The effect of lithium on urinary MHPG in unipolar and bipolar depressed patients

Twenty-four hour urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolite thought best to reflect brain norepinephrine metabolism, was studied longitudinally in ten depressed patients before and during the acute and chronic phases of lithium treatment. Five of the patients were identified as bipolar I (prior history of mania), 3 as bipolar II (history of hypomania) and 2 as unipolar (history of depression).During acute lithium administration (first week) there was no consistent pattern of change in MHPG. Comparing the predrug period with the third and fourth week of treatment, all of the responders showed an increase in MHPG, while the non-responders showed no change or a decrease. It is concluded that the change in clinical state is the most important variable contributing to MHPG changes in these patients.There was a tendency for the pretreatment MHPG excretion to be low in the patients who went on to show a clear-cut antidepressant response to lithium compared to those who were unequivocal non-responders. The predrug MHPG for the bipolar patients (prior history of mania) was significantly lower than the unipolar patients, a difference which apparently contributes to the lower MHPG in the lithium responders, all of whom were in the bipolar group.Scholar of the MRC of Canada from the Université de Sherbrooke and subsequently visiting scientist at the NIMH.     

Avoiding drug-induced switching in patients with bipolar depression.

Antidepressant-induced switching is a major risk during the treatment of bipolar depression. Despite several clinical studies, questions remain regarding both the definition of these mood switches and the most appropriate therapeutic strategy to avoid this adverse effect.This review will first briefly consider the current guidelines for the acute treatment of bipolar depression. We will then review the mechanisms of action of antidepressant and mood stabilisers, and the switches induced by various types of antidepressant treatments, or triggered by antidepressant withdrawal, as well as by atypical antipsychotics. We then will address the risk of mood switch according to the type of mood stabiliser used. The propensity to mood switches in bipolar patients is subject to individual differences. Therefore we will describe both the clinical and biological characteristics of patients prone to mood switches under antidepressant treatment. However, the clinical characteristics of the depressive syndrome may also be a key determinant for mood switches. Various data help identify the most appropriate drug management strategies for avoiding mood switches during the treatment of bipolar depression. Selective serotonin reuptake inhibitors appear to be the drugs of first-choice because of the low associated risk of mood switching. Antidepressants must be associated with a mood stabiliser and the most effective in the prevention of switches seems to be lithium. Whatever the mood stabiliser used, effective plasma levels must be ensured. The optimal duration of antidepressant treatment for bipolar depression is still an open issue - prolonged treatments after recovery may be unnecessary and may facilitate mood elation. Moreover, some mood episodes with mixed symptoms can be worsened by antidepressants pointing to the need for a better delineation of the categories of symptoms requiring antidepressant treatment. Finally, as a result of this review, we suggest some propositions to define drug-induced switches in bipolar patients, and to try to delineate which strategies should be recommended in clinical practice to reduce as far as possible the risk of mood switch during the treatment of bipolar depression.     

Serotonergic function during lithium augmentation of refractory depression

Serotonergic mechanisms have been implicated in the pathophysiology of depression and in the neuropharmacology of antidepressant treatment. One measure of central serotonergic function is the prolactin (PRL) response to IVl-tryptophan (l-TRP). We used thel-TRP test to assess the role of serotonin in the mechanism of action of lithium augmentation in refractory major depression. Twenty-six patients with antidepressant-refractory major depression each received threel-TRP tests (after 2 weeks of placebo, after 4 weeks of active primary antidepressant, and after 1 week of lithium augmentation). Primary antidepressant treatment did not increase the PRL response, but lithium augmentation resulted in a statistically significant increase in PRL response as compared to both placebo pretreatment (P<0.04) and antidepressant treatment alone (P<0.025). This study supports a role for serotonergic mechanisms in the action of lithium augmentation.     

Polytherapy in bipolar disorder

Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder. The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression. For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.     

Lithium and renal function in relation to concomitant theory

Two hundred and fourteen patients (99 men, 115 women, age 21-87 years) were treated with lithium during the period 1963-1984 at the Psychiatric Unit, Danderyd Hospital. The patients were diagnosed as having bipolar depression (97), unipolar depression (54), cycloid psychosis (21), schizoaffective psychosis and depressive neurosis (42). Sixty patients were treated with lithium salt only, 73 patients received neuroleptic drugs in addition to lithium and 51 antidepressant drugs. Sixteen patients were treated with a combination of neuroleptic drugs, antidepressant drugs and lithium. Fourteen patients were treated with lithium and benzodiazepines. The aim of this retrospective lithium study was to examine the renal function in these different treatment groups. The results show that patients treated with a lithium salt and neuroleptic drugs have significantly lower urinary osmolality than those treated with a lithium salt only. Also tricyclic antidepressants in combination with a lithium salt appear to have an influence on renal function. The duration of concomitant therapy seems to be of importance for the effect on renal function. Eleven patients with the lowest osmolality values were investigated at the Renal Unit, Danderyd Hospital, but in no case was it necessary to withdraw the lithium treatment.     

Adding lithium to antidepressant therapy: factors related to therapeutic potentiation.

Lithium augmentation of antidepressant drugs was studied in 51 patients with endogenous refractory depression. The remission after 28 days of lithium was obtained in 28 patients (55%). Better effect of lithium was shown in bipolar than unipolar patients, with subjects with lower pre-lithium severity of depression and in those with rapid improvement (within 7 days) on lithium addition. Factors such as age, gender, number of prior antidepressant (or ECT) treatments, type of preceding antidepressant, mean plasma lithium concentration and the results of DST did not show any association with the outcome of lithium augmentation. The 'priming' effect of lithium may contribute to the mechanism of lithium potentiation in a proportion of depressed patients.     

Response to clomipramine after short course of lithium in treatment-resistant depression: Does lithium have a ‘priming’ effect?

A patient with a treatment-resistant depression of 15 months duration is reported. Initially he showed no response to clomipramine 150 mg daily for 1 month. When lithium carbonate 600 mg daily was added for 4 days he developed signs of lithium intoxication: drowsiness, confusion, and dystonia. After lithium was withdrawn the patient improved dramatically. We hypothesize that lithium may potentiate the antidepressant effect of tricyclic antidepressants (TCA) even if it is administered as a short course of treatment.     

A review of acute treatments for bipolar depression

Bipolar patients generally spend much more time in the depressed phase of their illness than the manic phase, and there are many more bipolar type II and bipolar spectrum disorder patients than there are bipolar type I. Additionally, there is a significant risk of suicide in bipolar patients when depressed. The treatment of the depressed phase of bipolar disorder is therefore a matter of some priority. Here, we review current evidence supporting the use of five groups of treatments: anti-depressants; lithium; anti-convulsants (valproate, and carbamazepine, lamotrigine, gabapentin); anti-psychotics; and other treatments (electroconvulsive therapy, benzodiazepines, sleep-deprivation, and dopamine agonists). From this review, it is apparent that the literature regarding the treatment of bipolar depression is significantly limited in several key areas. Nonetheless, from the evidence currently available, the treatments with the best evidence for efficacy are selective serotonin reuptake inhibitors (SSRIs) and lamotrigine. There is also some evidence in favour of bupropion and moclobemide. Although lithium and olanzapine monotherapies can also be beneficial, they appear less efficacious than antidepressants. One of the major concerns about treatment with antidepressants has been the risk of precipitating a switch into mania. However, recent studies suggest that, if a mood stabilizer and antidepressant are given concurrently, then the risk of switching is minimized. There is also recent evidence for an independent antidepressant action for at least one atypical antipsychotic. Therefore, the conclusion from this review, in contrast to previous suggestions, is that a combination of an atypical antipsychotic and either an SSRI or lamotrigine may provide a useful first-line treatment for depressed bipolar disorder patients. Further research is clearly required to examine this approach and compare it with other possible treatment options.     

碳酸锂联合氟西汀治疗双相情感障碍的疗效

目的评价碳酸锂联用氟西汀治疗双相情感障碍的疗效和安全性。方法68例双相情感障碍患者随机分成治疗组和对照组各34例。治疗组给予碳酸锂1.0 g·d^-1，氟西汀初始量20 mg·d^-1，最大40 mg·d^-1;对照组给予碳酸锂1.0 g·d^-1，阿米替林初始量25 mg·d^-1，1周后递增至150 mg·d^-1，根据病情调整剂量，最大剂量250 mg·d^-1。两组药物均为口服，疗程均为8周。采用汉密尔顿抑郁量表（HAMD）、临床总体评定量表（CGI）评定临床疗效，不良反应量表（TESS）评定不良反应。结果治疗组总有效率为90.9%，显效率为81.8%，对照组分别为80.8%和73.1%，两组比较差异无显著性（P＞0.05）。治疗组不良反应少，依从性好，且转躁率较低。结论碳酸锂联用氟西汀治疗双相情感障碍有效、安全。     

Paroxetine and amitriptyline augmentation of lithium in the treatment of major depression: a double-blind study

To study the efficacy and safety of antidepressant augmentation of ongoing lithium therapy, lithium-maintained patients suffering from an breakthrough episode of major depression were randomly assigned under double-blind conditions to receive paroxetine 20 mg/day (N = 19) or amitriptyline 75 mg/day (N = 23). The initial dosages could be increased after 2 weeks to 40 mg/day and 150 mg/day, respectively, and the patients were treated for a total of 6 weeks. Efficacy was assessed weekly with the 21-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impression Scale (CGI), and safety was assessed with the Dosage Record and Treatment Emergent Symptom Scale. After 4 weeks, a significantly greater proportion of patients in the paroxetine group had achieved a 50% reduction in baseline HAM-D scores, and the mean improvement in CGI severity of illness was significantly greater in the paroxetine group at weeks 3 and 5. The type and number of emergent events occurring during study treatment corresponded to the known side effect profiles of paroxetine and amitriptyline. Serum lithium levels were not affected by either antidepressant. The authors proposed that the more rapid improvement demonstrated by the group receiving the combination of lithium and paroxetine may be due to the synergistic serotonergic effects of these two medications.     

Leukocyte telomerase activity and antidepressant efficacy in bipolar disorder

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. Recently, shorten telomeres length has been reported in bipolar disorder (BD) and depression. The enzyme telomerase regulates telomeres׳ length, which has been associated with cellular viability; however it is not clear how telomerase may be involved in the pathophysiology and therapeutics of BD. In the present study, leukocyte telomerase activity was assessed in 28 medication-free BD depressed individuals (DSM-IV-TR criteria) at baseline and after 6 weeks of lithium therapy (n=21) also matching with 23 healthy controls. There was no difference between telomerase activity in subjects with BD depression (before or after lithium) and controls. Improvement of depressive symptoms was negatively associated with telomerase activity after 6 weeks of lithium therapy. This is the first study describing telomerase activity in BD research. Overall, telomerase activity seems not directly involved in the pathophysiology of short-term BD. Lithium׳s antidepressant effects may involve regulation at telomerase activity. Further studies with larger samples and long-term illness are also warranted.     

Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial.

Total sleep deprivation (TSD) shows powerful but transient clinical effects in patients affected by bipolar depression. Pindolol blocks the serotonergic 5-HT1A autoreceptor, thus improving the antidepressant effect of selective serotonin reuptake inhibitors. We evaluated the interaction of TSD and pindolol in the treatment of acute episodes of bipolar depression. Forty bipolar depressed inpatients were randomized to receive pindolol 7.5 mg/day or placebo for nine days in combination with three consecutive TSD cycles. Pindolol significantly improved the antidepressant effect of TSD, and prevented the short-term relapse after treatment. The response rate (HDRS scores < 8) at the end of treatment was 15/20 for pindolol, and 3/20 for placebo. Coadministration of pindolol and TSD resulted in a complete response, which could be sustained for six months with lithium salts alone, in 65% of cases. This results suggest a major role for serotonergic transmission in the mechanism of action of TSD, and makes TSD treatment more effective in the treatment of bipolar depression.     

Do age of onset and course of illness predict different treatment outcome among DSM IV depressive disorders with atypical features?

DSM IV defines its atypical features depression modifier mainly by current symptoms. Relative to depressed patients with melancholic features, those with atypical features often present with earlier onset of a more chronic disorder and are less likely to benefit from tricyclic antidepressant (TCA). We, therefore, hypothesized that within depressed patients with atypical features those with illness course most similar to that of melancholia would be most TCA-responsive, those whose illness course least resembled that of melancholia would be least TCA responsive. Two patient groups were treated with TCA, monoamine oxidase inhibitor, or placebo with nonresponders crossed to alternative treatment. One group met DSM IV criteria for atypical features and the other nearly met these criteria. Early onset, chronically depressed patients with DSM IV atypical features had poor TCA response relative to others. Patients with "probable" atypical features (mood reactivity plus one associated atypical feature) and nonresponders crossed to alternate treatment confirmed this. Findings suggest that application of DSM IV atypical features might best be limited to those with early onset of chronic dysphoria.     

Serotonin receptors in platelets of bipolar and schizoaffective patients: effect of lithium treatment

Rationale Abnormalities of serotonin (5HT) function have been implicated in mood disorders, and lithium treatment may produce its beneficial effects by modifying serotonergic mechanisms. It has also been observed that 5HT_2A receptors are upregulated both in the postmortem brain and platelets of patients with depression and suicidal behavior. However, the role of 5HT_2A receptors in bipolar disorders and in the mechanism of action of lithium is unclear.Objective The major objective of this study was to examine if abnormalities of 5HT_2A receptors are associated with bipolar or schizoaffective disorders and if treatment with lithium would cause changes in the 5HT_2A receptors.Methods 5HT_2A receptors were studied in the platelets obtained from drug-free normal control subjects and patients with bipolar (n=41) or schizoaffective (n=20) disorders during a drug-free washout period and after treatment (4.0±0.44 weeks) with lithium (n=16). The B_max and K_D of 5HT_2A receptors were quantitated by binding techniques using [¹²⁵I]lysergic acid diethylamide (LSD) as a ligand.Results We observed that the 5HT_2A receptor B_max was increased in platelets obtained from drug-free bipolar or schizoaffective patients as compared with normal control subjects. The 5HT_2A receptor density was even more increased in bipolar or schizoaffective suicidal patients, and the 5HT_2A receptor B_max in the non-suicidal bipolar or schizoaffective subgroup also was significantly higher than in normal control subjects. Treatment with lithium caused a significant increase in the B_max of platelet 5HT_2A receptors in bipolar or schizoaffective patients.Conclusions Our studies indicate that increased 5HT_2A receptors may be associated with the pathophysiology of bipolar illness and that treatment with lithium further increases the density of 5HT_2A receptors. Whether this increase in 5HT_2A receptors caused by lithium is associated with its therapeutic mechanism of action is unclear. It is also not clear whether the increase in 5HT_2A receptors in bipolar or schizoaffective patients, or in suicidal bipolar or schizoaffective patients, is a trait or state marker.     

Reserpine augmentation of desipramine in refractory depression: clinical and neurobiological effects

Early studies showed dramatic improvement in some depressed patients when a brief course of parenteral reserpine was added to ineffective tricyclic antidepressant (TCA) treatment. We treated eight patients with DSM-III melancholic major depression with desipramine (DMI)2.5 mg/kg/day (plasma levels>125 ng/ml) for at least 4 weeks. All patients failed to respond and received reserpine 5 mg IM b.i.d. over 2 days, in seven cases as a placebo-controlled, double-blind trial. One patient had dramatic resolution of depressive and psychotic symptoms within 48 h, but relapsed within 2 weeks; two other patients had transient hypomanic symptoms. Depression ratings did not significantly change for the sample as a whole, but plasma and cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) decreased and CSF levels of homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA) increased. Despite robust effects on central monoamine metabolism, reserpine augmentation appears insufficiently effective for routine use in managing refractory depression.     

Adjunct low dose lithium carbonate in treatment-resistant depression: a placebo-controlled study

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.     

Maintenance efficacy of divalproex in the prevention of bipolar depression.

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.     

Bipolar depression: an overview

Depressive episodes are significant in bipolar illness since patients can spend up to one-third of their lives in depression. Although the treatment of bipolar depression remains an understudied area, new data from randomized, controlled trials and naturalistic studies have expanded the range of treatments available. The main aim in the treatment of bipolar depression is the prevention of the patient switching to mania and cycle acceleration, and antidepressant therapy may be contraindicated because of the risk for switching. Guidelines for the acute treatment of bipolar depression emphasize treatment with a mood stabilizer, of which lithium has been the most thoroughly studied in randomized, controlled trials in acute bipolar depression. Lamotrigine has also demonstrated significant efficacy in recent studies and has been approved by the FDA.     

Fenfluramine augmentation in tricyclic-refractory depression

The clinical efficacy of lithium augmentation in refractory depression is hypothesized to depend on the ability of lithium to enhance presynaptic 5-hydroxytryptamine (5-HT) function. Since fenfluramine promotes release and inhibits reuptake of presynaptic 5-HT, we assessed its efficacy in augmenting ongoing tricyclic antidepressant treatment of refractory depression. Fifteen patients with DSM-III major depression failed to respond to treatment with desipramine 2.5 mg/kg/day or more (plasma levels of at least 125 ng/ml) given for at least 4 weeks. Fenfluramine 40-120 mg/day was then added to the ongoing desipramine in a placebo substitution design. There was no statistically significant evidence of either transient or sustained clinical improvement during the 2 weeks of fenfluramine augmentation. One patient appeared to respond to the treatment, but one appeared to worsen. Fenfluramine more than doubled steady-state plasma levels of desipramine. These findings suggest that lithium's efficacy as an augmenting agent depends on properties that are not shared by fenfluramine. Fenfluramine cannot be recommended in the routine management of refractory depression.     

Bipolar depression: management options

Bipolar depression is the predominant abnormal mood state in bipolar disorder. However, despite the key pertinence of this phase of the condition, the focus of research and indeed of clinical interest in the management of bipolar disorder has been mainly on mania. Bipolar depression has been largely neglected, and early studies often failed to distinguish depression due to major unipolar depression from that due to bipolar disorder. Consequently, many treatments used in the management of major depression have been adopted for use in bipolar depression without any robust evidence of efficacy. The selective serotonin reuptake inhibitors (SSRIs), bupropion, tricyclic antidepressants and monoamine oxidase inhibitors are all effective antidepressants in the management of bipolar depression. They are all associated with a small risk of antidepressant-induced mood instability. The mood stabilisers lithium, carbamazepine and valproate semisodium (divalproex sodium) all appear to have modest acute antidepressant properties. Among these, lithium is supported by the strongest data, but the use of lithium in the treatment of bipolar depression as a monotherapeutic agent is limited by its slow onset of action. Recently, there has been a growing body of evidence suggesting that lamotrigine may have particular effectiveness in both the acute and prophylactic management of bipolar depression. Clinical management of bipolar depression involves various combinations of antidepressants and mood stabilisers and is partly determined by the context in which the depressive episode occurs. In general, 'de novo' and 'breakthrough' (where the patient is already receiving medication) bipolar depression may be successfully managed by initiating mood stabiliser monotherapy, to which an antidepressant or second mood stabiliser may be added at a later date, if necessary. Breakthrough episodes of bipolar depression occurring in patients receiving combination therapy (two mood stabilisers or a mood stabiliser plus an antidepressant) require either switching of ongoing medications or further augmentation. If this fails, then novel strategies or ECT should be considered. Bipolar depression is a disabling illness and the predominant mood state for the vast majority of those with bipolar disorder. It therefore warrants prompt management once suitably diagnosed, especially as it is associated with a considerable risk of suicide and in the majority of instances is eminently treatable.