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Third-generation antidepressants: do they offer advantages over the SSRIs?

Third-generation antidepressants are a group of antidepressant agents of variable action, not confined to serotonin reuptake inhibition. These agents include venlafaxine, reboxetine, nefazodone and mirtazapine. Claims have been made for these agents in terms of improved efficacy, faster speed of onset of effect and greater safety in the treatment of depression compared with previous medications, such as the selective serotonin reuptake inhibitors (SSRIs). This article reviews the evidence for these improvements. Thirty active comparator studies were reviewed involving the third-generation antidepressant agents. While there were isolated reports of improvements over comparator agents for venlafaxine, reboxetine and mirtazepine, there were no convincing differences between third-generation agents and comparators in terms of overall efficacy, relapse prevention and speed of onset. The third-generation antidepressants were, however, of equivalent safety to SSRIs and maintained improvements in safety over first-generation agents.

Antidepressive Agents↗

[Indications for new antidepressants with reference to ICD-10: a waggish question or the future of psychiatry?].

The biological psychiatry's postulate is that depression is related to a lack of balance between the dopaminergic, noradrenergic and serotonergic monoaminergic neurotransmitters systems. These systems are related to cortico-striatal-thalamo-cortical circuits, involving the association and limbic prefrontal cortex and the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus). The pharmacology of depression recently grows rich from "new" antidepressive agents, having selective monoaminergic activity: Selective Serotonin presynaptic Reuptake Inhibition ("SSRIs"), selective Reversible Inhibition of the Monoamine oxidase A ("RIMAs"), selective dopaminergic or noradrenergic agents. The last International Classification of mental and behavioural Disorders proposed by the World Health Organisation: the ICD-10, proposes a "new" classification of the depressive disorders based on atheoric "practical" diagnostic criteria. These criteria are unrelated to neurobiochemical, neuroanatomical or neurophysiological data. Reviewing the diagnostic criteria of depressive disorders proposed by the ICD-10 in relation to the neuroanatomic structures subtending the monoaminergic theory of the depressions, the author attempts to answer to the question: is the "new" pharmacology of the depressions that constitute the "new" antidepressants blind or correlable to the "new" nosology of the depressive disorders proposed by the ICD-10? Finally, indications in first intention of the "new" antidepressive agents for each depressive disorder defined by the ICD-10 are proposed.

Antidepressive Agents↗

Antidepressants in the general hospital.

An approach to the use of antidepressant medication in the general hospital is presented. The type of depression most likely to respond to chemotherapy is described, categories of available antidepressant agents are discussed, and relevant pharmacologic aspects are outlined. This paper suggests clinical guidelines for the use of these drugs, particularly in medical and surgical patients.

Aged↗

Postpartum and nonpostpartum depression: differences in presentation and response to pharmacologic treatment.

Following childbirth, major depression (postpartum depression) affects approximately 8-12% of new mothers. However, little is known about the pharmacological management of postpartum depression, and no studies to date have assessed differences in treatment response between women with postpartum and nonpostpartum major depression. The authors reviewed the records of 26 women with postpartum major depression and 25 women with major depression unrelated to childbearing (nonpostpartum depression) who presented to them for treatment over a 4-year period. Compared with the nonpostpartum depressed patients, the postpartum depressed women were significantly more likely to present with anxious features. Also, cases of postpartum depression were more severe than cases of nonpostpartum depression. While the postpartum patients were equally as likely to recover (as defined by a Clinical Global Impression score of 1 or 2) compared to the nonpostpartum-depressed patients, their time to response was significantly longer. By 3 weeks of pharmacotherapy, 75% of the nonpostpartum cases had recovered, in contrast to only 36% of the postpartum cases. Further, postpartum patients were significantly more likely to be receiving more than one antidepressant agent at the time of response to treatment. Length of depression prior to treatment did not explain the difference in treatment response. Presence of depressive symptoms during pregnancy and timing of onset of the depression (before vs. after 4 weeks of delivery) did not affect likelihood of treatment response in this sample. Women with postpartum depression appear to be significantly more likely than the nonpostpartum women to present with anxious features, take longer to respond to pharmacotherapy for depression, and require more antidepressant agents at the time of response to treatment.

Adult↗

Dual effects of bryostatin-1 on spatial memory and depression.

Dementia and depression are clinical symptoms commonly associated in patients. Emerging evidence suggests that the two diseases share many profiles in their development and underlying neural/molecular mechanisms. Thus, interest is raised in developing new classes of antidepressant agents with activity of cognitive enhancement. Here, we show that bryostatin-1, a protein kinase C substrate activator, at bilateral intracerebroventricular doses of 0.64 or 2 pmol/site, significantly enhanced learning and memory of rats in a spatial water maze task. When applied at the doses at which it exhibits memory-enhancing activity, bryostatin-1 showed a significant antidepressant activity, as determined in an open space swim test. Both effects were not observed when a smaller dose was administered and were largely eliminated by co-administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a protein kinase C inhibitor. These results support the hypothesis that memory processing and mood regulation share common neural mechanisms. Restoring impaired mood regulation with antidepressant agents that also exhibit memory-enhancing activity may represent one of the new strategies in the fight against depression associated with memory impairments.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

Antidepressant medication in the treatment of bulimia nervosa.

Antidepressant therapy has been shown to be efficacious in the treatment of bulimia nervosa, a serious eating disorder that can be associated with substantial morbidity and mortality. Seven antidepressant drugs have been tested in double-blind, placebo-controlled studies. Five of these studies demonstrated strongly positive findings, one a weakly positive finding, and one a negative finding. However, inadequate doses of medication may have been used in the latter two studies. In all of the positive studies, antidepressant agents appeared effective even in bulimic subjects who did not display concomitant depression, indicating that this treatment modality should not be reserved only for depressed bulimic patients. Although not yet tested in double-blind studies, trazodone also appears effective in the treatment of bulimia nervosa. Results from one large open study suggested that trazodone has comparable efficacy to the tricyclic antidepressant agents. Trazodone would be a particularly attractive treatment for bulimia nervosa because of its low anticholinergic side-effects profile; placebo-controlled studies are required, however, before definitive recommendations can be made.

Antidepressive Agents↗

An open study of methylphenidate in bipolar depression.

BACKGROUND: The treatment of bipolar depression is problematic. Mood stabilizing agents are often inadequate, while antidepressants may induce mania or mood destabilization. Methylphenidate has been advocated as an effective antidepressant agent in unipolar depression, and depression secondary to medical illness. Amphetamine administration has been shown to reduce manic behavior. These independent observations suggest that methylphenidate may be a safe and effective agent in bipolar depression. METHODS: Fourteen depressed subjects with DSM-IV bipolar illness and a Hamilton-depression (HAM-D) scale score of at least 15 had methylphenidate added to a stable mood stabilizer regiment. Patients were followed weekly for 4 weeks and then biweekly for an additional 8 weeks. RESULTS: HAM-D scores dropped from 16.9 +/- 1.79 SD at baseline to 9.4 +/- 9.73 on week 12 (p = 0.12, t = 1.84, df= 6) and 9.8 +/- 7.56 on last observation carried forward (LOCF) (p = 0.019, t = 2.8, df = 10). Psychiatric symptom assessment scale (PSAS) scores dropped from 17.9 +/- 5.63 at baseline to 4.8 +/- 7.47 at week 12 (p = 0.016, t = 4.02, df= 4) and 6.3 +/- 6.75 on LOCF (p = 0.007, t = 3.74, df = 7). Three individuals stopped secondary to anxiety, agitation, and hypomania, respectively. CONCLUSION: In this brief, open study, methylphenidate was effective and relatively safe in depressed bipolar subjects.

Adult↗

Women and bipolar disorder: an update.

The major clinical challenges facing women with bipolar illness, and the practitioners who care for them, are the management of rapid cycling and of the postpartum period. Among patients with rapid cycling bipolar disorder, the treatment of depression is particularly problematic. The most commonly prescribed mood stabilizers are more potent antimanic than antidepressant agents, and the use of antidepressants may precipitate mania or rapid cycling. The availability of new anticonvulsant medications that may have both mood-stabilizing and antidepressant effects is an important development in this regard. In the postpartum period, women with bipolar illness are at uniquely high risk for relapse. The possible reasons for this high risk, and options for the management of pregnancy and the postpartum period in bipolar women, are discussed.

Antidepressive Agents↗

When at first you don't succeed: sequential strategies for antidepressant nonresponders.

Now, more than ever before, a wealth of options exists for depressed patients who do not benefit from treatment with standard, first-line antidepressant agents. In this paper, alternate antidepressant strategies are reviewed within the context of a five-stage strategy, ranging from lesser to greater degrees of treatment resistance. The overall strategy recommended progresses from simpler (i.e., an alternate monotherapy) to more complex strategies (i.e., combination or augmentation regimens), with the nonselective monoamine oxidase inhibitors (+/- lithium salts) and electroconvulsive therapy typically reserved for treatment of Stages III and IV of resistance, respectively. Psychotherapeutic management also is an important ingredient in the ongoing treatment of these patients, particularly to counteract the demoralization and frustration that understandably accompany the failure to respond to so many treatments.

Antidepressive Agents↗

Interaction of neuroleptics and antidepressants with rat brain alpha 2-receptors: a possible relationship between alpha 2-receptor antagonism and antidepressant action.

The relative potencies of a variety of neuroleptic drugs and antidepressant agents in competing for the binding of 3H-clonidine and 3H-yohimbine to alpha 2-adrenergic receptors of the rat cerebral cortex were quantified. The rank order of potencies of neuroleptics tested in competing for both ligand bindings is: clocapramine, carpipramine much greater than perphenazine, fluphenazine, alpha,beta-flupentixol greater than propericiazine, levomepromazine greater than chlorpromazine, pimozide greater than moperone much greater than haloperidol, sulpiride. Among the antidepressants, mianserin is the most potent antidepressant. Amitriptyline has a substantial affinity, while desipramine, imipramine, and clomipramine are the least potent. It is concluded that a number of neuroleptics and antidepressant agents display a potent or moderate affinity to alpha 2-receptor sites. These findings support the suggestion that some neuroleptics enhance the release of norepinephrine (NE) mainly by acting on presynaptic alpha 2-receptors, and that the alpha 2-receptor blocking property may have an important role in the mechanism of the antidepressant effect of some neuroleptic compounds.

Animals↗

The cost of antidepressant overdose.

Ninety percent of suicide attempts referred to a general hospital are by self-poisoning. Among women, drug overdose is the commonest means of suicide. In a retrospective naturalistic review of 200 patients who were treated in the Critical Care Unit of a general hospital following medication overdose, 12% were antidepressant overdoses. The mean duration of hospital stay for overdose with tricyclic antidepressants (TCA) was more than double that for overdose with selective serotonin reuptake inhibitors (SSRI) (7 vs 3 days; z = 2.20, p < 0.05). The dollar cost of hospital treatment for patients who overdosed on TCAs was four times greater than that for patients who overdosed on SSRIs ($22,923 vs $5,379; z = 2.30, p < 0.05). The tricyclic compounds clearly have a price advantage over more recently introduced antidepressant agents fluoxetine, sertraline, paroxetine, venlafaxine, and bupropion. The apparent cost advantage of prescribing a less expensive drug may be nullified by the cost associated with adverse consequences.

Antidepressive Agents↗

Hypertension and depression.

Despite the high prevalence of depression and hypertension, the relationship between the two diseases has received little attention. This paper reviews the epidemiological, pathophysiological, and prognostic aspects of this association, as well as its implications for treatment. A Medline search was conducted using the following key words: depression, blood pressure, blood pressure variability, physical morbidity, hypertension, mood, stress, hypertension, antidepressive agents, and genetics, from 1980 to 2004. We found descriptions of increased prevalence of hypertension in depressed patients, increased prevalence of depression in hypertensive patients, association between depressive symptomatology and hypotension, and alteration of the circadian variation of blood pressure in depressed patients. There is considerable evidence suggesting that hyperreactivity of the sympathetic nervous system and genetic influences are the underlying mechanisms in the relationship between depression and hypertension. Depression can negatively affect the course of hypertensive illness. Additionally, the use of antidepressive agents can interfere with blood pressure control of patients with hypertension by inducing changes in blood pressure and orthostatic hypotension.

Antidepressive Agents↗

S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial.

We report a pilot study of S-adenosyl-methionine (SAM) in 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAM was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale (HDS). One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean HDS score before treatment was 27.09 +/- 6.04 (mean +/- standard deviation) and was 9.55 +/- 7.29 after SAM treatment (p < 0.0001). Although uncontrolled and preliminary, this study suggests that SAM is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease.

Aged↗

Psychiatric symptoms as late onset of Wilson's disease: neuroradiological findings, clinical features and treatment.

We describe a case of Wilson's disease with late psychiatric onset. Major depressive disorder was the first clinical manifestation at the age of 38 years. After pharmacotherapy with antidepressive agents, a manic episode was observed. Extrapyramidal hand tremor and micrography were the first neurological signs. Emotional lability occurred during worsening of extrapyramidal signs. Diagnosis was based on urinary and serum copper levels, ceruloplasmin serum level, Kayser-Fleischer ring, and liver biopsy that detected cirrhosis. Magnetic resonance imaging revealed basal ganglia hyperintensity on T1-weighted images, and hypodensity in the central part and hyperintensity in the peripheral part of the lentiform nucleus on T2-weighted images. Hyperintensity on T2-weighted images was also observed in the dorsal part of the midbrain. 123I-iodobenzamide single photon emission computed tomography (IBZM-SPECT) detected a normal distribution of the drug in the brain, with better signal in the right side and deficit of D2-dopaminergic receptors in the basal ganglia. Abnormal manganese erythrocyte level was observed. Treatment was based on penicillamine, zinc salts, low-copper diet, antidepressant agents, interpersonal psychotherapy and neurorehabilitation.

Adult↗

Binding of some antidepressants to the 5-hydroxytryptamine transporter in brain and platelets.

Antidepressant agents with properties to inhibit 5-hydroxytryptamine (5-HT, serotonin) uptake in brain tissue and platelets bind with high affinities to neuronal and platelet membranes. [3H]Imipramine, [3H]paroxetine and [3H]citalopram label specific binding sites related to the 5-HT transporter. [3H]Paroxetine and [3H]citalopram appear to be better ligands than [3H]imipramine. The former label a homogenous population of binding sites, whereas the displaceable binding of [3H]imipramine is heterogenous. Recent observations in several laboratories, which have taken the heterogeneity of [3H]imipramine binding into account, indicate that the binding of antidepressants to the 5-HT transporter probably occurs to the same site that binds 5-HT for transport and not to a separate site as previously suggested. Additional bonds to subsites in close vicinity to the 5-HT recognition site may contribute to the binding. No convincing evidence has been presented of the existence of an endogenous ligand other than 5-HT itself that binds to the [3H]imipramine binding site. Recent studies also suggest that repeated treatment of rats with antidepressant agents does not produce any alterations of the binding of [3H]imipramine or [3H]paroxetine to membranes of cerebral cortex. It is also doubtful whether the density of the 5-HT uptake site in platelets measured with these ligands is decreased in affective disorders as first reported.

Animals↗

Overview of antidepressants currently used to treat anxiety disorders.

The syndromes of anxiety and depression may reflect separate disorders with overlapping symptoms. They also may be comorbid or reflect illnesses with similar underlying pathophysiology based upon a spectrum of central nervous system dysfunction. Antidepressants effectively treat both anxiety and comorbid anxiety-depression. Tertiary tricyclic antidepressant agents (TCAs) with dual serotonergic-noradrenergic effects, such as imipramine and amitriptyline, appear consistently effective across the anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are particularly effective in panic disorder and obsessive-compulsive disorder. SSRIs are similar in efficacy to TCAs but are more tolerable and cause fewer serious adverse events. However, they are relatively slow to act, and efficacy data are limited in states such as generalized anxiety disorder. Newer antidepressants, such as mirtazapine, nefazodone, and venlafaxine XR, may provide some benefits across the broad spectrum of anxiety disorders with the safety and tolerability that are the hallmarks of third generation antidepressants.

Antidepressive Agents↗

Pharmacology of amineptine: synthesis and updating.

Amineptine is a tricyclic antidepressant agent with the unique capacity to decrease selectively the uptake of dopamine (DA) without affecting the uptake of noradrenaline (NA) and serotonin (5HT). The effect is obtained both in vitro and in vivo by the use of suitable methodology. Amineptine can be differentiated from amphetamine both on the basis of pharmacological as well as biochemical parameters. In vivo, amineptine increases striatal homovanillic acid without affecting the levels of other metabolites of DA, namely, 3, 4, dihydrozoxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT). However, by using relatively high doses of amineptine, the extracellular DOPAC level--assessed by the use of pulse voltammetry--was decreased preferentially in the nucleus accumbens but not in the striatum. Chronic treatment with amineptine, as with other antidepressant agents, induces a down-regulation of beta-adrenergic receptors. Amineptine enters the brain and its pharmacological effects are likely due to the unchanged drug rather than to its two main metabolites.

Animals↗

Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience.

BACKGROUND: Antidepressant agents may have a therapeutic role in functional gastroenterologic disorders, but controlled investigations in irritable bowel syndrome (IBS) have not provided satisfactory practice recommendations. To help with future study design, we reviewed a five-year clinical experience with antidepressant agents in out-patients with IBS. METHODS: Presenting features, treatment course, and clinical outcome were determined from a chart review of 138 patients attending a university-based gastroenterology practice. RESULTS: Patients were treated with up to five antidepressants in separate, consecutive trials if a satisfactory end-point had not been reached. Tricyclic antidepressants were utilized 130 times, newer antidepressants 39 times, and anxiolytic-antidepressants 47 times. Improvement and complete remission in bowel symptoms occurred in 89% and 61% of patients, respectively, during antidepressant therapy. Median dosages being prescribed when remission occurred were less than those conventionally used in clinical psychiatry (50 mg/day for several tricyclic antidepressants). Age, gender, symptom duration, and presence of psychological symptoms did not discriminate those who remitted from those who did not, whereas a pain predominant symptom pattern was more commonly associated with symptom remission (P < 0.05 comparing symptom patterns). Symptom remission was more likely during the first antidepressant treatment than with subsequent trials in the group with continued symptoms (P = 0.01), but nearly half of the patients with side effects or no benefit from the first agent who went on to subsequent trials remitted during treatment with an alternative antidepressant. CONCLUSIONS: The design of this retrospective review is not capable of determining the efficacy of antidepressants for IBS. Our observations in conjunction with other available data suggest that future trials should employ low daily dosages, carefully assess pain response, include patients with and without active psychiatric symptoms, and utilize a second agent for subjects intolerant or unresponsive to the first.

Adolescent↗