Six things to know about the homicides of doctors: a review of 30 years from Italy.

BACKGROUND: Healthcare workers have a 16 times greater risk of suffering workplace violence than workers in other sectors and around 50% experience workplace violence in the course of their career. The objective of this study is to explore the characteristics and circumstances of work-related killings of doctors. METHODS: Work-related homicides of doctors over the period 1988-2019 were identified retrospectively through the Italian national statistical agencies. Variables such as perpetrator, motive and location of the crime were obtained through forensic psychiatric work. After classification, the absolute and percent values of the main characteristics of the homicides were calculated. RESULTS: Over the period considered, 21 doctors were killed in Italy in connection with their professional activity. In 52% (n = 11) of cases, the killer was one of the doctor's patients, in 29% (n = 6) of cases it was a patient's relative, in 19% (n = 4) an occasional patient (first consultation). The location of the homicide was a community clinic in 48% (n = 10) of cases, the street in 19% (n = 4) of cases, the doctor's home in 14% (n = 3), the hospital in 14% (n = 3) and the patient's home in 5% (n = 1). In 57% (n = 12) of cases the perpetrator was not affected by any mental disorders. The motive for the homicide was revenge in 66.7% (n = 14) of cases; in 28.6% (n = 6) the revenge was preceded by stalking. CONCLUSIONS: Doctors should be aware that the risk of being killed is not limited to hospital settings and that their patients' family members might also pose a threat to them.

[Guidelines in psychiatry: clinical and forensic issues]. / Linee guida in psichiatria: criticità cliniche e forensi.

Treatment guidelines (GL) in psychiatry represent a useful and functional tool to be explored and enhanced in terms of the contribution of patient care and the promotion of scientific improvement. However, they show some limitations, both clinical and forensic. The objective of this paper is to examine the objectives, the clinical limitations and the applicability of the GL on professional liability (forensic aspects). From a clinical point of view, the GL have objectives that are functional to the promotion of physical and mental health, among which the constitutional observance of the right to health, the improvement of public health, the implementation of best clinical practices, the promotion of scientific research, the professional training of operators in the field of physical and mental health. However, GL cannot replace a contextualized clinical judgment. GL must be applied, in the single clinical case, in light of their multiple criticalities, including the limits of the methodology used for their formulation, the differences between the GL' recommendations, the difficulty of their application in daily clinical practice, the lack of specific treatment interventions. From a forensic psychiatric point of view, GL, as currently conceived, cannot be used in terms of professional liability without their interpretation on a legal basis with forensic psychiatric methodology, similarly to any other clinical and scientific information, with its qualifications and criticalities.

[The psychiatrization and unpredictability of interpersonal violent behavior]. / Sulla psichiatrizzazione e imprevedibilità del comportamento violento sulla persona.

The relationship between mental illness and violent behavior is a complex phenomenon. Scientific literature indicates that the presence of a mental disorder, even severe, is not sufficient, alone, to predict or motivate violent behavior, which seems to be more associated with other intermediate variables. The phenomenon of psychiatrization of violent behavior can be defined, from a psychiatric-forensic point of view, as the prejudicial and erroneous attribution to mental illness as a causal factor in relation to violent behavior. This phenomenon has consequences in psychiatric clinical practice, but also at the level of social stigmatization, management of organizational and economic resources, and the judicial system. In this paper, clinical criticalities related to the psychiatrization of violent behavior will be analyzed, including the need to differentiate clinical etiology and legal causality, predictability and avoidability, protective clinical factors and clinical risk factors, the limits of categorical psychiatric diagnosis, the need for specific victimological information, the criticalities of pharmacotherapy. Some forensic criticalities will also be analyzed, including errors in clinical and forensic methodology (psychiatrization of the symptom, prejudicial contamination, diagnostic overshadowing, legal causalization of protective and risk factors, the use of categorical diagnosis in the forensic field, the psychiatrization of non-pathological human experiences, the criminalization of the subject with mental disorder). In conclusion, it is highlighted that an individual can have a psychic disorder, even severe, but this disorder is not necessarily in a causal relationship with violent behavior. The lack of a causal relationship makes predictability of violent behavior difficult, even impossible depending on the case, both in the general population and in individuals with psychiatric disorders.

[Clinical interview in psychiatric difficult situations]. / Il colloquio in situazioni psichiatriche di crisi.

There are here described a number of basic principles underlying an effective clinical interview in psychiatric difficult situations (violent or suicidal patients, victims of serious physical and psychological damages, authors of inadequate or anti-social requests to the therapist). The aim of the present study is to provide the psychiatric operator with useful skills for the optimal management of the interview in difficult situations both at diagnostically and therapeutically level. The methodology was based on examination of the literature and personal experience of the authors. The authors highlighted 18 working hypothesis that may represent beneficial instruments in situations of difficult psychiatric interview. Further studies will deepen under the clinical, actuarial and statistical validity the principles covered in various clinical and crisis situations with difficulty to the interview, in relation also to specific types of patients for a more updated training of the operators in the field of mental health.

[Charges and convictions of psychiatrists for the violent behavior of the patient: psychiatric-forensic remarks]. / Osservazioni psichiatrico-forensi sulle imputazioni e condanne agli psichiatri per il comportamento violento del paziente.

Purpose of the present study is to point-out a number of psychiatric-forensic remarks about the management of violent behavior against the person (VBP) amongst psychiatric patients. The study is the authors' personal contribution based on clinical and forensic experience as experts in the management of psychiatric patients with VBP. Twelve psychiatric-forensic remarks have been highlighted in the present study: 1) VBP is a multifactorial event; 2) the risk of VBP against the person may change rapidly over time in quantity and quality; 3) there are no methods for reliable prediction of VBP in a single clinical-case; 4) there are no medications with an indication of "heal" the VBP; 5) there are no therapeutic measures that neutralize always, quickly and without recurrences VBP; 6) there exist clinical hypotheses to assess VBP; 7) there exist principles of victimology to assess VBP; 8) there are emotional reactions that can affect the evaluation and clinical and forensic management of VBP; 9) the responsibility of the psychiatrist has to be evaluated at the moment of the events; 10) the responsibility of the psychiatrist must be contextualized in the single clinical-case; 11) there is the need to clarify the individual professional responsibility of psychiatrists who treated a patient; 12) there is the need to clarify the criteria for the definition of the guarantee role. The above-mentioned twelve psychiatric-forensic remarks have implications in the assessment and management of psychiatric patients with violent behavior. They may constitute a basis for further discussion aiming to obtain consensus amongst psychiatrists about good clinical practice and forensic implication in the management of psychiatric patients with VBP and to avoid charges and convictions.

[Murder of the doctor]. / L'omicidio del medico.

AIM: To examine possible risk factors for the doctor to be killed by the patient in the clinical practice by examining a series of murders that involved physicians. METHODS: This aim has been achieved through a retrospective review on clinical cases of doctors killed by patients within the period between 1988 and 2013, in Italy. RESULTS: In this period 18 Italian doctors have been killed in the workplace, with a rate of 0.3/100,000. In 7 cases, the murder resulted in the context of doctor-dissatisfaction; in 7 cases the murder was committed by a psychiatric patient; 1 case in the context of a stalking; 3 cases occurred in a workplace which was not safe enough. Four categories of at-risk contexts have been identified. One category includes a murder in the context of a doctor-dissatisfaction, perceived by patient. The second category concerns murders committed by patients suffering from mental illness. A third category includes homicides in a workplace which is not safe. The last category comprises the murder in the context of stalking. CONCLUSIONS: These categories identify specific dangerous situations for physicians, in which are highlighted elements that have played a crucial role in the murder and for which special precautions are suggested preventive.

[Suicidal contagion and collusion between therapist and patient]. / Il contagio e la collusione suicidaria tra terapeuta e paziente.

The purpose of the present study is to point out suicidal contagion and suicidal collusion describing clinical cases, to improve professional skills in suicidal risk evaluation and management. In suicide contagion we described three typologies of contagion between therapist and patient: 1) suicide contagion of the environment on the therapist and on the patient; 2) suicide contagion of the therapist on the patient; 3) suicide contagion of the patient on the therapist. We described also four typologies of suicidal collusion with specific kind of patients: 1) with patient suffering of physical illness; 2) with patient suffering of a serious mental illness; 3) with manipulative patients; 4) with patient who is aggressive toward himself and toward other people. In conclusion we pointed out the importance of an adequate recognizement and management of suicidal contagion and collusion to decrease patient suicidal risk.

The symptom structure of bipolar acute episodes: in search for the mixing link.

OBJECTIVE: The nature of mixed mood episodes is still a matter of controversy amongst experts. Currently, the approach to this syndrome is mainly categorical and very restrictive. The factor-structure of bipolar mood episodes has not been studied yet. We performed a dimensional analysis of the structure of bipolar episodes aimed at identifying a factor deconstructing mixed episodes; furthermore, we analyzed correlations of factors emerging from the factorial analysis of the Brief Psychiatric Rating Scale (BPRS) with Temperament Evaluation of Memphis-Pisa-Paris-San Diego (TEMPS-A) and predominant polarity. METHOD: 187 consecutive bipolar I inpatients hospitalized for DSM-IV-TR acute mood episodes (depressive, manic or mixed) underwent a standardized assessment, including the 24-item Brief Psychiatric Rating Scale (BPRS 4.0), the 21-item Hamilton Depression Rating Scale (HDRS-21), the Young Mania Rating Scale (YMRS) and the TEMPS-A. Principal factor analysis was performed on BPRS-24 items. RESULTS: This analysis revealed five factors corresponding to "psychosis", "euphoric mania", "mixity", "dysphoria" and "inhibited depression", capturing 71.89% of the rotated variance. The mixity factor was characterized by higher rates of suicidal ideation, more mixed episodes, higher frequencies of antidepressant (AD) use, depressive predominant polarity and anxious temperament. DISCUSSION: The factor-structure of the BPRS in inpatients with bipolar I disorder with an acute episode of any type is pentafactorial; one factor identified is the mixity factor, which is independent from other factors and characterized by anxiety and motor hyperactivity and by the absence of motor retardation. Our results should prompt reconsideration of proposals for DSM-5 diagnostic criteria for the mixed features specifier. Limitations of the study include the relative small sample, the absence of drug-naïve patients and the use of rating scales no specific for mixed states.

Treatment strategies according to clinical features in a naturalistic cohort study of bipolar patients: a principal component analysis of lifetime pharmacological and biophysic treatment options.

BACKGROUND: The treatment of patients with bipolar disorder (BD) is complex and psychiatrists often have to change treatment strategies. However, available data do not provide information about the most frequent patterns of treatment strategies prescribed in clinical practice and clinical/socio-demographic factors of drugs prescription. OBJECTIVE: The aims of this study were: (1) to identify specific patterns of life-time treatment strategies in a representative sample of bipolar patients; (2) to assess consistency with guidelines recommendations; and (3) to investigate clinical/socio-demographic of patients. METHODS: Six-hundred and four BD I and II out-patients were enrolled in a naturalistic cohort study at the Barcelona Bipolar Disorders Program, in a cross-sectional analysis. A principal component analysis was applied to group psychotropic drugs into fewer underlying clusters which represent patterns of treatment strategies more frequently adopted in the life-time naturalistic treatment of BD. RESULTS: Three main factors corresponding to three main prescription patterns were identified, which explained about 60% of cases, namely, Factor 1 (21.1% of common variance), defined the "antimanic stabilisation package" including treatments with antimanic mechanism of action in predominantly manic-psychotic BD I patients; Factor 2 (20.4%), "antidepressive stabilisation package" that grouped predominantly depressed patients, and Factor 3 (16.4%) defined the "anti-bipolar II package", including antidepressant monotherapy in BD II patients with depressive predominant polarity, melancholic features and higher rates of suicide behaviours. CONCLUSIONS: This study identified three patterns of lifetime treatment strategies in three specific and different groups of naturalistically treated bipolar patients.

Risk factors for antidepressant-related switch to mania.

OBJECTIVE: Treatment of bipolar depression with antidepressants is strongly debated on the basis of the methodologically poor and insufficient data supporting their use and the widely held belief that antidepressants can induce new episodes of abnormal mood elevation or accelerate the rate of cycling. The present study aimed at identifying clinical risk factors for switch into hypomania, mania, or mixed states, within 8 weeks after introduction of an antidepressant or after increasing its dosage, in a prospective, longitudinal design. METHOD: 221 consecutive DSM-IV-TR depressed bipolar I and II disorder patients were treated with antidepressants, which were added to previously prescribed mood stabilizers and/or atypical antipsychotics. No patient was on antidepressant monotherapy. The patients were enrolled from October 2005 through January 2010. The primary outcome was the assessment of switch to mania or hypomania within 8 weeks after the introduction or dose increase of an antidepressant. Both groups were compared with analysis of variance and χ² procedures. RESULTS: Treatment-emergent affective switch was detected in 54 patients (24.4%) (switch group) while 167 patients (75.6%) (nonswitch group) did not experience a treatment-related switch. The main clinical differences significantly associated with the occurrence of an antidepressant-related switch, after performing logistic regression analysis, were higher rate of previous switches (P < .001) in the switch versus the nonswitch group, lower rate of responses to antidepressants (P < .001) in the switch versus the nonswitch group, and earlier age at onset (P = .026) in the switch versus the nonswitch group. DISCUSSION: Bipolar patients with an earlier age at onset and an illness course characterized by lower rate of response to antidepressants and higher rate of switches into mania or hypomania were found to be the ones with higher switch risk. Nevertheless, a greater number of previous antidepressant exposures was not associated with the occurrence of an antidepressant-associated switch. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01503489.

New treatment guidelines for acute bipolar mania: a critical review.

A number of treatment guidelines for bipolar disorder have been published and updated in the last few years. They are aimed at providing a synthesis of the best available scientific knowledge, and their application to every-day work should be helpful to clinicians. The aim of this report is to critically review recent guidelines focusing on the treatment of manic/hypomanic and mixed episodes. Guidelines are quite heterogeneous in methodology and conclusions, but they all agree that the treatment of manic/hypomanic and mixed episodes should generally be initiated with a medication such as lithium (Li), valproate (VPA) or atypical antipsychotics (AAP), including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone as monotherapy. All guidelines agree on stopping ongoing antidepressant medication during mania. Combination therapy including Li or VPA with an AAP is suggested usually as second-line choice, sometimes as first-choice treatment for severe mania. Carbamazepine is mostly suggested as second line and not recommended in combination. Other antiepileptic drugs are not recommended for the treatment of mania, although lamotrigine may be maintained if it was prescribed previously for the prevention of depressive episodes. Main sources of discrepancies among guidelines include benefit-risk ratio issues (how much priority is given to efficacy over safety and tolerability), starting with combination versus monotherapy, and how to deal with treatments which are more experience-based than evidence-based (i.e.: electroconvulsive therapy).

Gender differences in a cohort study of 604 bipolar patients: the role of predominant polarity.

BACKGROUND: Some clinical differences between gender regarding the course and outcome of bipolar disorders have already been described and some others remain still controversial. AIMS: To explore gender differences regarding clinical and socio-demographic characteristics amongst bipolar patients with particular attention to predominant polarity and depressive symptoms. METHOD: Data were collected from DSM-IV type I and II bipolar patients (n=604), resulting from the systematic follow-up of the Bipolar Disorders Program, Hospital Clinic of Barcelona, over an average follow-up of 10 years. Socio-demographic and clinical variables were collected in order to detect gender-related differences. RESULTS: Bipolar women are more likely than men to show a predominance of depressive polarity as well as a depressive onset whilst men would be more likely to suffer from comorbid substance use disorders. Women significantly have a higher lifetime prevalence of psychotic depression and a higher prevalence of axis II comorbid disorders. Bipolar women are also more likely to have a family history of suicide and a lifetime history of attempted suicide. Suicide attempts are more often violent amongst bipolar men. In a backward logistic regression model, two variables were responsible for most gender-related clinical differences: type of predominant polarity - more likely to be depressive amongst women - (B=-0.794, p=0.027, Exp(B)=0.452; CI= 0.223-0.915), alcohol abuse (B=-1.095, p=0.000, Exp(B)=2990; CI= 1.817-4.919) and cocaine abuse (B=0.784, p=0.033, Exp(B)=2.189; CI= 1.066-4.496) - more prevalent amongst men. CONCLUSION: The main characteristic featuring bipolar women is depression, both at illness onset and as a predominant polarity all along the illness course. This may have important diagnostic and therapeutic implications.

[Psychopathology and risk of homicide committed by a patient with schizophrenia]. / Sulla psicopatologia e sulla valutazione del rischio dell'omicidio compiuto dal paziente con disturbo schizofrenico.

We describe, thirteen psychopathologic dynamics based on defense mechanism and primary process thinking, that could determined an homicide committed by a patient with schizophrenia. The purpose of this study is to allow: a) to improve diagnosis of the homicidal act; b) to emphasize psychopathological elements which can be treated by specific forensic psychotherapy; c) to prevent an homicidal recidivism through evaluation of risk passing to the homicidal act.

Mania and depression. Mixed, not stirred.

OBJECTIVE: Current criteria for mixed bipolar episode do not allow an adequate understanding of a vast majority of bipolar patients with mixed (hypo) manic-depressive features, keeping the qualification of "mixed episodes" for bipolar type I only. This study was aimed to test the existence of a bipolar-mixed continuum by comparing the characteristics of three groups classified according to patterns of past and current manic or mixed episodes. METHOD: 134 bipolar I inpatients were divided according to their pattern of excitatory "mixed-like" episodes in three groups: 1) lifetime history of purely manic episodes without mixed features (PMA); 2) lifetime history of both manic and mixed episodes (MIX) and 3) lifetime history exclusively of mixed, but not manic, episodes (PMIX). Differences in clinical and demographic characteristics were analyzed by using chi-square head-to-head for categorical data, one-way ANOVA for continuous variables and Tukey's post-hoc comparison. Logistic regression was used to control for data validity. RESULTS: PMIX had higher rates of depressive predominant polarity and less lifetime history of psychotic symptoms, and had received more antidepressants both lifetime and during 6 months prior to index episode. PMIX had more suicide attempts and Axis I comorbidity than PMA. DISCUSSION: PMIX is likely to have a higher risk for suicide and higher rates of comorbidities; current DSM-IV-TR criteria are not fit for correctly classifying these patients and this may affect treatment appropriateness. The concept of "mixicity" should be extended beyond bipolar I disorder to other bipolar disorder subtypes.

[Therapist's reactions on the treatment of suicidal patients]. / Reattività inadeguata del terapeuta nei confronti del paziente a rischio suicidario.

In the present study, we describe fourteen therapists' reactions (Avoidance, Rejection, Suicidal collusion, Over-involvement, Overprotection, Loss of patients' responsibilities, Loss of therapists' responsibilities, Reaction to the feeling of being exploited, Creation of dependency, Manipolatory acting out, Feeling of undergoing an iniquity, Patients psychopathology inflation, Therapists' psychopathology inflation, Suicidal Burnout Syndrome), based on emotions, behaviors and cognitivity, toward patients with suicidal risk. These responses can interfere with a correct assessment and management of suicidal risk in psychiatric patients. The purpose of the present clinical study was to improve therapist's professional skills through the recognition and management of his own responses to suicidal patients.

Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients.

OBJECTIVES: The aim of this study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder. METHOD: We enrolled a sample of 144 patients followed for up to 20 years in the referral Barcelona Bipolar Disorder Program and compared subjects who had experienced at least one mixed episode during the follow-up (n=60) with subjects who had never experienced a mixed episode (n=84) regarding clinical variables. RESULTS: Nearly 40% of bipolar I disorder patients treated with antidepressants experienced at least one mixed episode during the course of their illness; no gender differences were found between two groups. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, only suicide attempts (p<0.001), the use of serotonin norepinephrine reuptake inhibitors (p=0.041), switch rates (p=0.010), and years spent ill (p=0.022) were significantly associated with the occurrence of at least one mixed episode during follow-up. CONCLUSIONS: The occurrence of mixed episodes is associated with a tendency to chronicity, with a poorer outcome, a higher number of depressive episodes, and greater use of antidepressants, especially serotonin norepinephrine reuptake inhibitors.

Differential outcome of bipolar patients receiving antidepressant monotherapy versus combination with an antimanic drug.

INTRODUCTION: Despite antidepressants are widely used in treating bipolar depression, there is much debate about their utility and their potential dangers, involving mood switches and suicidality. Our hypothesis was that the pattern of initial antidepressant prescription, i.e., alone (AM) or in combination with stabilizers (AC) might impact the long-term outcome of patients with bipolar disorder (BP). We aimed to test this hypothesis and to identify outcome measures that could be predicted by initial AM or AC treatment in patients with BP. METHODS: We included 95 patients with DSM-IV BP from a pool of 138 patients following a BP program. Patients were rated for initial AM vs. AC treatment when they were first seen in primary care and subdivided into two groups accordingly. Differences in their clinical course were sought investigating course both retrospectively and prospectively (mean follow-up 10 years). Primary outcome measures comprised suicidality and switch rate. RESULTS: There were significantly more patients who switched in the AM group than in the AC group. The number of suicide attempts was higher in the AM group. Significance was retained after performing logistic regression. LIMITATIONS: Sample size was small and severe BP patients might be overrepresented in this sample. DISCUSSION: Initial AM treatment of patients subsequently diagnosed as BP may entrain a course characterized by higher proneness to switch and suicidal behaviour. Accurate initial diagnosis of bipolar depression should prompt combined treatment with antimanic drugs.

New treatment guidelines for acute bipolar depression: a systematic review.

INTRODUCTION: Bipolar depression poses a great burden on patients and their families due to its duration, associated functional impairment, and limited treatment options. Given the complexity of the disorder and the advances in treatment, a number of clinical guidelines, consensus statements and expert opinions were developed with the aim to standardize treatment and provide clinicians with treatment algorithms for every-day clinical practice. Unfortunately, they often led to conflicting conclusions and recommendations due to limitations of the available literature. As findings emerge from research literature, guidelines quickly become obsolete and need to be updated or revised. Many guidelines have been updated in the last 5 years, after the last review of bipolar disorder (BD) treatment guidelines. OBJECTIVE: The purpose of this work is to systematically review guidelines, consensus meetings and treatment algorithms on the acute treatment of bipolar depression updated or published since 2005, to critically underline common and critical points, highlight limits and strengths, and provide a starting point for future research MATERIALS AND METHODS: The MEDLINe/PubMed/Index Medicus, PsycINFO/PsycLIT, Excerpta Medica/EMBASE, databases were searched using "depression", "bipolar", "manic-depression", "manic-depressive" and "treatment guidelines" as key words RESULTS: The search returned 204 articles. Amongst them, there were 28 papers concerning structured treatment algorithms and/or guidelines suggested by official panels. After excluding those guidelines that were not performed by scientific societies or international groups and those published before 2005, the final selection yielded 7 papers When looking into guidelines content, the results indicate a trend to the gradual acceptance of the use of the atypical antipsychotic quetiapine as monotherapy as first-line treatment. Antidepressant monotherapy is discouraged in most of them, although some support the use of antidepressants in combination with antimanic agents for a limited period of time. Lamotrigine has become a highly controversial option. CONCLUSION: The management of bipolar depression is complex and should be differentiated from management of unipolar depression. Guidelines may be useful instruments for helping clinicians to choose and plan bipolar depression treatment by integrating the more updated scientific knowledge with every-day clinical practice and patient-specific factors; however, a further effort is needed in order to improve guidelines implementation in clinical practice. The latest updates on treatment guidelines for bipolar depression give priority to novel treatment approaches, such as quetiapine, over more traditional ones, such as lithium or antidepressants. Lamotrigine is a controversial option.

Lithium: still a cornerstone in the long-term treatment in bipolar disorder?

BACKGROUND: Scientific literature considers lithium a key treatment for the acute and long-term management of bipolar disorder (BD). Despite its worldwide clinical use, the effectiveness of lithium has been questioned. The aim of this work is to critically review the available data on randomized controlled trials (RCTs) concerning long-term lithium treatment. METHODS: A systematic search for long-term treatment RCTs with at least 6 months of follow-up was performed. Six RCTs enrolling 1,561 bipolar I and II patients of adult and pediatric age, randomizing 534 to lithium, were identified. All studies are controlled trials sponsored by industry, investigating new treatments for BD, with lithium as an active comparator, and therefore not specifically designed to study lithium efficacy or safety. RESULTS: RESULTS from earliest studies suggest a high effectiveness of lithium against both mania and depression, while more recent studies highlight lithium as more effective than placebo in mania and hypomania, without significant evidence in depression. Lithium does not achieve significant differences in efficacy when compared with divalproex; it seems less effective than lamotrigine in preventing depression and less effective than olanzapine in manic and mixed episodes. CONCLUSIONS: Despite a number of methodological issues (enriched designs, unbalanced samples, potential inclusion of lithium nonresponders in some studies), lithium appears to have a clear antimanic prophylactic activity and some efficacy in the prevention of depression. Lithium should still have a major role in the long-term treatment of BD.