***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Depressed out patients ( n = 51 ) resistant to treatment with maprotiline were treated in a blind , r and omized , single-centre study , for 6 weeks with either the reversible and selective monoamine oxidase A-inhibitor ( MAO-A-I ) , brofaromine or lithium addition to maprotiline . The Hamilton Rating Scale for Depression was scored by an independent rater before and after the 6 week treatment period . No significant differences in efficacy were found between the two treatment regimes . In the patients who completed the trial , brofaromine was well tolerated with the exception of insomnia . Anticholinergic effects as well as thyroid dysfunctions ( 17 out of 20 ) were more frequent in the maprotiline/lithium group This open , prospect i ve study investigated the efficacy of lithium augmentation in elderly patients who had failed to respond to a 6-week course of antidepressant medication . Twenty-one patients ( age range , 64 to 88 years ) with DSM-III-R unipolar , nonpsychotic major depression refractory to a 6-week course of nortriptyline , fluoxetine , or phenelzine  underwent a minimum of 2 weeks of lithium augmentation . Five patients had a complete response , 3 had a partial response , and 13 did not respond . Half of the patients developed dose-limiting side effects , most commonly neuromuscular or neurologic . Patients developing side effects were significantly older ( p = 0.05 ) , and there was a tendency for side effects to occur more frequently in patients treated with fluoxetine . The rate of response to lithium augmentation in this elderly population was lower than that reported for most open and controlled studies in younger patients . Possible reasons for this are discussed Thirty-four patients with tricyclic-resistant depressive illness took part in a nine-week , double-blind , placebo-controlled trial of lithium augmentation . In addition to the maximum tolerated doses of their tricyclic antidepressant , the experimental group ( n = 16 ) received 250 mg lithium daily for three weeks , followed by 750 mg lithium daily for six weeks , while the controls ( n = 18 ) received placebo for three weeks followed by three weeks each of 250 mg lithium daily and 750 mg lithium daily . There was no significant difference between placebo and 250 mg lithium for weeks 0 - 3 of the trial . However , there was a significantly greater improvement on the MADRS for weeks 3 - 6 for those subjects on 750 mg lithium than for those on 250 mg lithium . In addition , using a 50 % fall in the HRSD as a criterion of drug responsiveness , 22 % responded to placebo , 18 % to 250 mg lithium , and 44 % to 750 mg lithium . Thus , lithium in normal , but not in low , dose has a significant antidepressant effect in TCA-resistant depression . Further controlled studies using lithium in normal dose in trials which have a greater duration of placebo exposure are required to confirm the lithium augmentation effect Resistance to antidepressant therapy is a common clinical problem in the treatment of affective disorders .  Adjunctive low dose lithium is a promising strategy based on biochemical models and encouraging clinical trials . After a mean duration of 9.2 months of conventional therapy , 16 healthy patients with treatment-resistant depression were treated for a minimum of 2 weeks with either adjunctive lithium or placebo using a double-blind design . We found no difference between the two groups in rate or degree of response . The two most dramatic responses occurred in patients treated with placebo , although 50 % of patients treated with lithium had at least a partial response . The number of patients studied was clearly inadequate to avoid a type 2 error . The cumulative response rate reported in the literature of greater than 60 % , however , suggests that lithium is indeed an effective adjunct in some patients with treatment-resistant depression . Our patients differed from those in other studies in that they were treated with a lower dose of lithium , the duration of conventional antidepressant therapy  was longer , and , finally , they were less depressed and possibly depressed for a longer period . These differences may explain the comparable lithium and placebo responses in this study OBJECTIVE Use of lithium to augment antidepressant medication has been shown to be beneficial in the acute treatment of depression . The authors examined the efficacy of lithium augmentation in the continuation treatment of unipolar major depressive disorder . METHOD Thirty patients with a refractory major depressive episode who had responded to acute lithium augmentation during an open 6-week study participated in a r and omized , parallel-group , double-blind , placebo-controlled trial of lithium augmentation during continuation treatment . After a 2 - 4-week stabilization period following remission , patients were r and omly assigned to receive either lithium or placebo for a 4-month period . Antidepressant medication was continued throughout the study . RESULTS Relapses ( including one suicide ) occurred in seven ( 47 % ) of the 15 patients who received placebo in addition to antidepressants . None ( 0 % ) of the 14 patients who received lithium augmentation with antidepressants suffered a relapse during the double-blind phase of the study . Five of the seven relapsing patients in the placebo group developed a depressive episode , and the other two experienced a manic episode . CONCLUSIONS Lithium augmentation in the continuation phase of treatment of unipolar major depressive disorder effectively protects patients against a relapse .  Patients who respond to lithium augmentation  should be maintained on lithium augmentation for a minimum of 6 months or even longer The authors conducted an open-label study of the efficacy and tolerability of venlafaxine and of lithium augmentation in out patients with depression who were not responding to venlafaxine . Out patients aged 18 to 70 years were eligible if they had a minimum baseline score of 16 on the 17-item Hamilton Rating Scale for Depression ( HAM-D ) .  Patients were started on venlafaxine 37.5 mg twice daily for 1 week . For weeks 2 through 4 , the dose of venlafaxine was increased to 75 mg twice daily , and for weeks 5 through 7 , the dose was further increased to 75 mg three times daily . At the end of the 7-week treatment period , patients with a < 50 % decrease in their HAM-D scores from baseline were given lithium carbonate 600 mg once daily . The dose of lithium carbonate was adjusted to maintain plasma levels in the range of 0.6 to 1.0 mmol/mL. Efficacy was assessed with the 17-item HAM-D , Montgomery-Asberg Depression Rating Scale , and the Clinical Global Impressions Scale . Data were analyzed on an intent-to-treat basis . At the end of the 7-week treatment period , 35 % of patients showed a > or = 50 % decrease in their HAM-D scores from baseline . Lithium augmentation was initiated in 23 patients . The results showed that the addition of lithium was well-tolerated and led to a further decrease in the HAM-D scores , with eight patients responding and two of them presenting a remission . The addition of lithium to venlafaxine was found to be a well-tolerated strategy in treatment-resistant patients Although lithium augmentation is the foremost and most well-documented treatment strategy for treatment resistant depression , knowledge of factors related to response remains scanty . Findings with the combined dexamethasone/corticotropin-releasing hormone ( DEX/CRH ) test are associated with response to treatment with a tricyclic antidepressant . This study investigated the potential predictive value of the DEX/CRH test for lithium augmentation response in major depressive disorder . The DEX/CRH test was conducted prior to lithium augmentation in 30 patients with a major depressive episode who had not responded to an antidepressant monotherapy trial of at least 4 weeks . Response status was assessed weekly using the Hamilton Rating Scale for Depression . For multivariate prediction , a logistic regression analysis was performed . Eleven ( 37 % ) patients responded to lithium augmentation within 4 weeks . Responders showed higher ACTH response and lower cortisol response in the DEX/CRH test , but results were not statistically significant . However , non-responders had a statistically significant higher cortisol/ACTH peak ratio ( 3.43+/-1.75 ) compared to responders ( 2.18+/-1.38 ) ( P=0.027 ) . This ratio is an indicator for the sensitivity of the adrenal cortex to ACTH . A cortisol/ACTH peak ratio of 1.8 was identified as the best cutoff point to differentiate responders from non-responders . In conclusion , results suggest a more sensitive adrenal cortex in non-responders to lithium augmentation . The findings would be in line with the assumption of a more chronic course of depression with more pronounced biological alterations in the non-responder group , because chronic depression is known to cause enlargement of the adrenal gl and with a subsequent hypersensitivity to ACTH . Results of this study should be confirmed in a larger study group Lithium augmentation is a well established strategy for treatment-resistant depression . The exact mode of its action is unknown , but an enhancement of serotonergic transmission is hypothesized . The authors investigated changes in the hypothalamic-pituitary-adrenocortical ( HPA ) system during lithium augmentation and their correlation to clinical response by means of the combined dexamethasone/CRH test ( DEX/CRH test ) . Thirty patients with unipolar major depressive episodes ( DSM IV ) who had not responded to an adequate trial with an antidepressant were assessed on the day before lithium augmentation ( baseline ) with the DEX/CRH test ( pretreatment with 1.5 mg dexamethasone p.o . at 11 P.M. and CRH stimulation at 3 P.M. on the next day ) . Twenty-four patients were re-assessed after response was determined or , in cases of non-response , four weeks after initiation of lithium augmentation . Response to lithium augmentation was measured by weekly ratings on the Hamilton Depression Rating Scale ( HDRS 17-item version ) . Response was defined as a ΔHDRS of ⩾50 % and an endpoint score of < 10 . Patients had a significantly higher ACTH and cortisol response to CRH stimulation  during lithium augmentation compared with the values at baseline . There was no difference in ACTH and cortisol reaction between responders and non-responders to lithium augmentation . This increase is in contrast to the known normalization of HPA-axis overdrive after treatment with a tricyclic antidepressant like amitriptyline . Because the effect was independent of response status we suggest that this increase reflects an effect of lithium that is independent from the psychopathological state or its change . This effect might be explained by the serotonergic effects of lithium Although considerable evidence exists on the efficacy of lithium as an augmenting agent in refractory depression , the underlying neurobiology of this phenomenon is unknown . In patients with major depression , changes of the hypothalamic‐pituitary‐adrenocortical ( HPA ) system have been detected by means of the dexamethasone suppression test ( DST ) , when administered during treatment with tricyclic antidepressants . We investigated whether the DST also reveals alterations of the HPA system during lithium augmentation . We also sought to identify whether response to lithium augmentation can be predicted with the DST . Twenty‐five patients with unipolar major depression , who did not respond to an adequate antidepressant monotherapy of at least 4 weeks , were measured for basal ( pre‐dexamethasone , 0800h ) cortisol and ACTH levels and were administered the DST the day before initiation of lithium augmentation treatment . The same neuroendocrine procedures were repeated after 3 to 4 weeks . Criteria of response to lithium augmentation , defined as a reduction of the Hamilton Depression Rating Scale ( HDRS17 ) score by ≥50 % and an end point score of 9 or less , were determined by weekly HDRS ratings . The DST revealed a statistically significant increase of the post‐dexamethasone cortisol values ( P=0.021 ) and an increase in the post‐dexamethasone ACTH values ( P=0.051 ) during lithium augmentation as compared to pre‐treatment baseline evaluations . The pre‐dexamethasone hormone values were unchanged . The number of non‐suppressors at baseline was one and increased to three at follow‐up . Results of DST did not predict response to lithium augmentation , which occurred in 40 % of subjects . Results suggest that lithium augmentation increases HPA system activity , as indicated by the increase of post‐dexamethasone cortisol and ACTH levels measured by the DST . This is in contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants . Depression and Anxiety 17:43–48 , 2003 . © 2003 Wiley‐Liss , There is compelling evidence from placebo-controlled studies that lithium augmentation is an effective strategy in the acute and continuation treatment of refractory unipolar major depression . Authors prospect ively investigated the 1-year outcome of 22 subjects diagnosed with unipolar major depression who had participated in a 4-month placebo-controlled , double-blind continuation study of lithium augmentation without relapse . At the end of the double-blind phase , the blinded medication ( lithium in 14 patients , placebo in 8 patients ) was tapered off over a 1-week 
    Output:
    
Animal studies offer robust evidence that lithium augmentation increases 5-HT neurotransmission , possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways .
Conclusions : Augmentation of antidepressants with lithium is the best-documented augmentation therapy in the treatment of refractory depression .
Emerging data from animal studies suggest that the 5-HTergic system is involved in the augmentatory effect of lithium