Raccogliamo qui una serie di articoli, comparsi nel corso di questo mese, che mettono in dubbio sia l'efficacia che molti aspetti della sicurezza dei farmaci antidepressivi.

EFFETTO DELLA PUBBLICAZIONE SELETTIVA DEI TRIAL SULL'EFFICACIA APPARENTE DEGLI ANTIDEPRESSVI
[SELECTIVE PUBLICATION OF ANTIDEPRESSANT TRIALS AND ITS INFLUENCE ON APPARENT EFFICACY]
Turner EH, Matthews AM, Linardatos E, et al.
NEJM 2008; 358:252-260

Gli autori di questo studio hanno confrontato il numero di trial registrati presso la FDA e il numero di trial pubblicati, nell'ambito della dimostrazione dell'efficacia di 12 agenti antidepressivi. L'analisi ha mostrato che, di 74 studi registrati, nel 31% dei casi i risultati non erano stati pubblicati. In particolare, tra gli studi che la FDA ha giudicato portatori di risultati positivi, solo uno non è stato pubblicato, mentre gli studi aventi esito negativo, salvo tre eccezioni, o non sono stati affatto pubblicati (22 casi) o sono stati presentati in modo da fare intendere che avessero dato risposta positiva (11 casi). Questo tipo di selezione ha generato l'impressione che il 94% dei trial condotti abbia dimostrato l'efficacia degli antidepressivi, mentre l'analisi della FDA rileva che la percentuale reale è del 51%; questa selezione ha determinato un incremento dell'efficacia stimata del 32%, complessivamente, con percentuali che oscillano dall'11 al 69% per i singoli farmaci.
Si tratta di un modo di procedere non corretto, che può portare a conseguenze negative per i ricercatori, i partecipanti agli studi, i medici e i pazienti.

ABSTRACT
BACKGROUND Evidence-based medicine is valuable to the extent that the evidence base is complete and unbiased. Selective publication of clinical trials - and the outcomes within those trials - can lead to unrealistic estimates of drug effectiveness and alter the apparent risk-benefit ratio.
METHODS We obtained reviews from the Food and Drug Administration (FDA) for studies of 12 antidepressant agents involving 12,564 patients. We conducted a systematic literature search to identify matching publications. For trials that were reported in the literature, we compared the published outcomes with the FDA outcomes. We also compared the effect size derived from the published reports with the effect size derived from the entire FDA data set.
RESULTS Among 74 FDA-registered studies, 31%, accounting for 3449 study participants, were not published. Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall.
CONCLUSIONS We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

TERAPIA ANTIDEPRESSIVA E RISCHIO DI DIABETE DI TIPO 2
[TYPE OF ANTIDEPRESSANT THERAPY AND RISK OF TYPE 2 DIABETES IN PEOPLE WITH DEPRESSION]
Brown LC, Majumdar SR, Johnson JA
Diabetes Res Clin Pract 2008; 79:61-67


RIASSUNTO
OBIETTIVO Obiettivo di questo studio era la valutazione del diverso rischio di diabete tra le persone che assumono farmaci antidepressivi.
METODI Per perseguire l'obiettivo è stato condotto uno studio caso controllo nested, usando i dati provenienti dalla provincia canadese di Saskatchewan, disponibili per il periodo dal 1° gennaio 1991 al 31 dicembre 2001. La lunghezza media del follow-up è stata di 4,07 anni. il diabete di tipo 2 e la depressione maggiore sono state identificate attraverso i codici diagnostici ICD-9 e la prescrizione di farmaci antidiabetici e antidepressivi.
RISULTATI L'analisi di regressione logistica multivariata è stata usata per stimare l'odds ratio (OR) e l'intervallo di confidenza al 95% (IC). Sono stati identificati 2.391 soggetti in terapia con antidepressivi, di età media (±DS) pari a 53,6 (±16,4) anni e per il 66% femmine. Dopo l'aggiustamento multivariato, l'uso concomitante di inibitori selettivi della ricaptazione della serotonina (SSRI) e di antidepressivi triciclici (TCA) è risultato associato ad un significativi incremento del rischio di diabete di tipo 2 (OR aggiustato 1,89; IC 95% 1,35-2,65).
CONCLUSIONI L'uso associato di antidepressivi triciclici e inibitori selettivi della ricaptazione della serotonina era associato ad un rischio quasi doppio di diabete di tipo 2 rispetto all'uso dei soli triciclici, indipendentemente da età, sesso, patologie concomitanti e gravità dello stato depressivo. Gli individui che assumono l'associazione dovrebbero essere monitorati da vicino relativamente a questo rischio.

ANTIDEPRESSIVI E DISTURBI DELL'OMEOSTASI DEL GLUCOSIO
[THE ASSOCIATION BETWEEN ANTIDEPRESSANT USE AND DISTURBANCES IN GLUCOSE HOMEOSTASIS: EVIDENCE FROM SPONTANEOUS REPORTS]
Derijks HJ, Meyboom RHB, Heerdink ER, et al.
Journal European Journal of Clinical Pharmacology 2008, Jan 15 [Epub ahead of print]

Questo studio caso-controllo, che ha preso in considerazioni tutte le segnalazioni di ADR attribuite ad antidepressivi, antipsicotici e benzodiazepine, ha rafforzato l'ipotesi, già esistente, che l'impiego di farmaci antidepressivi può alterare il controllo dell'omeostasi del glucosio. In particolare, l'iperglicemia è risultata maggiormente associata agli antidepressivi con alta affinità per i recettori 5-HT_2c e H₁ e per il trasportatore della noradrenalina, mentre l'associazione con l'ipoglicemia è stata più pronunciata per i farmaci con alta affinità per il trasportatore della serotonina.

ABSTRACT
OBJECTIVES Depression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper- and hypoglycaemia.
METHODS Based on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper- or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper- or hypoglycaemia-inducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI).
RESULTS Overall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20-1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40-2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT2c receptor, histamine-1 receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter.
CONCLUSION The results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.

USO DI ANTIDEPRESSIVI E RISCHIO DI TROMBOEMBOLISMO VENOSO
[ANTIDEPRESSANT DRUG USE AND RISK OF VENOUS THROMBOEMBOLISM]
Jick SS, Li L
Pharmacotherapy 2008; 28: 144-150

Lo studio caso-controllo nested, condotto su 782 pazienti con diagnosi di tromboembolismo venoso che assumevano antidepressivi, confrontati con un gruppo controllo di non utilizzatori, ha evidenziato un incremento del rischio di sviluppare la patologia per gli utilizzatori di antidepressivi triciclici, in particolare di amitriptilina, mentre non è emerso un aumento del rischio in associazione al consumo di inibitori selettivi della ricaptazione della serotonina o altri antidepressivi.

ABSTRACT
OBJECTIVE To evaluate the risk of idiopathic venous thromboembolism associated with antidepressant use and to further assess the risk by class of antidepressant and by individual antidepressant drug.
DESIGN Nested case-control study.
DATA SOURCE United Kingdom General Practice Research Database.
SUBJECTS Seven hundred eighty-two case patients with a confirmed diagnosis of venous thromboembolism who were taking an antidepressant drug and 3085 matched control subjects.
MEASUREMENT AND MAIN RESULTS We identified all people in the database aged 70 years or younger with venous thromboembolism who had filled at least one prescription for an antidepressant drug between 1990 and 2005; up to four control subjects were matched to each case patient by age, sex, practice attended, index date, and duration of computerized medical record. We compared the risks of current and recent use of antidepressant drugs with nonuse of an antidepressant before the index date (date of diagnosis of venous thromboembolism) by using conditional logistic regression. Current exposure to tricyclic antidepressants was associated with a small increased risk of idiopathic venous thromboembolism compared with nonuse (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1-1.8), whereas we found no increased risk among users of selective serotonin reuptake inhibitors or other antidepressant drugs. When we evaluated individual drugs, we found that amitriptyline conferred an increased risk of thromboembolism (OR 1.7, 95% CI 1.2-2.4) that increased with increasing dose (> 25 mg/day). No other individual antidepressant drug was associated with an increase in risk of venous thromboembolism.
CONCLUSION Current exposure to amitriptyline, particularly at high doses, was associated with an increased risk of idiopathic venous thromboembolism.

USO DI ANTIDEPRESSIVI E RISCHIO DI EVENTI CEREBROVASCOLARI
[RISK OF CEREBROVASCULAR EVENTS ASSOCIATED WITH ANTIDEPRESSANT USE IN PATIENTS WITH DEPRESSION: A POPULATION-BASED, NESTED CASE-CONTROL STUDY]
Yan Chen, Jeff J Guo, Hong Li, et al.
Ann Pharmacother 2008; 42: 177-184

Questo studio caso-controllo ha valutato l'impatto dell'uso di antidepressivi sul rischio di eventi cerebrovascolari, rilevando un incremento del rischio del 24% per gli utilizzatori di inibitori selettivi della ricaptazione della serotonina, del 34% per i pazienti in terapia con antidepressivi triciclici e del 43% nel caso di esposizione corrente a farmaci di altre classi.

ABSTRACT
BACKGROUND Given the widespread use of antidepressants and the negative consequence of cerebrovascular events (CVEs), an evaluation of the risk of CVEs associated with antidepressants is warranted.
OBJECTIVE To examine the association between the use of an antidepressant and risk of CVEs among patients diagnosed with depression.
METHODS A case-control study was performed using a managed care medical claims database from 1998 through 2002. A total of 1086 cases with CVEs were identified and matched with 6515 controls by age, sex, and the year of the index date of depression. Case patients were categorized by stroke type: hemorrhagic stroke, ischemic stroke, and other CVEs. Diagnoses of depression, CVEs, and other medical comorbidities were identified based on International Classification of Diseases, Ninth Revision, codes. Patients were defined as current users (antidepressant ended 30 days before CVE), recent users (31-60 days before CVE), past users (61-90 days before CVE), and remote/nonusers ( 91 days before CVE or nonuse). Cox proportional hazards regression analysis was conducted to estimate the risk of CVEs associated with antidepressant use.
RESULTS A 24% increased risk of a CVE was noted in patients with current exposure to selective serotonin-reuptake inhibitors (SSRIs; adjusted hazard ratio [HR] 1.24; 95% CI 1.07 to 1.44), 34% increased risk for current exposure to tricyclic antidepressants (HR 1.34; 95% CI 1.10 to 1.62), and 43% increased risk for current exposure to other antidepressants (HR 1.43; 95% CI 1.21 to 1.69). The risk of ischemic stroke in current SSRI users was significantly higher (HR 1.55; 95% CI 1.00 to 2.39) compared with remote/nonusers.
CONCLUSIONS Current users of antidepressants may be at increased risk of a CVE. Clinicians should consider the relationship of antidepressants with the occurrence of CVEs when determining the risk-benefit profile of pharmacologic treatment in patients with depression, particularly those with existing risk factors for a CVE.

INIBITORI DEL REUPTAKE DELLA SEROTONINA E RISCHIO DI TOSSICITÀ DEL TRATTO GASTROINTESTINALE SUPERIORE
[MODERATE AND HIGH AFFINITY SEROTONIN REUPTAKE INHIBITORS INCREASE THE RISK OF UPPER GASTROINTESTINAL TOXICITY]
Lewis JD, Strom BL, Localio AR, et al.
Pharmacoepidemiol Drug Saf 2008; Jan 10 [Epub ahead of print]

Il rilascio di serotonina da parte delle piastrine è importante per la regolazione dell'omeostasi. Per questo motivo è stata suggerita l'associazione tra sanguinamenti gastrointestinali e uso di inibitori selettivi della ricaptazione della serotonina. Lo studio, caso-controllo, condotto sui pazienti ospedalizzati per sanguinamenti gastrointestinali, ha evidenziato che l'uso di questi farmaci è associato ad un incrementato rischio di ospedalizzazione per tossicità del tratto gastrointestinale superiore, senza differenze significative tra inibitori ad alta o moderata affinità per il trasportatore.

ABSTRACT
OBJECTIVE Serotonin release from platelets is important for regulating hemostasis. Some prior studies suggest an association between use of selective serotonin reuptake inhibitors and gastrointestinal bleeding and a possible synergistic effect of these medications with non-steroidal anti-inflammatory drugs (NSAIDs). This study examined the effect of medications that inhibit serotonin uptake on upper gastrointestinal toxicity.
METHODS 359 case subjects hospitalized for upper gastrointestinal bleeding, perforation, or benign gastric outlet obstruction were recruited from 28 hospitals. 1889 control subjects were recruited by random digit dialing from the same region. Data were collected during structured telephone interviews. Antidepressant medications were characterized according to their affinity for serotonin receptors. Exposure to medications required use on at least 1 day during the week prior to the index date.
RESULTS Any moderate or high affinity serotonin reuptake inhibitor (MHA-SRI) use was reported by 61 cases (17.1%) and 197 controls (10.4%). After adjusting for potential confounders, MHA-SRI use was associated with a significantly increased odds of hospitalization for upper gastrointestinal toxicity (adjusted OR = 2.0, 95%CI 1.4-3.0). A dose-response relationship in terms of affinity for serotonin uptake receptors was not observed (p = 0.17). No statistical interaction was observed for use of high dose NSAIDs or aspirin concomitantly with MHA-SRIs (p = 0.5). When MHA-SRIs were used concomitantly with high dose NSAIDs, the adjusted odds ratio for the association with upper gastrointestinal toxicity was 3.5 (95%CI 1.9-6.6).
CONCLUSIONS Use of MHA-SRIs is associated with an increased risk of hospitalization for upper gastrointestinal toxicity.

USO DI ANTIDEPRESSIVI E PERDITA DI MASSA OSSEA
[USE OF ANTIDEPRESSANTS AND RATES OF HIP BONE LOSS IN OLDER WOMEN: THE STUDY OF OSTEOPOROTIC FRACTURES]
Diem SJ, et al.
Arch Intern Med 2007; 167:1240-1245

È stata di recente identificata la presenza di trasportatori per la serotonina nell'osso, facendo sorgere il dubbio che i farmaci che bloccano il reuptake della serotonina possano alterare il metabolismo osseo. Lo studio di coorte, condotto sulle donne partecipanti allo Studio sulla Fratture Osteoporotiche, ha mostrato un incremento del tasso di perdita di massa ossea alle anche associato all'uso di inibitori selettivi della ricaptazione della serotonina, ma non di antidepressivi triciclici.

ABSTRACT
BACKGROUND Serotonin transporters have recently been described in bone, raising the possibility that medications that block serotonin reuptake could affect bone metabolism.
METHODS We assessed current use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) and obtained serial bone mineral density (BMD) measurements in a cohort of 2722 older women (mean age, 78.5 years) participating in the Study of Osteoporotic Fractures, a prospective cohort study of community-dwelling women. Hip BMD was measured at the sixth examination and an average of 4.9 years later at the eighth examination. We categorized women as nonusers (used no SSRIs or TCAs at either examination; n = 2406), SSRI users (used SSRIs but no TCAs at either examination; n = 198), or TCA users (used TCAs but no SSRIs at either examination; n = 118). Depressive symptoms were identified using a cutoff score of at least 6 on the Geriatric Depression Scale.
RESULTS After adjustment for potential confounders, including the Geriatric Depression Scale score, mean total hip BMD decreased 0.47% per year in nonusers compared with 0.82% in SSRI users (P<.001) and 0.47% in TCA users (P = .99). Higher rates of bone loss were also observed at the 2 hip subregions for SSRI users. Results were not substantially altered when women who scored at least 6 on the Geriatric Depression Scale were excluded from the analysis.
CONCLUSION Use of SSRIs but not TCAs is associated with an increased rate of bone loss at the hip in this cohort of older women.

SINDROME DELLE GAMBE SENZA RIPOSO INDOTTA DA ESCITALOPRAM
[RESTLESS LEGS SYNDROME INDUCED BY ESCITALOPRAM Case Report and Review of the Literature]
Page RL, Ruscin JM, Bainbridge JL, et al.
Pharmacotheapy 2008, 28: 271-280

La sindrome delle gambe senza riposo è un disturbo sensomotorio, caratterizzato da una sensazione di fastidio alle gambe, che la persona avverte quando va a dormire o comunque quando è a riposo. Queste parestesie coinvolgono un irresistibile bisogno di muovere le gambe, cosa che provoca un temporaneo sollievo, ma a spese del sonno e della qualità della vita. La patofisiologia è stata messa in relazione ad una disfunzione delle vie dopaminergiche. Certi antidepressivi, tra cui gli inibitori selettivi del reuptake della serotonina e gli inibitori del reuptake di serotonina e noradrenalina.
In passato sono stati pubblicati case report che collegavano fluoxetina, sertralina, citalopram, paroxetina, e mirtazapina alla sindrome; questo report, che descrive il caso di una donna di 34 ann, associa per la prima volta anche escitalopram al disturbo.

ABSTRACT
Restless legs syndrome (RLS) is a sensorimotor disorder characterized by distressing sensations deep inside the limbs, typically occurring at bedtime or rest. These paresthesias involve an irresistible urge to move the limb, which provides temporary relief but at the expense of sleep and quality of life. The pathophysiology of RLS has been related to dopaminergic pathway dysfunction, thereby aligning it closely with depression from both pathophysiologic and treatment perspectives. Certain antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), may induce or exacerbate RLS. We describe the case of a 34-year-old woman with no history of RLS who came to the emergency department with acute decompensated heart failure. After 7 days of hospitalization, she was waitlisted to receive a heart transplant. Her mood became depressed, and she requested a psychiatric consultation; escitalopram 10 mg at bedtime was started. Within 2 days of starting therapy, she developed very severe (determined by a score based on an RLS symptom rating scale) RLS symptoms, warranting the discontinuation of escitalopram. Within 2 days of stopping therapy, her RLS symptoms improved considerably (rated as mild). One week later, the patient was rechallenged with a lower dose of escitalopram, and her very severe RLS symptoms reappeared. Within 2 days of stopping escitalopram, her RLS symptoms again improved, with complete resolution 1 week later. Using the Naranjo adverse drug reaction probability scale, which assesses the probability of a drug causing an adverse event, the patient's score was 9, indicating a definite adverse drug reaction. Although published case reports have linked fluoxetine, sertraline, citalopram, paroxetine, and mirtazapine to RLS, this is the first report, to our knowledge, of escitalopram as a cause of RLS. Based on this case and additional data published with other SSRIs and SNRIs, we believe that escitalopram should be added to the list of agents that can induce RLS.