A review of the use of augmentation therapy for the treatment of resistant depression: implications for the clinician

OBJECTIVE: To critically review the literature on augmentation therapy in resistant depression in order to assist the clinician to make a reasoned choice. Augmentation therapy is defined as the addition of a second agent to an existing antidepressant regimen with the aim of achieving improved clinical response. METHOD: The available literature which related specifically to currently popular augmentation strategies in treatment resistant depression for the past 20 years was examined. The scientific evidence supporting the efficacy of these regimens and their safety was reviewed. RESULTS: Considerable research on lithium augmentation has been undertaken, and on triiodothyronine augmentation to a lesser degree. A number of other drugs have been trialed as augmentation agents with claims of success; however, most of the evidence supporting these agents is anecdotal and in the form of case reports. There are very few well-performed double-blind placebo-controlled studies of augmentation therapy. CONCLUSIONS: Because of possible complex pharmacodynamic and pharmacokinetic interactions, augmentation therapy is not without its potential complications. Lithium augmentation of tricyclic antidepressants can be recommended as a safe and effective strategy and there is a body of scientific evidence supporting the addition of T3 as an effective augmentation agent. Recent research with pindolol augmentation of selective serotonin re-uptake inhibitors (SSRIs) is encouraging, but these findings require replication. There is no empirical evidence supporting buspirone, carbamazepine, sodium valproate, methylphenidate or amphetamine as effective augmentation agents, or that adding a tricyclic to a SSRI has usefulness in relieving depressive symptoms. There is a need for considerable research in this area, with more prospective well-controlled placebo studies.     

Neurobiological mechanisms involved in antidepressant therapies

Selective serotonin reuptake inhibitors (SSRIs) are effective in alleviating the symptoms of depression. However, clinical improvement is only obtained after several weeks of treatment. SSRIs, when administered acutely to animals, have little effect on synaptic levels of serotonin. This suggests the existence of one or more regulatory mechanisms controlling serotonergic neurotransmission. The firing rate of dorsal raphe serotonergic neurons is under the control of somatodendritic 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, the release of serotonin from nerve terminals is under the control of 5-HT autoreceptors (5-HT1B subtype in rodents, 5-HT1D in other species), whereas the control of the activity of tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis, is complex, involving 5-HT1A but possibly other 5-HT receptors including the 5-HT1B/D subtype. During prolonged administration with a SSRI, these three feedback systems become desensitized and their regulatory effects on serotonergic neurotransmission are weakened or lost. This has the effect of allowing the synaptic levels of serotonin to rise with a consequently increased stimulation of one or more types of postsynaptic 5-HT receptor. Thus, it is only after prolonged administration that the pharmacological activity of SSRI is fully expressed in terms of synaptic serotonin levels. This may explain the latency of antidepressant action seen with these drugs in humans. Various other classes of antidepressant therapies (tricyclic antidepressants and monoamine oxidase inhibitor drugs, electroconvulsive therapy) have long-term effects on one or more of the feedback mechanisms such that an increase in synaptic concentrations of serotonin may be a common mechanism of many antidepressant therapies.     

Combination therapies in antidepressive drug refractory depression--an overview

Despite the availability of a wide range of effective antidepressant drugs, nearly 30% of depressed patients fail to respond to antidepressant treatment. Various pharmacological strategies have been developed to treat such refractory depression, of which augmentation therapies are one of the most important. This article reviews both benefits and risks of all known augmentation therapies. Among these treatment strategies the efficacy of lithium augmentation is very well documented by a large number of controlled studies - lithium augmentation can therefore be recommended in depression refractory to antidepressant treatment. The efficacy of triiodothyronine (T3) augmentation and the combination of different antidepressants - like a TCA-MAOI combination - is described in a large number of case reports and uncontrolled studies; the number of placebo controlled double blind studies, confirming the efficacy of these treatment strategies, is however relatively small. T3 augmentation and combined antidepressant treatment may therefore be considered in the treatment of refractory depression; in contrast to lithium augmentation these combination therapies are however only second-line strategies. Other augmentation therapies (TCA + stimulants, TCA + reserpine, TCA + yohimbine, TCA + fenfluramine, SSRI + buspirone) are very interesting clinical research strategies, but don't have too much importance in clinical practice at the moment.     

Paroxetine. A review of its pharmacology, therapeutic use in depression and therapeutic potential in diabetic neuropathy

Paroxetine is a selective serotonin reuptake inhibitor effective in a once-daily administration regimen in the treatment of depression. In elderly patients (aged > or = 60 years) with major depression, short term (6 weeks) treatment with paroxetine produces clinical improvements significantly superior to those seen with placebo and similar to those with tricyclic antidepressant agents, mianserin and fluoxetine. There is evidence that paroxetine has positive effects on co-existing anxiety and does not precipitate agitation. Paroxetine has also shown potential in the symptomatic treatment of diabetic neuropathy; however, further clinical experience is needed to confirm this preliminary result. Short term paroxetine therapy is associated with fewer anticholinergic and CNS adverse effects, but generally more gastrointestinal disturbances, than tricyclic antidepressants and mianserin. Unlike the tricyclic agents, paroxetine does not significantly affect cardiovascular function or impair psychomotor performance. This tolerability profile should be particularly beneficial in elderly patients, who are generally more susceptible than younger patients to the anticholinergic and CNS adverse events associated with tricyclic antidepressant drugs, and in whom there is a higher prevalence of pre-existing cardiovascular disease. It also suggests an important potential advantage over tricyclic antidepressants in the setting of overdosage. Thus, primarily because of its better tolerability profile and potentially lower toxicity in overdosage and in patients with cardiovascular disease, paroxetine appears to be a more attractive option than tricyclic antidepressants for the treatment of depression in late life. Future research should attempt to define more fully the efficacy of paroxetine as long term prophylactic therapy for recurrent depression and to assess how its overall therapeutic profile compares with other selective serotonin reuptake inhibitors in the elderly.     

Pharmacotherapy for obsessive-compulsive disorder

BACKGROUND: Pharmacotherapy for obsessive-compulsive disorder (OCD) was seldom beneficial before clomipramine, a potent selective serotonin reuptake inhibitor (SSRI), became available. Subsequent progress in pharmacotherapy for OCD has increased the possibility of effective treatment for most sufferers. METHOD: Randomised controlled trials of pharmacotherapy for OCD were reviewed, as well as reports of beneficial pharmacotherapy found in open trials and case reports. RESULTS: SSRIs are well-tolerated by patients with OCD, even in large doses. Proserotonergic augmentation is seldom helpful but antipsychotic augmentations seem beneficial for many OCD patients with comorbid tics. CONCLUSIONS: Potent SSRIs are the pharmacotherapy of choice for OCD, with a more limited role reserved for monoamine oxidase inhibitors. If one SSRI is ineffective, others may be beneficial. Non-drug therapies are also important in OCD: behaviour therapy is frequently helpful but infrequently available and neurosurgery is sometimes helpful when all other treatments have failed.     

Cost effectiveness study of a year follow-up of selective serotonin reuptake inhibitor (SSRI) and augmentor combination compared with SSRI and placebo

We describe a method for evaluating the value of increased cost of pharmacological augmentation that, taken for 6 weeks, accelerates the action of an antidepressant. We test the hypothesis that, if onset of action is taken into account, any added direct costs of the augmenting agent are offset by longer term cost effectiveness. Data to illustrate the method were based on a double-blind randomized placebo controlled study, in which 80 patients originally took part. Patients received the selective serotonin reuptake inhibitor (SSRI) antidepressant paroxetine and an augmenting agent (pindolol) or placebo. After 6 weeks, patients were offered SSRI alone on an open label basis for up to 6 months. At that point they were discharged to their general practitioner or local psychiatric services and subsequently assessed by us at one year. We have used techniques of decision analysis, cost effectiveness and cost benefit and have included a sensitivity analysis. The direct costs over one year of SSRI and augmenting agent, if taking the acceleration effect into account, represented greater cost effectiveness than the SSRI antidepressant alone. The cost effectiveness analysis was positive in both cases. We conclude that the direct costs of treatment are higher than those of previous calculated with SSRIs; but the rate of onset must be taken into account. The application of the model appears valid and useful, and may be used as part of the evaluation of other augmentation regimes.     

Paroxetine and galactorrhea

The authors report a case of galactorrhea following antidepressant treatment where paroxetine might be responsible. Paroxetine is a selective serotonergic reuptake inhibitor (SSRI). Galactorrhea occasionally is a dopamine-mediated side effect observed with neuroleptic drugs. However, the ability to produce extrapyramidal side effects is known for tricyclic as well as for SSRIs. Thus the potential of SSRIs to induce dopamine-dependent side effects is a clinical reality and it was not surprising to observe galactorrhea due to paroxetine. However, in a review of the literature no reported cases of galactorrhea associated with paroxetine were found.     

Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors

The recently introduced antidepressants, the selective serotonin reuptake inhibitors (SSRIs) [citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline], are known for their clinical efficacy, good tolerability and relative safety. They differ from each other in chemical structure, metabolism and pharmacokinetic properties. Therapeutic drug monitoring of these compounds is not widely used, as the plasma concentration ranges within which clinical response with minimal adverse effects appears to be optimal are not clearly defined. Almost all recent assays developed for the quantitative determination of SSRIs and their metabolites in blood are based either on the separation of SSRIs by high performance liquid chromatography (HPLC) or gas chromatography (GC). Citalopram and fluoxetine have been introduced as racemic compounds. There are some differences in the pharmacological profile, metabolism and pharmacokinetics between the enantiomers of the parent compounds and their demethylated metabolites. Stereoselective chromatographic methods for their analysis in blood are now available. With regard to the SSRIs presently available, no clearcut plasma concentration-clinical effectiveness relationship in patients with depression has been shown, nor any threshold which defines toxic concentrations. This may be explained by their low toxicity and use at dosages where serious adverse effects do not appear. SSRIs vary widely in their qualitative and quantitative interaction with cytochrome P450 (CYP) isozymes in the liver. CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs. There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A. Fluvoxamine strongly inhibits the N-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients. Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in promoting a serotonin syndrome. A combination of moclobemide and fluvoxamine has successfully been used in refractory depression, but more studies are needed, including plasma-concentration monitoring, before this combined treatment can be recommended. Paroxetine is a substrate of CYP2D6, but other enzyme(s) could also be involved. Its pharmacokinetics are linear in poor metabolisers of sparteine, and non-linear in extensive metabolisers. Due to its potent CYP2D6 inhibiting properties, comedication with this SSRI can lead to an increase of tricyclic antidepressants in plasma, as shown with amitriptyline and trimipramine. CYP3A has been claimed to be involved in the biotransformation of sertraline to norsertraline. Clinical investigations (with desipramine) confirmed in vitro findings that CYP2D6 inhibition by sertraline is only moderate. (ABSTRACT TRUNCATED)     

Buspirone augmentation of antidepressant therapy

Thirty outpatients meeting DSM-III-R or DSM-IV criteria for major depression, single or recurrent episode, and failing to respond to an adequate trial of an antidepressant (>6 weeks at recommended dosage) received buspirone (20-30 mg/day) for 4 or 5 weeks in addition to their existing antidepressant. Of the 22 patients who had buspirone added to their selective serotonin reuptake inhibitor antidepressant regimen (fluoxetine, paroxetine, or citalopram), 59% (13/22) showed complete or partial remission of their depressive symptomatology. Similarly, 63% (5/8) of patients treated with buspirone in addition to clomipramine showed complete or partial remission. The mean score on the Clinical Global Impressions Scale fell by 64% (from 4.7 to 1.7; p < 0.0001) in treatment responders (complete and partial). No serious side effects were observed during combination therapy. Seventy-nine percent (11/14) of initial responders (both complete and partial) who remained on augmentation therapy for at least 4 months were symptom-free at follow-up. Buspirone augmentation may produce marked clinical improvement in depressed patients who are initially unresponsive to standard antidepressant therapy.     

Rapid conversion from one monoamine oxidase inhibitor to another

BACKGROUND: Numerous sources state that switching from one monoamine oxidase (MAO) inhibitor to another can be done only after a 14-day washout period. In hospitalized patients and severely depressed outpatients, such a wait may be impracticable. METHOD: We reviewed the case histories of eight consecutive and random patients whom we converted from one MAO inhibitor to another within less than the recommended waiting period. RESULTS: Only one patient experienced troubling adverse effects, and these effects were brief and time-limited. The patient's symptoms were indicative of either withdrawal from tranylcypromine or a mild serotonin syndrome. All other patients tolerated the conversion well with minimal or no adverse effects. Four of the eight patients eventually responded to the new MAO inhibitor. CONCLUSION: These results suggest that some patients can be cautiously but rapidly switched from one MAO inhibitor to another without prolonged drug-free periods. Unquestionably, this strategy should be used only when the clinical picture mandates a rapid conversion. Further, it should be reserved for those patients with established high compliance and should include close monitoring and the use of a low-tyramine diet. Extreme caution must still be undertaken in utilizing this approach until larger studies more accurately determine the frequency of serious adverse effects.     

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.     

Management of the depressive component of bipolar disorder

Acute bipolar depression (ABD) and breakthrough depression occurring during maintenance therapy of bipolar disorder are associated with significant morbidity and an increased risk of suicide. Lithium is an effective mood stabilizer for ABD, but its onset of antidepressant action is slow and additional antidepressant therapy is often prescribed. The extent to which other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant activity is unclear. Preliminary initial research suggests three potential advantages that selective serotonin reuptake inhibitors have over tricyclic antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a lower frequency of antidepressant-induced mania. Bupropion may also have significant advantages. However, further research is needed to confirm these findings. Monoamine oxidase inhibitors are the antidepressant of choice for atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest response rate of all treatments for ABD. Further research is needed to explore combination treatments with mood stabilizers and antidepressants for the effective treatment of ABD.     

Epidemiology and treatment of post-stroke depression

Depression is a common and serious complication after stroke. According to epidemiological studies, at least 30% of stroke patients experience depression, both early and late after stroke. However, in clinical practice only a minority of the patients are diagnosed and even fewer are treated. There are several studies confirming the magnitude of the problem but the main conclusion which can be drawn from the few treatment studies published is that tricyclic antidepressants cannot be recommended for the treatment of post-stroke depression, mainly because of the high frequency of contraindications and adverse effects. Until now there has only been 1 double-blind, placebo-controlled treatment study from which some general conclusions can be drawn. The study evaluated a selective serotonin reuptake inhibitor (citalopram) and concluded that the drug was well tolerated and effective for the treatment of post-stroke depression. However, when treatment was initiated very early, both the treatment group and the placebo group improved equally during the first 7 weeks after stroke. This finding could indicate diagnosis difficulties during the first few weeks after stroke. A recent study, although small, comparing the combination of drugs with either noradrenergic (desipramine plus mianserin) or noradrenergic and serotonergic effects (imipramine plus mianserin) for post-stroke depression, indicated that drugs with the dual effect may be more effective. Many more double-blind placebo-controlled treatment studies and studies comparing the efficacy and adverse effects of various antidepressants in patients with post-stroke depression need to be conducted. According to 3 small studies, electroconvulsive therapy (ECT) seems to be quite well tolerated and therefore ECT may also be considered in the treatment of post-stroke depression. Future studies should also address the long term efficacy of treatment for post-stroke depression.     

Lithium neurotoxicity at low therapeutic doses Hypotheses for causes and mechanism of action following a retrospective analysis of published case reports

Lithium has been the pharmacologic treatment for the management of manic-depressive illness for many years. While the therapeutic efficacy of lithium is invaluable, it can cause a variety of neurotoxicities at normal therapeutic doses or concentrations. A systematic search through the Medline database was performed. 41 Cases of neurotoxic adverse effects of lithium at low therapeutic concentrations were observed (< 65 years, 14 males & 21 females/> 65 years, 6 females). Although a higher percentage of female subjects experienced lithium neurotoxicity, no statistically significant difference between the two groups was noted (Fisher's exact test, P = 0.07). The analysis of the data shows that among case reports of lithium neurotoxicity, drug interaction effect is an important factor. More than 50% (51.2%) of the patients received at least one neuroleptic medication with their lithium treatment, 22% received concomitantly an antidepressant, 22% an antiepileptic (carbamazepine) and 17% an anxiolytic. It is our hypothesis that these drug associations are an important contributing factor to lithium neurotoxicity. The high percentage of neurotoxicity which is associated with neuroleptics warrant caution in the daily clinical practice when these two classes of medications are combined. It is hypothesised that neuroleptics, in particular the phenothiazines, might increase lithium influx in red blood cells and that the enhanced levels of lithium in the tissue may possibly be responsible for the neurotoxic effects. Concomitant administration of medications such as neuroleptics with lithium require caution with regular clinical observations and drug plasma concentration monitoring.     

A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression

BACKGROUND: Case reports and open studies have reported beneficial therapeutic effects of adding buspirone to a selective serotonin reuptake inhibitor (SSRI) in the management of treatment-refractory depression. This is the first placebo-controlled study to evaluate the efficacy and safety of this combination. METHOD: One hundred nineteen patients (82 women, 37 men) who fulfilled criteria for a major depressive episode according to DSM-IV and who had failed to respond to a minimum of 4 weeks (mean = 211 days) of treatment with citalopram or paroxetine were randomly assigned to 4 weeks of treatment with an SSRI plus buspirone (N = 58) or an SSRI plus placebo (N = 61). In addition, 97 patients participated in an optional open-label poststudy treatment phase with the SSRI plus buspirone for 2 weeks. The primary outcome measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale. RESULTS: A total of 50.9% of patients in the buspirone group and 46.7% in the placebo group responded after 4 weeks of treatment. The difference in response rate was not statistically significant. No statistically significant differences were found in the frequency of adverse events. At the follow-up of the open SSRI plus buspirone treatment, 69.4% of patients had responded. CONCLUSION: Adding buspirone to an SSRI is a safe and well-tolerated drug regimen. This study failed to demonstrate any difference in efficacy between buspirone or placebo augmentation of an SSRI. It could be argued, however, that the study was inconclusive due to the unusually high placebo response.     

Antidepressant overdoses and resultant emergency department services: the impact of SSRIs

Suicide is a major source of morbidity and mortality in patients with mental illness. The selective serotonin reuptake inhibitors (SSRIs) and other newer nontricyclic antidepressants appear to have less clinically significant toxicity in overdose, resulting in lower costs of treatment when compared with tricyclic antidepressant (TCA) overdoses. The resource utilization and cost of treatment for SSRI overdoses may not be less if (1) these agents are commonly ingested with other potentially toxic substances, or (2) health care practices have not changed in response to the apparent greater safety of SSRIs. This study evaluates demographic variables of antidepressant overdoses to determine whether differences exist in treatments and monitoring. Additionally, this study evaluates costs associated with care and the impact of co-ingestants on those same factors.     

Moclobemide. An update of its pharmacological properties and therapeutic use

Unlike older monoamine oxidase inhibitors, which irreversibly and nonselectively bind monoamine oxidase (MAO), moclobemide is a reversible and selective inhibitor of the MAO-A isozyme. Moclobemide only weakly potentiates the pressor response induced by tyramine or other indirectly acting sympathomimetics; therefore, there is no need to avoid dietary tyramine or over-the-counter decongestants with moclobemide as there is with older MAO inhibitors. Recent clinical trials and meta-analyses have confirmed the efficacy of moclobemide in the treatment of depressive disorders. Moclobemide has been shown to have similar efficacy to tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and nonselective, irreversible MAO inhibitors. Long term follow-up studies of 6 to 12 months' duration have demonstrated that the antidepressant efficacy of moclobemide is maintained. Moclobemide, given alone or in combination with another antidepressant, has shown some efficacy in patients with refractory depression; however, comparative trials are required to confirm these findings. Data are also available to show clinical efficacy of moclobemide in the management of social phobia. Comparative studies have established that moclobemide is better tolerated at therapeutic dosages and has less toxicity in overdose than TCAs and nonselective, irreversible MAO inhibitors. Moclobemide lacks the anticholinergic, sedative and cardiovascular effects associated with many of the older antidepressants. Compared with SSRIs, moclobemide has a similar overall tolerability, although it tends to cause fewer gastrointestinal effects than the SSRIs and has not been reported to interfere with sexual function. In summary, recent data which confirm and extend its comparative therapeutic efficacy and low potential for adverse effects have established moclobemide as an effective treatment in depressive disorders. The drug is also effective in patients with a primary diagnosis of social phobia. Its lack of adverse anticholinergic, cardiovascular, cognitive and psychomotor effects makes moclobemide a particularly useful option in the elderly or patients with cardiac disease.     

Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response

It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.     

Hyponatremia as a side effect of serotonin uptake inhibitors

Hyponatraemia is a possible, potentially serious adverse reaction to treatment with selected serotonin re-uptake inhibitors (SSRIs). The article consists in a review of the 27 cases of such reactions that have been reported to the Swedish Medical Products Agency. The data from these reports suggest the risk of hyponatraemia to be particularly manifest during the first few weeks of treatment, and to be greater in women, the elderly, and patients concomitantly treated with diuretics. In the event of vague, non-specific symptoms occurring in conjunction with SSRI treatment, measurement of the serum sodium concentration is recommended.