Lithium Augmentation Research Articles

Reply: Hemorrhages during Escitalopram—Venlafaxine— Mirtazapine Combination Treatment of Depression

Dear Editor: The publication of Dr Benazzi's case report (1) is somewhat worrying. Although the report does not suggest that the treatment in this case is routine or normal practice, the concluding statement that clinicians should take care when combining several antidepressants that increase serotonin appears to condone the treatment outlined in the paper. Apart from the fact that all treatment algorithms for resistant depression recommend lithium augmentation prior to combined antidepressants, which in most cases come well down the list of strategies, given the limited evidence for this intervention, and putting aside the fact that, when recommended, the combination of antidepressants refers to 2 antidepressants, to add 2 antidepressants at once to an alreadyprescribed antidepressant is to court disaster. That nasal and rectal bleeding were the only consequences of this dangerous cocktail could be viewed as fortunate. What level of hemoglobin this patient bled down to is not revealed in the report, and it must be presumed that this was checked and was not of great concern. What is of concern is the risk that this report will encourage this sort of prescribing. References I. Benazzi F. Hemorrhages during escitalopram-venlafaxine-mirtazapine combination treatment of depression. Can J Psychiatry 2005;50:184. Andrew Al-Adwani, MRCPsych North Lincolnshire, UK Reply: Hemorrhages During Escitalopram-VenlafaxineMirtazapine Combination Treatment of Depression Dear Editor: I thank Dr Al-Adwani for his comments on the treatment of resistant depression, as the topic is a hot one. There are several guidelines on the treatment of depression, which should be distinguished as bipolar disorder I, bipolar disorder II, and major depressive (unipolar) disorder. Among these disorders, the treatment of bipolar II depression is the most understudied, even if bipolar II depression is at least as common as unipolar depression in nontertiary care outpatients (1,2). The several guidelines on the treatment of bipolar and unipolar depression follow different steps. What matters most is that these guidelines are the result of a consensus among academic experts, based on literature reviews and personal opinions, not on data from usual clinical practice. The result is that these guidelines are detached from real-world clinical practice (described as an irrelevant evidence base for clinical practice; 3). Even if we rely on the evidence we can find in the literature, this is of little help; at most it may guide the choice of a second antidepressant when the first one has failed. I have been in clinical practice for 21 years with the National Health Service as part-time consultant and with my private outpatient practice. In this latter setting (which is also the setting of most of my studies), I have thousands of visits yearly. Patients often come to see me after the failure of 1 or 2 antidepressants. …

Lithium augmentation in treatment-resistant depression: influence of polymorphisms in tryptophan hydroxylase 2 gene (TPH2) on therapy response

In the therapy of treatment-resistant depression lithium augmentation has been shown to be an effective method. About 50% of lithium-augmented patients respond to this strategy (Bauer et al., 2003). Nevertheless, mechanisms and predictors for the clinical efficacy of lithium augmentation are still unknown, although genetic factors (for example by modulating serotonergic neurotransmission) are discussed to play an important role for the treatment response (Serretti et al., 2002; Serretti et al., 1999). Results of our own study group suggest an influence of a polymorphism in the 5HTTLPR (Stamm et al., submitted). This study investigates the association between genetic polymorphisms of tryptophane-hydroxylase type 2 (TPH2) and the response to lithium augmentation treatment in 49 patients with treatment-resistant depression. The Cox-Regression-Survival-Analysis showed no significant difference between the three TPH2 genotypes. Further results including a bigger sample are pending and expected for summer 2005. We also await results on the possible association with other genetic polymorphisms (for example G-protein beta–3). Furthermore, possible interactions of these genetic polymorphisms and their common effect on treatment response to lithium augmentation shall be investigated.

Evaluating algorithm-guided treatment for depression: The German Algorithm Project (GAP)

The introduction of algorithms in the treatment of patients suffering from major depressive disorder (MDD) is considered as an important instrument in avoiding and overcoming treatment-resistant depression. The multiphasic German Algorithm Project has evaluated algorithm-guided treatment of inpatients with MDD. Phase I (open observational trial) showed a moderate acceptance but good clinical effectiveness of a standardized stepwise drug treatment regimen (SSTR). Phase II (randomized controlled trial) demonstrated a higher probability of achieving remission for SSTR patients compared to patients with treatment as usual (TAU). Phase III was a recently finished randomized controlled multi-center trial within the German Research Network on Depression which compared an SSTR and a computerized documentation and expert system (CDES) with TAU. Within the SSTR we compared three different second-step strategies in the case of non-response to an initial antidepressant monotherapy (SSTR1: lithium augmentation, SSTR 2: dose escalation, SSTR 3: switch to other compound). Preliminary analyses show a faster remission for algorithm-treated patients compared to TAU (F=3.045; p=0.18) with SSTR1 showing the greatest difference to TAU (p=0.02). TAU was associated with a higher average rate of residual symptoms at the end of treatment. Algorithm-guided treatment of depression may lead to a faster remission and reduce hospitalization times, particularly with an SSTR including lithium augmentation.

Managing clozapine-induced neutropenia with lithium

Aims and MethodTo review the efficacy and safety of lithium augmentation for the management of clozapine-induced neutropenia. Medline search January 1966 to March 2004.ResultsThe ability of lithium to increase the white cell count (WBC) is well documented. A small number of published case reports of the successful treatment of clozapine-induced neutropenia with lithium were identified. Lithium does not protect against agranulocytosis.Clinical ImplicationsLithium may be useful in raising the WBC in patients whose baseline count is too low to allow treatment with clozapine to start and to protect against clozapine-induced neutropenia, thus allowing more patients to benefit from treatment with clozapine. It does not protect against agranulocytosis. There is no way of identifying patients whose neutropenia will progress to agranulocytosis. Careful monitoring is essential. Lithium is not licensed to increase WBC. Psychiatrists should be aware of the medicolegal implications of prescribing off-label.

Therapeutic Alternatives for Difficult-to-Treat Depression: A Narrative Review of the State of the Evidence

Despite the large number of depressed patients who do not respond to first-line antidepressants, the evidence base of alternate strategies is quite thin. In this article, a simple 5-stage system for categorizing treatment-resistant depression (TRD) is described and the evidence pertaining to the major strategies currently utilized is summarized using four grades, ranging from D (case reports only) to A (multiple positive placebo-controlled trials). It is concluded that the level of evidence supporting many of the contemporary strategies used for TRD (eg, combinations of antidepressants and augmentation with medications such as pindolol, buspirone, or modafinil) is scanty at best. Even the fundamental question concerning "to augment or to switch" is not answerable with available data. It is noted that the best-documented treatments (ie, lithium augmentation, switching to a monoamine oxidase inhibitor, and electroconvulsive therapy) are among the least utilized. This state of affairs will improve with completion of the studies of Systematic Treatment Alternatives to Relieve Depression, a large multicenter study of difficult-to-treat depression funded by the National Institute of Mental Health. There is a need for greater collaboration among academicians and organizations, such as the American Psychiatric Association, the National Institute of Mental Health, and the pharmaceutical industry, to ensure that sufficient research is conducted so that clinician's choices for patients with TRD can be guided by empirical evidence.

Serotonin transporter gene polymorphism and response to lithium augmentation in patients with treatment-refractory depression

The promoter region of the serotonin transporter gene (5HTTLPR) displays a polymorphism, which consists in the presence or absence of a 44 base-pair segment producing either a long (l), or short (s) allele. Previous studies have suggested a superior response of l-allele carriers to selective serotonin reuptake inhibitors (1). We examined the association of the 5HTTLPR polymorphism with the response to lithium augmentation, which is thought to enhance serotoninergic activity (2). Posthoc genotyping was performed in 46 patients with treatment-resistant depression who had undergone a 4-week lithium augmentation treatment. One subgroup was treated according to a stepwise treatment algorithm (SSTR) [n=28], the other was treated as usual (TAU) [n=18]. Survival analysis revealed a significantly more rapid response and a higher probability of response in carriers of the ss-genotype, but only in TAU patients (p<0,01). Ss-carriers might more than others profit by early lithium augmentation. The absence of this difference in SSTR patients may be due to factors selecting a higher degree of refractoriness throughout the highly standardized treatment procedure before reaching the lithium augmentation step.

Psychosocial functioning in patients with treatment resistant depression

Background. – Depression is a disorder that causes disability, with a profound adverse impact on all areas of psychosocial functioning. This is particularly true for those with treatment resistant depression (TRD). However, to date, no systematic assessments of psychosocial functioning for patients with TRD have been conducted. Methods. – In the present study, we used the Longitudinal Interval Follow-up Evaluation (LIFE) scale to measure psychosocial functioning in 92 patients with TRD. These patients met formal criteria for TRD and were part of a clinical trial examining the efficacy of lithium augmentation of nortriptyline. Results. – Clinicians rated this sample of patients as experiencing mild to moderate impairment in work-related activities, good to fair interpersonal relations, poor level of involvement in recreational activities, and mild impairment of ability to enjoy sexual activity. Patients and clinicians rated global social adjustment as poor. Conclusions. – Patients with formally defined TRD experience significant impairment in psychosocial functioning. In this sample a tendency existed for both clinicians and patients to assign more severely impaired global ratings when compared with ratings for specific functional areas.

Lithium for Schizophrenia Revisited

Clinicians frequently use lithium to augment antipsychotic medication in schizophrenia. Therefore, we undertook a systematic review and meta-analysis of the use of lithium in the treatment of schizophrenia. Randomized controlled trials examining lithium (as a sole or an adjunctive compound) in participants with schizophrenia or related disorders were searched in the register of the Cochrane Schizophrenia Group. No language restrictions were applied. The Boolean phrase [lithium* or lithicarb or eskalith or lithobid or lithane or cibalith-s or quilonum or hypnorex] was used to locate articles. The search strategy initially identified 90 references. The authors of the included studies were contacted to obtain original patient data. The data were combined in a meta-analysis. The main outcome parameters were the number of patients with a clinically significant response and the number of patients leaving the studies early. The meta-analysis includes 20 studies (N = 611). The evidence shows that lithium as a sole agent is ineffective in the treatment of schizophrenia. Eleven trials examined the augmentation of antipsychotics with lithium. More patients who received lithium augmentation than those who received antipsychotics alone were classified as responders. However, the superiority was not consistent across different response thresholds, and when patients with prominent affective symptoms were excluded from the analysis, the advantage of lithium augmentation was not significant (p =.07). Significantly more patients taking lithium left the trials early, suggesting a lower acceptability of lithium augmentation compared with that of taking antipsychotics alone. Despite some evidence in favor of lithium augmentation, the overall results are inconclusive. A large trial of lithium augmentation of antipsychotic medications will be required in order to detect a benefit of small effect size in patients with schizophrenia who lack affective symptoms.

Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms.

For now more than 50 years, lithium has been the gold standard for the pharmacologic treatment of bipolar disorder. However, its utility is not restricted to acute mania and prophylactic treatment of bipolar disorder. A relatively new indication for its use is the addition to an antidepressant in the acute treatment phase of unipolar major depression. To date, this treatment approach called lithium augmentation is the best-documented approach in the treatment of refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment. In a recent double-blind, placebo-controlled trial, lithium augmentation has demonstrated to also be effective in the continuation treatment phase to prevent early relapses. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. In contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants, neuroendocrine studies on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined DEX/CRH test. Here we review new data on the efficacy and mechanism of action of lithium augmentation.

Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms.

This systematic review examines the evidence and discusses the clinical relevance of lithium augmentation as a treatment strategy for refractory major depressive episodes. It also examines hypotheses on the mode of action of lithium augmentation, with a focus on serotonin (5-HT) and neuroendocrine systems, and proposes recommendations for future research. We searched the Medline computer database and the Cochrane Library for relevant original studies published in English from January 1966 to February 2003. The key words were as follows: lithium, augmentation strategies, lithium augmentation, major depression, refractory depression, treatment-resistant depression, neuroendocrinology, and serotonin. Of 27 prospective clinical studies published since 1981, 10 were double-blind, placebo-controlled trials, 4 were randomized comparator trials, and 13 were open-label trials. Five of 9 acute-phase placebo-controlled trials demonstrated that lithium augmentation had substantial efficacy. In the acute-treatment trials, the average response rate in the lithium group was 45%, and in the placebo group, 18% (P < 0.001). One placebo-controlled trial showed the efficacy of lithium augmentation in the continuation-phase treatment. Summarizing the open and controlled data, approximately 50% of patients responded to lithium augmentation within 2 to 6 weeks. 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. 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.

Lithium for schizophrenia.

Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, among them lithium. To review the effects of lithium for the treatment of schizophrenia and schizophrenia-like psychoses. The reviewers searched the Cochrane Schizophrenia Group's register (March 2002). This register is compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. We also contacted pharmaceutical companies and authors of relevant studies to identify further trials and to obtain original patient data. All randomised controlled trials comparing lithium to antipsychotics or to placebo (or no intervention), whether as sole treatment or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizophrenia-like psychoses. Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were extracted independently by at least two reviewers. Dichotomous data were analysed using relative risks (RR) and the 95% confidence interval (CI) estimated. Where possible the number needed to treat (NNT) or number needed to harm statistics were calculated. Continuous data were analysed using weighted mean differences (WMD). The review currently includes 20 studies with a total of 611 participants. Most studies were small, of short duration and incompletely reported, but a number of authors were willing to share their data with us. Three studies comparing lithium with placebo as the sole treatment showed no difference in any of the outcomes we analysed. In eight studies comparing lithium with antipsychotic drugs as the sole treatment more participants in the lithium group left the studies early (n=270, RR 1.8, CI 1.2 to 2.9, NNT 9, CI 5 to 33). Several of the outcomes relating to these studies suggested that lithium is less effective than antipsychotic drugs, but it was difficult to summarise the data, because a variety of rating scales were used in the studies. Eleven studies examined whether the augmentation of antipsychotic drugs with lithium salts is more effective than antipsychotic drugs alone. More participants who received lithium augmentation had a clinically significant response (n=244, RR 0.8, CI 0.7 to 0.96, NNT 8, CI 4 to 33). However, statistical significance became borderline when participants with schizoaffective disorders were excluded in a sensitivity analysis (n=120, RR 0.8, CI 0.6 to 1.0, p=0.07). Furthermore, more participants in the lithium augmentation groups left the studies early (n=320, RR 2.0 CI 1.3 to 3.1, NNT 7, CI 4 to 14), suggesting a lower acceptability of lithium augmentation compared to those on antipsychotics alone. No superior efficacy of lithium augmentation in any specific aspect of the mental state was found. While based on very little data, there were no differences between groups for adverse events. There is no randomised trial based evidence that lithium on its own is an effective treatment for people with schizophrenia. The evidence available on augmentation of antipsychotics with lithium is inconclusive, but it justifies further, large, simple and well-designed trials. These should concentrate on two target groups: 1) people with no affective symptoms, so that trialists can determine whether lithium has an effect on the core symptoms of schizophrenia, 2) people with schizoaffective disorders for whom lithium is widely used in clinical practice, although there is no evidence to support this use.

Lithium augmentation in treatment-refractory unipolar depression * Authors' reply

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Bromocriptine augmentation therapy in a patient with Cotard's syndrome

A 72-year-old female with bipolar I disorder developed Cotard's syndrome, i.e., various delusions of negation accompanied by severe depressive symptoms. She responded neither to the combination of antipsychotic drug and antidepressant nor to the lithium augmentation therapy. However, the delusions and depressive symptoms improved dramatically after the addition of bromocriptine 2.5–5 mg/day to the combination of clomipramine and lithium. This report suggests that bromocriptine augmentation therapy might be effective at least for some patients with Cotard's syndrome in mood disorders.

Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder

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 gland with a subsequent hypersensitivity to ACTH. Results of this study should be confirmed in a larger study group.

Randomised controlled trials investigating pharmacological and psychological interventions for treatment-refractory depression. Systematic review.

About 30% of people with depression do not respond to an antidepressant at the recommended dose and can be described as having treatment-refractory depression. To summarise the findings from all randomised controlled trials (RCTs) that have assessed the efficacy of a pharmacological or psychological intervention for treatment-refractory depression. We used a systematic search strategy to identify RCTs that included adults aged 18-75 years with a diagnosis of unipolar depression that had not responded to a 4-week course of a recommended dose of an antidepressant. We identified 16 RCTs. None of the included trials assessed the efficacy of psychotherapy. All the trials were too small to detect an important clinical response. We found only two trials on lithium augmentation, which randomised 50 subjects in total. There is little evidence to guide the management of depression that has not responded to a course of antidepressants. Treatment-refractory depression is an important public health problem and large pragmatic trials are needed to inform clinical practice.

Lithium Augmentation Increases the ACTH and Cortisol Response in the Combined DEX/CRH Test in Unipolar Major Depression

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.

Treatment of Resistant Depression by Adding Noradrenergic Agents to Lithium Augmentation of SSRIs

Treatment of Resistant Depression by Adding Noradrenergic Agents to Lithium Augmentation of SSRIs

Discontinuation of lithium augmentation in an elderly cohort.

To observe the effects of gradual discontinuation of lithium augmentation therapy in a group of patients over the age of 65 years and to measure the rate of relapse and to identify any factors which would predict relapse. This was a naturalistic study involving 21 patients who were on lithium augmentation and whose lithium was discontinued for a variety of clinical reasons. In most cases lithium was tapered and discontinued over a period of 2-12 weeks. Demographic and other variables were collected at baseline and compared between those who remained well and those that subsequently relapsed. Eleven patients (52.4%) relapsed following discontinuation of lithium augmentation. Those who relapsed had been on lithium for significantly longer than those who remained well off lithium (p = 0.007). There was a trend towards more hospital admissions in the relapse group (p = 0.062). When lithium augmentation therapy is discontinued in elderly depressives over half of these patients relapse. A longer duration of prediscontinuation lithium treatment and more hospital admissions appear to be associated with increased risk of relapse.

Practitioner versus medication-expert opinion on psychiatric pharmacotherapy of mentally retarded patients with mental disorders.

The agreement of practicing psychiatrists with medication experts regarding how psychotropic drugs should be used to treat behavioral and psychiatric problems in patients with mental retardation was studied. The medication survey used in developing guidelines on the treatment of behavioral and psychiatric problems in mental retardation was sent to 85 psychiatrists who had been identified as caring for the mentally retarded in the Texas public mental health system. The comparison of these practitioners with the medication experts included first-line and second-line treatment choices. Survey analysis was based on using 95% confidence intervals (CIs) to determine the type of rating. If the 95% CIs for the practitioners' responses overlapped the 95% CIs for experts, the two groups were judged to be in agreement. Thirty-seven practitioners (43.5%) completed and returned the survey. Few differences between the practitioners and the medication experts were found with respect to treatments for specific mental illness diagnoses. However, the practitioners rated venlafaxine and mirtazapine higher than the medication experts. Lithium augmentation of therapy with selective serotonin-reuptake inhibitors for nonpsychotic depression was rated first-line by the practitioners and second-line by the medication experts. Practicing psychiatrists and medication experts generally agreed about the use of psychotropic drugs for mental illness in patients with mental retardation.

Dr. Bauer and Colleagues Reply

Back to table of contents Previous article Next article Letter to the EditorFull AccessDr. Bauer and Colleagues ReplyMICHAEL BAUER, M.D., PH.D., TOM BSCHOR, M.D., DIETER KUNZ, M.D., ANNE BERGHÖFER, M.D., ANDREAS STRÖHLE, M.D., and BRUNO MÜLLER-OERLINGHAUSEN, M.D., MICHAEL BAUERSearch for more papers by this author, M.D., PH.D., TOM BSCHORSearch for more papers by this author, M.D., DIETER KUNZSearch for more papers by this author, M.D., ANNE BERGHÖFERSearch for more papers by this author, M.D., ANDREAS STRÖHLESearch for more papers by this author, M.D., and BRUNO MÜLLER-OERLINGHAUSENSearch for more papers by this author, M.D., Los Angeles, Calif.Published Online:1 Aug 2001https://doi.org/10.1176/appi.ajp.158.8.1338AboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We appreciate the comments by Dr. Faedda and colleagues suggesting that rapid lithium discontinuation may uncover latent bipolar disorder in patients unresponsive to antidepressant treatment and that these patients may represent a separate group with a disproportionately high risk of bipolarity. Such interpretation, however, should be made with some caution.Dr. Faedda et al. base their interpretation on two points. First, the rate of switching to mania in our study seemed higher than that found by Akiskal et al. (1995). However, the number of subjects in our placebo group (N=15) was too small to estimate reliably a switching rate, and it is difficult to directly contrast findings from the 11-year, long-term study by Akiskal et al. with findings from our short-term study of acute and continuation treatment. Second, Dr. Faedda et al. feel that the increased risk of rapid recurrence, particular of mania, after lithium discontinuation played a role in our results. This is possible; nevertheless, what may be more important is that each subject was taking antidepressants—mostly tricyclics—throughout our study, including the period after lithium discontinuation. A switching rate of 13.3% in patients taking antidepressants does not seem unusually high. There have been numerous reports that, on average, tricyclic antidepressants induce switching in 9% of the patients treated for depression (1) and, in some studies, even up to 25% (2). With respect to the suggestion that unipolar patients who are unresponsive to antidepressants may represent a particular group with a disproportionately high risk of switching, we are not aware of any report in the literature to support this supposition.The possible effect of lithium discontinuation is more difficult to evaluate. The risk of rapid recurrence after lithium discontinuation is controversial (3) and may depend on patient selection. In addition, the studies reporting an increased risk are all long term, generally extending for years (4), and the observation may not be applicable to our study, in which subjects were treated with lithium for only 8–10 weeks.We agree that it is wise in practice to look for indications of bipolarity in individual subjects and in the family histories of patients who receive lithium augmentation and to taper lithium gradually (5). Finally, we agree that the two unipolar subjects who switched to mania after lithium augmentation and discontinuation during the double-blind phase of our study, in fact, suffered from a pseudounipolar illness (bipolar disorder with a unipolar course). Of these two patients, one had already experienced three depressive episodes before the index episode, and the other had a family history of major depressive disorder. This observation would be in agreement with the finding of Angst et al. (6), who reported that patients with three or more unipolar depressive episodes are especially prone to a diagnostic change from unipolar to bipolar disorder.