Bipolar depression: a review of randomised clinical trials.

Randomised, controlled trials have been completed in the study of the response of bipolar depression to lithium, antiepileptic drugs, antidepressants (particularly the selective serotonin re-uptake inhibitors) and a few miscellaneous agents including pramipexole. In most cases, only one randomised, controlled trial has been completed, perhaps because that can be sufficient to gain US FDA approval for an additional approved use for a medication already approved for another use (usually mania). Despite numerous early studies of lithium, only one recent study was completed with sufficient controls. In virtually all trials, the controlled comparison has been with placebo. A review of risk factors, as well as adverse events and kinetics based on these studies, focuses on net benefits, in particular for quetiapine and lamotrigine. All antidepressants present with some risk for induction of mania and/or cycle acceleration and are best used in combination with mood stablisers; greatest risk for destabilisation seems to be with venlafaxine.

Seligiline transdermal system in depression.

Seligiline, a monoamine oxidase inhibitor, has been previously approved by the US FDA for adjunctive treatment of Parkinson's disease. At present, it has been found to be effective in a transdermal system when administered daily in the treatment of major depressive disorder. The minimum dosage of 6 mg/24 h was effective in two trials; this dosage did not require any dietary precautions. Higher doses of 9 mg/24 h and 12 mg/24 h may also not require restrictions, however, current data is insufficient. Furthermore, a randomized 52-week prevention study found significant benefits for continuance of this treatment. There are several types of safety data available. First, there have been no reports of hypertensive crisis in any patient receiving selegiline via this transdermal system at any of the three doses. Tyramine challenge studies have found a comfortable cushion of safety at selegiline doses of 6 mg/24 h. Other side effects include a slightly higher rate of orthostatic hypotension, insomnia and, most frequently, application site reactions. There are no significant effects on weight or sexual side effects. In terms of drug interactions, carbamazepine was found to significantly increase seligiline levels (however, carbamazepine should be contraindicated). Direct sympathomimetics may be safe, but indirect ones are thought to put the patient at risk. Finally, due to risk of serotonin syndrome, other medications contraindicated include: selective serotonin re-uptake inhibitors, serotonin-noradrenaline re-uptake inhibitors and multiple analgesics - in particular meperidine. To prevent toxic drug interactions at initiation of seligiline transdermal system therapy, all mediactions that are at risk should be completely stopped a minimum of 4-5 times their respective half-lifes for full elimination. This is generally a time period of 1 week. Upon stopping treatment with selegiline, 2 weeks should pass prior to beginning any medication at risk for drug interactions.

Anticonvulsants in the treatment of bipolar mania.

A series of antiepileptic drugs have been investigated in terms of their ability to treat mania (with later applications for the treatment of bipolar depression and prevention of relapses). These include divalproex, carbamazepine, oxcarbazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate and zonisamide. Although these drugs are all antiepileptic in action, they bring about these effects by different mechanisms; in particular, their impact on GABA differs significantly. Perhaps for this reason, their impact on mania varies greatly, with double-blind significant results evident only for valproate, carbamazepine and oxcarbazepine. Only valproate and carbamazepine are approved by the US FDA for use in mania; oxcarbazepine has never been found significantly effective in large-scale studies. Of the other options, both gabapentin and topiramate failed in large-scale investigations; tiagabine failed in small sample reports. Although lamotrigine has been successful in the prevention of depression relapse in bipolar disorder, it has not been effective in treating mania. Finally, there are no findings of large scale double-blind studies on the use of levetiracetam and zonisamide. A review of the kinetics, side effects and complications of the antiepileptic drugs indicates that carbamazepine is useful, and has adverse event benefit over all other options. The potential of zonisamide awaits further testing.

Higher than Physician's Desk Reference (US) doses on atypical antipsychotics.

The Physician's Desk Reference (PDR) was established to provide for the practicing of a complete listing of all medications with the FDA-approved labelling, including dosage recommendations. Perhaps in order to maximise individual usage of medications, pharmaceutical companies have frequently targeted lowest possible doses for FDA approval. However, many patients with a variety of illnesses due to resistance and/or multiple illnesses, may need higher than these dose ranges to maximise therapeutic response. In terms of regularly prescribed atypical antipsychotics released over the past 10 years, only risperidone initially obtained approval for a dose for psychosis (16 mg) higher than that suggested currently (maximum of 8 mg). The dose that was approved for mania was lower: a maximum of 6 mg. The others: respectfully, olanzapine (schizophrenia: 15 mg, mania: 20 mg), quetiapine (schizophrenia: 750 mg; mania: 800 mg), ziprasidone (schizophrenia and mania: 160 mg) and aripiprazole (schizophrenia and mania: 30 mg) obtained approvals for psychosis that may limit adverse events but, at the same time, limit benefits. Other data from various sources (double-blind trials, open-label trials, reviews and case reports) have found safety and/or efficacy for the following maximum doses: olanzapine (40 mg), quetiapine (1600 mg), ziprasidone (320 mg) and aripiprazole (75 mg). Reports above those doses are included, but either are insufficient in numbers or bring up questions on safety. In many situations, feared increase in adverse events were not magnified by use of higher doses.

The effectiveness of St. John's Wort in major depressive disorder: a naturalistic phase 2 follow-up in which nonresponders were provided alternate medication.

BACKGROUND: A continuation study of an extract of St. John's wort (Hypericum perforatum) for depression was performed in follow-up to an acute study that found no significant difference between St. John's wort extract and placebo. METHOD: Seventeen subjects with DSM-IV-defined major depressive disorder who responded to St. John's wort extract in the acute-phase study (phase 1) were continued on double-blind treatment with the same preparation for 24 weeks. Ninety-five subjects who did not respond to either St. John's wort or placebo were treated with an antidepressant for 24 weeks. RESULTS: During antidepressant treatment, mean scores on the Hamilton Rating Scale for Depression for phase 1 nonresponders decreased significantly (p <.0001), with no significant difference between St. John's wort nonresponders and placebo nonresponders. Of the 17 subjects continued on treatment with St. John's wort extract, 5 (29.4%) relapsed. CONCLUSIONS: The subjects who did not respond to St. John's wort extract or placebo in phase 1 were, by and large, not resistant to antidepressant treatment. This suggests that the lack of efficacy found by Shelton et al. in the acute-phase study was unlikely to be the result of a high proportion of treatment-resistant subjects.

Aripiprazole: profile on efficacy and safety.

Aripiprazole (Abilitat, Bristol-Myers Squibb) is the most recent addition to the new class of atypical antipsychotic medications, following the release of clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Aripiprazole exhibits typical antagonism at dopamine (D2) receptors in the mesolimbic pathway, as well as having unique partial agonist activity at D2 receptors in the mesocortical pathway. As exemplified by other atypical antipsychotics, it displays strong 5-HT(2a) receptor antagonism and is similar to ziprasidone in also having agonistic activity at the 5-HT(1a) receptor. Among the atypical antipsychotics, aripiprazole displays the lowest affinity for alpha(1)adrenergic (alpha(1)), histamine (H1) and muscarinic (M1) receptors. This combination of effects may be responsible for its efficacy in positive and negative symptoms of schizophrenia and in bipolar disorder. Similarly, this profile may be the reason for the low rates of reported side effects observed. This includes general adverse events, a low incidence of reported weight gain and a low liability for inducing movement disorders. Other early data suggest that aripiprazole may induce reductions in plasma prolactin, as well as in plasma glucose and lipid profiles. Finally, results also support the proposition that aripiprazole may lead to reductions in corrected QT interval and have minimal drug interactions.

Antipsychotics: impact on prolactin levels.

Hyperprolactinaemia has been associated with a variety of side effects including amenorrhoea, galactorrhoea, sexual dysfunction, breast engorgement and osteoporosis. Since the mid-1970s, the impact of antipsychotics on human prolactin (hPrl) levels has been investigated. Baseline levels of hPrl were found to be similar in healthy controls and patients who were diagnosed as having schizophrenia. Short-term acute studies done after single parenteral or oral doses of phenothiazines found rapid two- to tenfold increases in hPrl. Similar increases were found in longer term studies that reported increases of three times in both men and women after 3 days that doubled again after several weeks of treatment. A study of longer term injectable fluphenazine enanthate found that elevation induced by a single injection lasted up to 28 days. The same results with significant increases have been reported with the butyrophenone, haloperidol. Substantial increases are found after single injections (up to nine times) and after weeks of treatment (up to three times sustained). Thus, early literature believed that there might be an association between these induced changes and response to therapy. However, prolactin is secreted by the anterior pituitary and is under inhibitory control of dopamine released from the tuberoinfundibular neurones. Thus, increases in prolactin are due to antipsychotic impact on tuberoinfundibular tract, one of four dopamine-related tracts. With the application of clozapine and other atypical antipsychotics, it was found that medications can successfully treat psychosis without increasing hPrl. In fact, early single-dose trails found clozapine to reduce hPrl by 16%. Later studies replicated this result and also found that up to 6 weeks of administration led to reductions in hPrl of up to 80%. Risperidone, however, has been found to persistently elevate hPrl in studies, despite its impact on other receptor sites. Olanzapine, quetiapine and ziprasidone have all been found to have little effect or produce decreases in hPrl. Most recently, aripiprazole, in early studies, appears to produce significant reductions in hPrl while maintaining therapeutic efficacy for psychosis.

Psychotropic drugs and the ECG: focus on the QTc interval.

The QT interval measuring depolarisation and repolarisation has, when lengthened, been implicated as a risk factor for the development of torsades de pointes and sudden death, particularly in patients predisposed to these complications due to cardiovascular impairment. Since some of the medications used in psychiatry have been implicated, an extensive review of available literature was made of the major classes, including antipsychotics, antidepressants, lithium, anticonvulsants and benzodiazepines. Further, where no publications were found on a particular medication, the pharmaceutical firms responsible for these items were contacted concerning possibly unpublished data. Results of the survey indicate that there may be difficulty in one of three situations: immediate (in the first minutes to hours after oral or parenteral administration), short-term use of 4 - 12 weeks or long-term use of 6 months. Based on this approach, the greatest concern is directed at the immediate application of haloperidol, droperidol, pimozide and trazodone, the short-term use of thioridazine, pimozide, sertindole, nortriptyline, clomipramine, doxepin and the long-term use of clozapine, olanzapine and carbamazepine. It is of interest that a reduction in QTc is reported with aripiprazole. Among the antidepressants, the tertiary tricyclic antidepressants (imipramine, amitriptyline and doxepin) appear to have a more general impact, while the secondary tricyclic antidepressants (nortriptyline, desipramine) may impact more on children and the elderly. Among other antidepressants, the only reports of torsades de pointes appeared to occur with mirtazapine. It was also of interest to find data showing no effect or reductions in QTc produced by sertraline, citalopram, paroxetine and bupropion in multiple studies. Effects of medications on other heart parameters are also briefly reviewed. In particular, the safety of sertraline in post-MI patients and of bupropion in heart disease patients is highlighted. Little information was available on other classes of medications used in psychiatric disorders. What is available concerning lithium, the anticonvulsants and the benzodiazepines indicates little effect on the QTc, although there may be effects on other cardiovascular parameters.