Vagus nerve stimulation in depression.

Ever since the introduction of chemical and electrical convulsive treatment for psychiatric disorders in the 1930s and 1940s, biological techniques have been used extensively in the amelioration of a variety of psychiatric disorders. Techniques of recent vintage have included transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation (VNS). Since VNS attenuates seizures in animal models, the treatment was initially developed and approved by the FDA for treatment of drug-resistant partial-onset epilepsy. Additional data, including the known neuroanatomy of the vagus nerve, effects of VNS on monoamines and mood improvement in patients with epilepsy who were treated with VNS, provided a rationale for further investigation in patients with primary mood disorders. VNS has been administered acutely for 10 weeks to 60 patients with treatment-resistant depression. Longer-term follow-up data has been analysed for the first 30 patients. Response rates have been at least 30% in the acute study. Similar to findings in epilepsy and in contrast to the usual results of long-term medication trials, longer term data regarding symptomatic and functional outcomes of depressed patients receiving VNS continue to look promising. As opposed to electroconvulsive therapy, VNS is not associated with cognitive impairment. These results have led to approval of VNS for the treatment of resistant depression (unipolar or bipolar) in both Europe and Canada. Currently, a pivotal double-blind acute study is underway in the US.

Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy.

UNLABELLED: After a brief review of epidemiology, the focus is on biochemistry of diabetes. Animal and human studies are reviewed in terms of the impact of alterations in catecholamines and serotonin (5-hydroxytryptamine, 5HT) on glucose utilization. Then, the implications of these experimental results for the choice of antidepressant in comorbid diabetes mellitus and depression as well as in diabetic neuropathy are discussed. Results of clinical investigations are then reviewed in terms of the above hypotheses. An Index Medicus Search for the past 10 years was supplemented by references from previous related reviews of the topic as well as by pending results, where available, not previously published. The range of prevalence of depression in diabetic patients has been 8-27%, depending on study criteria and procedures. An increase of catecholamines appears to increase glucose while both reducing insulin release and reducing sensitivity to insulin that is available. In contrast, increases in serotonergic function by increased precursor, increased release, or blocked metabolism and blocked reuptake in contrast seem to increase sensitivity to insulin and reduce plasma glucose. There have been six studies of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), at a dose of 60 mg/day pursued up to 12 months that have demonstrated that medication's usefulness in diabetic patients, with reductions in weight (to 9.3 kg), in FPG (to 45 mg%), and in HbA1c (to 2.5%). In studies in comorbid diabetes mellitus and depression, nortriptyline, a norepinephrine reuptake inhibitor that produces increased synaptic catechols, has led to worsening of indices of glucose control. However, fluoxetine and sertraline, both selective serotonin reuptake inhibitors, in the same patient group, have produced results consistent with reductions in glucose levels. In diabetic neuropathy, perhaps due to the fact that catecholamines and serotonin may both be implicated in pain pathways, dual-action antidepressants appear more effective at lower doses than do specific serotonergic agents. The tricyclic antidepressants (TCA) (66.7%) have had success in double-blind studies, particularly imipramine, with a 81% response rate. Yet, there are positive reports concerning the SSRIs (paroxetine, citalopram, sertraline), as well as nefazodone, that focus on serotonin selectivity. CONCLUSIONS: In comorbid diabetes mellitus and depression, most evidence supports the use of fluoxetine in control of glucose handling. Other characteristics in terms dosing, drug interactions, cognition, and sleep make sertraline an attractive alternative agent. In diabetic neuropathy without depression, the best choices among non-TCAs may include sertraline, citalopram, and perhaps, venlafaxine, since the TCAs appear to increase cravings and increase FBG levels.

Use of olanzapine in non-psychotic psychiatric disorders.

The history of antipsychotic medications begins in the 1950s with chlorpromazine, developed originally as an antihistamine but found to be an aid in the reduction of symptoms of delusions and hallucinations. This phenothiazine derivative was followed by numerous others in the same class (e.g., thioridazine) and then by antipsychotics in other classes (e.g., the popular haloperidol of the butyrophenone class). This group of medications is associated with a number of unpleasant side effects and complications. These included extrapyramidal symptoms (EPS), orthostatic hypotension, hyperprolactinemia and last, but certainly not least, tardive dyskinesia (TD). As a consequence, other alternative antipsychotics were developed in which D(2) blockade effect generally associated with EPS and TD was offset by 5-HT(2) antagonism. The first of this class was clozapine; however, it is associated with agranulocytopenia of sudden onset as well as seizure induction. However, olanzapine, a close structural relative, was soon synthesised for treatment of psychosis and particularly schizophrenia (Zyprexatrade mark, Eli Lilly). It was released in the US in November 1996 with FDA approval for that indication. However, antipsychotics have always been used for other psychiatric disorders, aside from schizophrenia. This includes, in particular, mania, where chlorpromazine use predated lithium as an effective treatment. Other uses for antipsychotics have included other mood disorders, dementia, childhood disorders and personality problems. Here, information on the application of olanzapine to non-schizophrenic disorders is reviewed. Despite the fact that the research post-dates FDA approval in 1996, there was already sufficient evidence for olanzapine's effectiveness in acute mania to obtain approval from the US FDA in March 2000. Other research supports its use as adjunctive therapy in depressive disorders. Phase IV studies and case reports have found limited support for olanzapine's use in a variety of other psychiatric disorders, behavioural disorders of dementia (including Alzheimer's disease), pervasive developmental disorder of childhood, obsessive-compulsive disorder and borderline personality disorder. In each of these latter diagnoses, double-blind studies are either underway or are planned to establish efficacy.

Rapid cycling bipolar disorder.

Rapid cycling bipolar disorder (RCBD) is defined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a type of manic-depressive illness in which the patient experiences four or more episodes of mania and/or major depression per year. It was first reported as a consequence of the reduced effectiveness of lithium carbonate in the treatment and prophylaxis of this form of bipolar disorder (BD) in contrast to those with less frequent cycling. Among the anticonvulsants, there have been reports with different degrees of controlled data concerning carbamazepine, valproate, lamotrigine, topiramate, gabapentin and primidone. There is a paucity of double-blind studies, but what is available supports the use of lamotrigine. There is open data supporting the use of carbamazepine, valproate and topiramate. Regarding other classes, nimodipine may have specific utility in ultradian- (ultra-ultra-) or ultra-RCBD and there is double-blind data regarding the specific utility of olanzapine in RCBD. Low thyroid function may be a factor in development of RCBD; therapies aimed at elevating thyroid levels, even beyond the usual range, have frequently produced benefits in open trials. More research is needed into the possible therapeutic benefits of verapamil, bupropion, choline, light therapy and electroconvulsive therapy (ECT).

Antipsychotic medication: effects on regulation of glucose and lipids.

Since the introduction of chlorpromazine in the 1950s, antipsychotics have been used for the treatment of schizophrenia. The phenothiazines were followed by the butyrophenones, particularly haloperidol. With all the movement disorder side effects of these medications (extrapyramidal syndrome, akathisia, tardive dyskinesia), the pharmaceutical industry has gradually released atypical antipsychotics. This class includes clozapine (released in the USA in 1990), risperidone (1994), olanzapine (1996), quetiapine (1998) and ziprasidone (2001). However, the rate of diabetes mellitus in patients with schizophrenia appeared to increase with the availability of this class of medications. In reviewing rate and degree of changes in weight, glucose control and lipid levels induced by typical and atypical antipsychotics, it was found that in contrast to case reports, there is a dearth of retrospective, open and controlled studies. However, in studies as early as 1964, significant weight increases were found to be associated with use of chlorpromazine. While the phenothiazines may have some effect on patients with chemical diabetes, there is little evidence of the typical antipsychotics producing diabetes mellitus de novo, or worsening diabetes that is already been discovered. Ziprasidone appears to be the antipsychotic with the most beneficial combination of effects: no weight gain, no change in glucose utilisation and reductions in cholesterol and serum triglycerides (TGs).

Ziprasidone: profile on safety.

Ziprasidone (Geodon, Pfizer) is the latest of a new class of atypical antipsychotics, following the release of clozapine, risperidone, olanzapine and quetiapine. It has a serotonin Type 2a/dopamine Type 2 (5-HT2a/D2) receptor (R) binding ratio of approximately 8:1; amongst the highest of its class. Furthermore, it is a potent 5-HT1aR agonist, and displays 5-HT1dR and 5-HT2cR antagonist activity, with unique effects on blocking the re-uptake of both 5-HT and noradrenaline (NE). Finally, ziprasidone has low-to-modest affinity for histamine (H1) and alpha 1-adrenoceptors and a negligible affinity for muscarinic (M1) Rs. This combination of effects may be responsible for its low rate of general adverse events, low rate of persistent prolactin elevation, low incidence of weight gain, low liability for inducing movement disorders, low rate of syncope and induction of decreases in lipid profile. Data on the effect of ziprasidone on the electrocardiogram (ECG) indicates a relatively higher degree of change in measure of QTc but no cases of mortality from overdoses, torsade de pointes (TdP) or excess in sudden and unexpected deaths.

Nefazodone treatment of adolescent depression: an open-label study of response and biochemistry.

OBJECTIVE: The purpose of this study was to find whether nefazodone, effective in adult depression, might be similarly improve symptoms of adolescent depression. Secondary purpose was to relate platelet serotonin content to response, and to find if nefazodone's effect on platelet content was similar to that of the SSRIs. METHOD: 10 adolescents meeting DSMIV criteria for major depression received up to 400 mg of nefazodone for an eight week period. Response was assessed at baseline, 1, 2, 4, and 8 weeks by BDI and HDRS; platelet serotonin (5HT) content was obtained at baseline and final visit (for two dropouts, this was done at last visit, i.e., week 4). RESULTS: In LOCF analysis, significant improvement was found in both HDRS (20.9 to 8.9, p = .01) and BDI (24.6 to 10.2, p = .01). Eight of nine patients with available data showed increases in platelet 5HT content (.02). In seven patients of eight completers with available data, there was a nonsignificant trend for patients with platelet 5HT baseline greater than 30 ng/10(8) platelets to show a greater change in HDRS than those with a baseline of less than 30 ng/10(8) platelets (p = .07). CONCLUSIONS: Further double-blind study of nefazodone in adolescent depression is indicated; nefazodone appears to increase platelet 5HT content.

The use of nimodipine in the treatment of mood disorders.

Nimodipine, a dihydropyridine calcium entry blocker, has been shown to protect from neuronal damage due to ischemia by providing for increased postischemic perfusion. Further, it has also been demonstrated to have antiepileptic properties. These two properties--calcium channel blockade and anticonvulsant benefits have been applied with success to mood disorder treatment. Although found helpful nearly a decade ago for uncomplicated mania, nimodipine may have particular benefits for those diagnostic subclasses of bipolar disorder most resistant to therapy, e.g., ultra-rapid-cycling bipolars and brief recurrent depressions.

Treatment of depression in comorbid medical illness.

The rate of comorbid depression and medical illness varies from 10 to 40%. Over the years, there has been a paucity of studies completed despite the importance of knowing which antidepressants are the most effective and safest to use in comorbid states. In this review, focus is placed on disorders in these important areas: cardiovascular disease, neurological disorders, diabetes mellitus and cancer. Cardiovascular disease complications can be related in many cases to platelet clumping produced by medications; reductions in morbidity can be achieved by reducing platelet adhesiveness. Specific results have shown sertraline administration to be safe in the post myocardial infarction (MI) state. This is a time of depression-induced increases of 200-300% in mortality. Evidence for safe administration of bupropion, as well as the selective serotonin re-uptake inhibitors (SSRIs) fluoxetine and paroxetine, is also available. The appearance of major depression and diabetes mellitus has been successfully treated with fluoxetine, sertraline and nortriptyline (NTI), however, NTI may lead to a worsening of glucose indices due to its noradrenergic specificity. Regarding neurologic disorders, there is controlled data showing the safety and efficacy of citalopram, sertraline and fluoxetine in post stroke depression. Parkinson's disease has been associated frequently with depression, as might be expected from its characteristic dopamine deficient state. For perhaps the same reason, the agents that can block re-uptake of dopamine i.e., tricyclic antidepressants (TCAs), have been effective in comorborbid depression with Parkinson's disease. In dementia, there is a paucity of information on new agents. However, double-blind data seems to show efficacy for sertraline, paroxetine and citalopram. There are few studies of cancer-related depression treated in a controlled fashion with antidepressants; imipramine, amitriptyline, fluoxetine, paroxetine, mirtazapine and mianserin (not available in the USA) all have support from some published studies.

Summary from the 153rd meeting of the American Psychiatric Association. 13-18 May 2000, Chicago, Illinois, USA.

The annual meeting of the American Psychiatric Association focuses on a variety of topics, including those on psychopharmacology. The latest developments are typically those found in the New Research sections, which is where this summary will focus.

Women's issues in mood disorders.

Since the introduction of antidepressants in the 1950s, it was assumed for the next several decades that there were no special reasons to look at the application of these medications to women. In the past half-century, particularly in the past decade, since the advent of the selective serotonin re-uptake inhibitors (SSRI), a series of specific foci have developed. Firstly, there appear to be differences in the degree of response to particular antidepressants between the genders. Secondly, there is data concerning hormonal effects of particular relevance to women, i.e. prolactin, which separates out among the antidepressants. Also of concern to women are the potential teratogenic effects of these medications, which impact on their use during pregnancy. Finally, there are certain diagnostic syndromes that are particularly relevant to women: premenstrual dysphoric disorder (PMDD); postpartum depression (PPD) and perimenopausal depression (PMD). It appears that the SSRIs may be more effective, relative to the older tricyclic antidepressants (TCA), in women than in men. The SSRIs have shown to be effective in treating these disorders, with the possibility of intermittent luteal phase treatment of PMDD. Non-antidepressant (AD) approaches have generally been found to be less effective. In the first trimester of pregnancy, there is data available supporting the safe use of SSRIs, particularly those first released, i.e. fluoxetine and sertraline. Finally, all SSRIs, with the exception of sertraline, can increase the risk of hyperprolactinaemia. This can lead to a variety of complications including amenorrhea and osteoporosis. This effect of sertraline, due to its unique profile in blocking re-uptake of dopamine, extends itself into additional relative benefits for sleep and memory. The issues associated for women with bipolar disorder are dealt with in terms of both increased risk of relapse during pregnancy and postpartum periods, as well as the relative risk of use of lithium and mood stabilizers in pregnancy and lactation.

Mirtazapine in major depression with comorbid generalized anxiety disorder.

BACKGROUND: A high proportion of patients with generalized anxiety disorder (GAD) have comorbid depressive illness. The presence of anxiety in depression has significant prognostic implications. Because of mirtazapine's early anxiolytic effects, the present study was undertaken as a preliminary investigation in patients with a diagnosis of major depression with comorbid GAD. METHOD: Mirtazapine was administered to 10 patients with DSM-IV major depressive disorder and comorbid GAD in an 8-week open-label study. Mirtazapine was increased from an initial daily dose of 15 mg to a maximum daily dose of 45 mg. RESULTS: Patients were found to have significant reductions in Hamilton Rating Scale for Depression scores, Hamilton Rating Scale for Anxiety scores, and Beck Depression Inventory scores, with improvement noted after the first week of therapy and continuing improvement over the 8 weeks of study. CONCLUSION: These positive preliminary findings support the further investigation of mirtazapine's potential value as a treatment for generalized anxiety disorder in addition to its established efficacy as an antidepressant drug.

Psychopharmacology of depression in the next millennium.

Over the last half of the 20th century, there have been a series of psychopharmacologic strategies for treatment of depression. As we approach the next century, new therapies in varying stages of American release are being developed. This review will focus on information available for the following proposed antidepressants: 1) reboxetine, a norepinephrine selective reuptake inhibitor; 2) milnacipran, a combined serotonin/norepinephrine reuptake inhibitor; 3) a new enantiomer of fluoxetine, a selective serotonin reuptake inhibitor; 4) duloxetine, another combined serotonin/norepinephrine reuptake inhibitor; 5) sunepitron, a combined 5-HT1A agonist and a2 antagonist; and 6) MK-869, a substance P inhibitor. Finally, other possible developing directions will be reviewed, including corticotropin-releasing factor.

Selective serotonin reuptake inhibitors in affective disorders--I. Basic pharmacology.

The selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, are the result of rational research to find drugs that were as effective as the tricyclic antidepressants but with fewer safety and tolerability problems. The SSRIs selectively and powerfully inhibit serotonin reuptake and result in a potentiation of serotonergic neurotransmission. The property of potent serotonin reuptake appears to give a broad spectrum of therapeutic activity in depression, anxiety, obsessional and impulse control disorders. However, despite the sharing of the same principal mechanism of action, SSRIs are structurally diverse with clear variations in their pharmacodynamic and pharmacokinetic profiles. The potency for serotonin reuptake inhibition varies amongst this group, as does the selectivity for serotonin relative to noradrenaline and dopamine reuptake inhibition. The relative potency of sertraline for dopamine reuptake inhibition differentiates it pharmacologically from other SSRIs. Affinity for neuroreceptors, such as sigma1, muscarinic and 5-HT2c, also differs widely. Furthermore, the inhibition of nitric oxide synthetase by paroxetine, and possibly other SSRIs, may have significant pharmacodynamic effects. Citalopram and fluoxetine are racemic mixtures of different chiral forms that possess varying pharmacokinetic and pharmacological profiles. Fluoxetine has a long acting and pharmacologically active metabolite. There are important clinical differences among the SSRIs in their pharmacokinetic characteristics. These include differences in their half-lives, linear versus non-linear pharmacokinetics, effect of age on their clearance and their potential to inhibit drug metabolising cytochrome P450 (CYP) isoenzymes. These pharmacological and pharmacokinetic differences underly the increasingly apparent important clinical differences amongst the SSRIs.