy", "excited", "nervous", "restless", "stomach turning" and "itchy skin". Triazolam, but not trazodone, significantly impaired learning, recall and performance. The present findings suggest trazodone may be a viable alternative to benzodiazepine hypnotics like triazolam, especially when needing to minimize drug-induced impairment. Future research could extend the present findings by replicating them in a clinically relevant population such as individuals with histories of drug abuse.

Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients.

BACKGROUND: Therapeutic effects of the tripeptide protirelin (thyrotropin-releasing hormone) have been postulated in the affective disorders, but direct assessment in humans has been hindered by poor blood-brain barrier permeability. METHODS: Eight medication-free inpatients with refractory depression received 500 micrograms of protirelin via a lumbar intrathecal injection and an identical sham lumbar puncture procedure, separated by 1 week, in a double-blind crossover design. RESULTS: Five of eight patients responded to intrathecal protirelin, defined as a 50% or greater reduction in an abbreviated Hamilton Rating Scale for Depression score. Suicidality also was reduced significantly (P < .05). Responses were rapid and clinically robust, but short-lived. CONCLUSION: Administration of protirelin by an intrathecal route induced a rapid improvement in mood and suicidality in these refractory depressed patients, supporting the hypothesis that thyrotropin-releasing hormone could be a positive modulator of mood.

Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders.

OBJECTIVE: The author's goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients. METHOD: Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism. RESULTS: Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism. CONCLUSIONS: These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.

Blunted left cingulate activation in mood disorder subjects during a response interference task (the Stroop).

Functional neuroimaging studies have found abnormal anterior cingulate activity in depressed subjects, and other studies have shown that the cingulate gyrus becomes active in healthy subjects during interference tasks. The authors hypothesized that subjects with mood disorder might show blunted cingulate activation during the standard Stroop interference task or during a modified version involving sadness-laden words. In contrast to 11 age- and sex-matched healthy control subjects who activated the left cingulate during the standard Stroop, 11 mood-disordered subjects activated the right anterior cingulate gyrus only slightly and instead showed increased activity in the left dorsolateral prefrontal and visual cortex. This study supports theories of blunted limbic and paralimbic activation and abnormal cingulate activity in depression and adds to the growing knowledge of the functional neuroanatomy of depression.

The place of anticonvulsant therapy in bipolar illness.

With the increasing recognition of lithium's inadequacy as an acute and prophylactic treatment for many patients and subtypes of bipolar illness, the search for alternative agents has centered around the mood stabilizing anticonvulsants carbamazepine and valproate. In many instances, these drugs are effective alone or in combination with lithium in those patients less responsive to lithium monotherapy, including those with greater numbers of prior episodes, rapid-cycling, dysphoric mania, co-morbid substance abuse or other associated medical problems, and patients without a family history of bipolar illness in first-degree relatives. Nineteen double-blind studies utilizing a variety of designs suggest that carbamazepine, or its keto-congener oxcarbazepine, is effective in acute mania; six controlled studies report evidence of the efficacy of valproate in the treatment of acute mania as well. Fourteen controlled or partially controlled studies of prophylaxis suggest carbamazepine is also effective in preventing both manic and depressive episodes. valproate prophylaxis data, although based entirely on uncontrolled studies, appear equally promising. Thus, both drugs are widely used and are now recognized as major therapeutic tools for lithium-nonresponsive bipolar illness. The high-potency anticonvulsant benzodiazepines, clonazepam and lorazepam, are used adjunctively with lithium or the anticonvulsant mood stabilizers as substitutes or alternatives for neuroleptics in the treatment of manic breakthroughs. Preliminary controlled clinical trials suggest that the calcium channel blockers may have antimanic or mood-stabilizing effects in a subgroup of patients. A new series of anticonvulsants has just been FDA-approved and warrant clinical trials to determine their efficacy in acute and long-term treatment of mania and depression. Systematic exploration of the optimal use of lithium and the mood-stabilizing anticonvulsants alone and in combination, as well as with adjunctive antidepressants, is now required so that more definitive treatment recommendations for different types and stages of bipolar illness can be more strongly evidence based.

Increased neural cell adhesion molecule in the CSF of patients with mood disorder.

Neural cell adhesion molecule (N-CAM) is involved in cell-cell interactions during synaptogenesis, morphogenesis, and plasticity of the nervous system. Disturbances in synaptic restructuring and neural plasticity may be related to the pathogenesis of several neuropsychiatric diseases, including mood disorders and schizophrenia. Disturbances in brain cellular function may alter concentrations of N-CAM in the CSF. Soluble human N-CAM proteins are detectable in the CSF but are minor constituents of serum. We have recently found an increase in N-CAM content in the CSF of patients with schizophrenia. Although the pathogenesis of both schizophrenia and mood disorders is unknown, ventriculomegaly, decreased temporal lobe volume, and subcortical structural abnormalities have been reported for both disorders. We have therefore measured N-CAM concentrations in the CSF of patients with mood disorder. There were significant increases in amounts of N-CAM immunoreactive proteins, primarily the 120-kDa band, in the CSF of psychiatric inpatients with bipolar mood disorder type I and recurrent unipolar major depression. There were no differences in bipolar mood disorder type II patients as compared with normals. There were no significant effects of medication treatment on N-CAM concentrations. It is possible that the 120-kDa N-CAM band present in the CSF is derived from CNS cells as a secreted soluble N-CAM isoform. Our results suggest the possibility of latent state-related disturbances in N-CAM cellular function, i.e., residue from a previous episode, or abnormal N-CAM turnover in the CNS of patients with mood disorder.

Rational polypharmacy in the bipolar affective disorders.

Bipolar affective illness represents a syndrome not readily treated by single agents. Approximately 50% of patients are inadequately responsive to lithium and the majority of patients require supplemental antidepressants, antimanic, antipsychotic or hypnotic medications. These traditional adjunctive medications are associated with potential problems. Antidepressants may precipitate mania (at a rate about double that of placebo) or cause cycle acceleration. Neuroleptics may be associated with either more profound or longer depressive phases, and clearly increase the risk of tardive dyskinesia, to which bipolar patients appear particularly predisposed. Moreover, there are subgroups of patients who are known to be poorly responsive to lithium. These include patients with rapid cycling, dysphoric mania, co-morbid drug or alcohol abuse, a pattern of depression-mania-well interval (D-M-I as opposed to the M-D-I pattern), and patients without a family history of bipolar illness in first-degree relatives. There is increasing recognition that the anticonvulsants carbamazepine and valproate are effective alternatives or adjuncts to lithium in the acute and long-term treatment of bipolar illness. Ideally, one would want to assess whether patients who were unresponsive to lithium were responsive to an anticonvulsant alone prior to utilizing lithium in addition to anticonvulsant combination therapy. However, from the clinical perspective, it is often more expedient to use an anticonvulsant adjunctively to lithium to assess the efficacy of this combination and establish mood stabilization. When lithium is not discontinued, the increased morbidity during lithium withdrawal also would not occur and would not confound the evaluation of the new agent. We suggest the initial use of acute adjuncts to lithium with the anticonvulsants carbamazepine or valproate (instead of neuroleptics) so that their efficacy can be assessed in the individual's acute episode, with the likelihood of a positive response in longer-term prophylaxis. Hypnotic benzodiazepines with anticonvulsant properties, such as clonazepam or lorazepam, are often used to help to induce sleep in escalating bipolar patients, and may be useful adjuncts as well. Patients who were inadequately responsive to either carbamazepine or valproate alone may be responsive to the anticonvulsant combination. In a similar fashion, one can also utilize several mood-stabilizing drugs (lithium and an anticonvulsant such as carbamazepine or valproate) in the treatment of depressive breakthroughs, and then augment this combination (if necessary) with a catecholamine-active antidepressant such as bupropion or a serotonin-selective reuptake inhibitor (SSRI) such as fluoxetine, paroxetine, sertraline or if necessary a monoamine oxidase inhibitor (MAOI). Once the patient has responded to a combination of drugs, it becomes problematic to decide whether the last agent added was the crucial ingredient in helping the patient achieve remission or that remission might have occurred with this agent alone. A conservative approach would have merit in patients who are finally stabilized on complex polypharmacy regimens only after many years of sequential trials; in this instance, the potential risk of re-exacerbating the illness with a taper of one of the drugs in the regimen. Rational polypharmacy should thus be implemented with careful delineation of the prior course of illness (typically using life chart methodology) and targeted treatment outcomes titrated against side effects, using sequential clinical trials in individual patients who have not adequately responded to monotherapy. In this fashion, it is hoped that pharmacodynamic differences among agents can be maximized and pharmacokinetic and side effects minimized.

The emerging role of cytochrome P450 3A in psychopharmacology.

Recent advances in molecular pharmacology have allowed the characterization of the specific isoforms that mediate the metabolism of various medications. This information can be integrated with older clinical observations to begin to develop specific mechanistic and predictive models of psychotropic drug interactions. The polymorphic cytochrome P450 2D6 has gained much attention, because competition for this isoform is responsible for serotonin reuptake inhibitor-induced increases in tricyclic antidepressant concentrations in plasma. However, the cytochrome P450 3A subfamily and the 3A3 and 3A4 isoforms (CYP3A3/4) in particular are becoming increasingly important in psychopharmacology as a result of their central involvement in the metabolism of a wide range of steroids and medications, including antidepressants, benzodiazepines, calcium channel blockers, and carbamazepine. The inhibition of CYP3A3/4 by medications such as certain newer antidepressants, calcium channel blockers, and antibiotics can increase the concentrations of CYP3A3/4 substrates, yielding toxicity. The induction of CYP3A3/4 by medications such as carbamazepine can decrease the concentrations of CYP3A3/4 substrates, yielding inefficiency. Thus, knowledge of the substrates, inhibitors, and inducers of CYP3A3/ and other cytochrome P450 isoforms may help clinicians to anticipate and avoid pharmacokinetic drug interactions and improve rational prescribing practices.

Carbamazepine but not valproate induces bupropion metabolism.

Bupropion (BUP) may be less likely than other antidepressants to cause switches into mania and rapid cycling, suggesting utility in bipolar disorder. The combination of BUP with the mood-stabilizing anticonvulsants carbamazepine (CBZ) or valproate (VPA) is a strategy that might further lessen the risk of mania. CBZ induces, and to a lesser extent VPA inhibits the hepatic metabolism of various medications, but their effects on BUP have not been previously studied. Inpatients with mood disorders had pharmacokinetic profiles of BUP and metabolites assessed after single, oral, 150-mg doses of BUP while receiving placebo (N = 17) or during chronic blind CBZ (N = 12) or VPA (N = 5) monotherapy. CBZ but not VPA therapy decreased BUP peak concentrations (Cmax) by 87% (p < 0.0001) and 24-h area under the curve (AUC) by 90% (p < 0.0001), threohydrobupropion Cmax by 81% (p <0.0009) and AUC by 86% (p < 0.002), and erythropydrobupropion Cmax by 86% (p < 0.05) and AUC by 96% (p < 0.05). CBZ increased hydroxybupropion (H-BUP) Cmax by 71% (p < 0.007) and AUC by 50% (p < 0.09) and H-BUP AUC by 94% (p < 0.02). Thus, CBZ markedly decreased BUP and increased H-BUP concentrations, whereas VPA did not affect BUP but increased H-BUP concentrations. Further studies are required to determine how these differential effects of CBZ and VPA on BUP pharmacokinetics influence the tolerability and efficacy of combination therapies with these agents.

Nimodipine increases CSF somatostatin in affectively ill patients.

Preliminary evidence suggests that nimodipine, an L-type calcium channel blocker, is effective in treating some patients with rapidly cycling affective disorders and some phases of Alzheimer's disease, i.e., two syndromes associated with transient or permanent reductions in cerebrospinal fluid (CSF) somatostatin, respectively. CSF somatostatin (SRIF) was measured in 14 affectively ill patients while they were medication-free and during chronic nimodipine treatment. CSF somatostatin significantly increased in patients during active nimodipine treatment compared with ones in the medication-free state. The current findings raise the possibility that nimodipine-induced increases in CSF somatostatin could potentially contribute to its spectrum of efficacy on neuropsychiatric disorders associated with cognitive or affective impairment. Further clinical and preclinical studies are indicated to elucidate the potential mechanisms involved in the elevation of CSF SRIF, whether it is reflected in regional changes in brain, and its possible relevance to nimodipine's clinical actions.

Cerebrospinal fluid total protein in patients with affective disorders.

Cerebrospinal fluid (CSF) total protein was evaluated in 240 patients with affective disorders and compared with findings in 55 normal comparison subjects. Subtype diagnoses were as follows: bipolar I (n = 108, 47 men, 61 women); bipolar type II (n = 67, 26 men, 41 women); and unipolar (n = 65, 22 men, 43 women). Men had significantly elevated values compared with women. In men with bipolar I disorder, mean CSF protein levels were found to be significantly elevated over those in normal subjects, with 31.9% above the traditional normal range cutoff of 45 mg/dl. Moreover, CSF protein levels in male bipolar I patients were found to be positively correlated with severity of depression at the time of the lumbar puncture and with duration of illness. It thus appears that increased protein levels may be associated with illness severity or progression in male patients with bipolar I disorder. Although elevated CSF protein is a nonspecific marker of cerebral pathology, further search for the potential underlying pathophysiological mechanisms related to this finding would now appear to be warranted.

Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation.

We report the initial results of the first controlled double-blind trial of nimodipine, a calcium channel antagonist, in the acute and prophylactic treatment of patients with treatment-refractory affective dysregulation. Active drug nimodipine (A) was substituted for placebo (B) in 12 patients. Patients were studied in a B-A-B design, with 3 of the 12 patients rechallenged with active drug in a B-A-B-A design (patients 9, 10, and 11). Five of the nine patients who completed the drug trial responded. One of three patients suffering from ultra-ultra-rapid (ultradian) cycling bipolar II disorder (patient 6) showed an essentially complete response; the other two ultradian patients (patients 4 and 9) showed evidence of a partial response on manic and depressive oscillations, one of which was confirmed in a B-A-B-A design. Only one of five less rapidly, but continuously cycling patients showed an excellent response (patient 10), and this was confirmed in a B-A-B-A design. The one patient who had recurrent brief depression (patient 11) showed a complete resolution of severe depressive recurrences, with response re-confirmed in an extended prophylactic trial with a B-A-B-A design. In the eight patients who completed self-ratings, nimodipine was associated with a significant reduction in the magnitude of mood fluctuations compared with the baseline placebo condition. Further clinical study of nimodipine, a calcium channel blocker with a unique profile of behavioral and anticonvulsant properties, appears warranted in patients with treatment-refractory affective illness characterized by recurrent brief depression and ultradian cycling.

New developments in the use of anticonvulsants as mood stabilizers.

There is increasing recognition that lithium is inadequate in the treatment of up to 50% of bipolar patients. In addition to subgroups that are nonresponsive from the outset, loss of efficacy (tolerance) and discontinuation-induced refractoriness have recently been observed. The anticonvulsants carbamazepine and valproate are effective alternative or adjunctive treatments, but tolerance can also occur during their long-term prophylactic use. New treatment algorithms for this loss of efficacy, including combination therapies, require further systematic study. Preliminary data suggesting that some patients with extremely rapid and chaotic mood fluctuations may respond to the L-type calcium channel blocker nimodipine are presented, and the theoretical implications discussed.

Synergy of carbamazepine and valproic acid in affective illness: case report and review of the literature.

Carbamazepine and valproic acid are anticonvulsants with mood-stabilizing properties. Basic and clinical research suggest that these medications used together may have synergistic anticonvulsant effects. Psychotropic synergy of the combination has yet to be explored systematically. We present the case of a patient with rapid-cycling bipolar disorder studied under double-blind conditions whose hypomanias and depressions were refractory to either carbamazepine or valproic acid alone, but responded dramatically to the combination. The superior response to the combination appeared to be due to pharmacodynamic rather than pharmacokinetic effects. The clinical and theoretical aspects of the use of carbamazepine and valproic acid in combination are discussed.