Clozapine, is widely prescribed for treatment of refractory schizophrenia, but its use may be limited by potentially serious adverse effects. The most feared complication remains agranulocytosis [absolute neutrophil count (ANC) < 500/mm3], which occurs in 1% of patients. Guidelines recommend immediate cessation until the granulocyte count normalizes, but little is known about the subsequent treatment and the possibility of restoring clozapine.

To know procedures that allow clozapine rechallenge after induced agranulocytosis in refractory schizophrenia.

We present a clinical case of agranulocytosis and evolution after simple reinstitution of clozapine.

A 38-year-old woman diagnosed refractory schizophrenia. After 10 years with clozapine (300 mg/day), we find neutropenia (ANC 1420/mm3) in a monthly control blood count with progression to agranulocytosis (ANC 460/mm3) in the following month. We suspend clozapine and started olanzapine (20 mg/day) with restoration of haematological values in a period of one month. The patient had psychotic decompensation at two months after the change with lack of response to different psychopharmacological strategies for five months. According to the hematology department we decided to re-introduce clozapine (200 mg/day) in combination with olanzapine with complete clinical remission. Between the 3rd and 9th week after rechallenge we observe a progressive decline in ANC, while remaining within the range of normal. From the 9th week and in the last 6 months neutrophil counts remained stable.

Although, more research is needed to establish the safety to rechallenge of clozapine after agranulocytosis, it must be an alternative to consider when other treatment strategies fail.

The authors have not supplied their declaration of competing interest.

The authors have not supplied their declaration of competing interest.

Agranulocytosis is a potentially life-threatening haematological side effect induced by typical and atypical neuroleptic. When agranulocytosis is associated with a specific anti-psychotic, the medication should be discontinued. This severe side effect is troublesome.

We report the case of a 60-year-old man, treated with amisulpride for schizophrenia, who developed an agranulocytosis. This patient had been treated with first and second generation anti-psychotic drugs during his life and had already been exposed to many neuroleptics without any signs of toxicity. However, after three days of the introduction of amisulpride he presented a rapid onset agranulocytosis (leukocytes 1.2 G/L and neutrophils 0.4 G/L). After discontinuation of amisulpride, blood count returned to normal. The favorable evolution after discontinuation of treatment: the normality of biological and cytological examinations is in favor of a causal relationship between this severe neutropenia al introduction of amisulpride.

This case report highlights the risk of amisulpride in inducing agranulocytosis, a risk underestimated in regard of the clozapine risk to induce agranulocytosis or neutropenia. For this reason, it seems reasonable to recommend performing a blood count before introduction and during the treatment by anti-psychotics.

The authors have not supplied their declaration of competing interest.

Drug-induced liver injury is a major problem of pharmacotherapy and is also frequent with anti-depressive psychopharmacotherapy.

However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepressants.

We performed a quantitative signal detection analysis using pharmacovigilance data from the Uppsala monitoring center from the WHO that records adverse drug reaction data from worldwide sources; we calculated reporting odds ratios (ROR) as measures for disproportionality within a case-/non-case approach for several frequently prescribed anti-depressants.

Both positive controls, amineptine (ROR 38.4 [95% CI: 33.8–43.6]) and nefazodone (ROR 3.2 [95% CI: 3.0–3.5]), were statistically associated with hepatotoxicity. Following amineptine, agomelatine (ROR 6.4 [95% CI: 5.7–7.2]) was associated with the second highest ROR, followed by tianeptine (ROR 4.4 [95% CI: 3.6–5.3]), mianserin (ROR 3.6 [95% CI: 3.3–3.4]) and nefazodone.

In line with previous studies our results support the hypothesis that agomelatine and several other anti-depressants may be associated with relevant hepatotoxicity. However, the used data and applied method do not allow a quantitative evaluation of hepatotoxicity or assessment of substance–specific differences regarding the extent of hepatotoxicity.

The authors have not supplied their declaration of competing interest.

The interferon therapy is associated with numerous adverse psychiatric effects, such as tension, irritability, insomnia, etc.

The goal of this study was to examine the severity and the frequency of anxiety in persons with chronic hepatitis C receiving pegylated interferon alpha combined with ribavirin. We have also tried to assess the efficiency of trazodone in treatment of symptoms of anxiety in patients receiving pegylated interferon.

The total of 36 patients whose diagnosis of chronic hepatitis C has been confirmed both serologically and patohistologically, receiving interferon therapy, ages 22 to 60, participated in this study. The control group consisted of 32 patients, all with same diagnosis, corresponding with those in the study group in terms of gender, age duration of the illness and the level of education. All patients received pegylated interferon alpha 2a, administered subcutaneously once per week, along with oral ribavirin. The research used the following instruments of clinical assessment: structural clinical interview–SCID, ICD–10; Hamilton anxiety rating scale–HAM-A, and the self-report scale for assessment of anxiety–state-trait anxiety inventory–STAI-Form Y. The testing using these instruments was conducted four weeks after the start of the treatment, then after eight weeks, after 12, 24 and 48 weeks, i.e. at the end of the treatment. The patients in the study group received 150–300 mg of trazodone per day, starting at the week 6 of interferon treatment.

The research showed that in the beginning of the interferon treatment approximately one quarter of the patients exhibited symptoms of anxiety in both groups. The administration of trazodone showed beneficial effects in reduction of anxiety induced by the treatment with pegylated interferon.

The author has not supplied his/her declaration of competing interest.

Intramuscular paliperidone palmitate (PP) is a long-acting, atypical anti-psychotic for once monthly intramuscular (IM) administration in the treatment of patients with schizophrenia.

To study the effectiveness (efficacy and quality of life) of ARP in the maintenance treatment of schizoaffective disorder.

A non-randomized, prospective naturalistic study was performed in out-patients with schizoaffective disorder unsuccessfully treated with oral anti-psychotics. Efficacy of ARP over time was evaluated by using brief psychiatric rating scale (BPRS 24-items), quality of life was evaluated by using QL-Index, both at T0 and at most recent visit (T1). Data were analyzed with Student's t-tests and Pearson correlations (α value, two tailed). Paired t-test was applied for BPRS and for Ql-Index total scores (T0–T1).

Data were available for 8 outpatients consecutively prescribed ARP and naturalistically treated attending at the psychiatric clinic, university of Sassari. Mean time on ARP treatment was 207.14 days (sd 137.2). BPRS mean total score at T0 was 57 (sd 13.2) and at T1 was 39.7 (sd 10.8). QL-Index mean total score was at T0 5.43 (sd 1.6) and at T1 7.14 (sd 2.7). Paired sample test showed a statistically significant difference in decreasing symptoms at BPRS over time (P = 0.001) and QL-Index total score (P = 0.023). The analyses showed a significant improving at the following BPRS sub-items: anxiety (P = 0.005), mood elevation (P = 0.014) conceptual disorganization (P = 0.048), emotional withdrawal (P = 0.05), tension (P = 0.02) and distractibility (P = 0.03).

The authors have not supplied their declaration of competing interest.

Co-morbid obsessive-compulsive disorder (OCD) in bipolar disorder (BD) negatively affects clinical course and outcome, and considerably complicates its treatment.

To show a therapeutic approach still rarely used in case of resistant bipolar disorder associated with OCD.

Presentation of the clinical case of Mr. M.H., who is treated in our department since 2008 for OCD-bipolar co-morbidity, followed by a literature review.

Mr. M.H. is a 29-year-old male patient. He developed BD associated to OCD at age 20. In order to control bipolar symptoms, the patient received several trials of anti-psychotics combined with mood stabilizers with little improvement. Resistant BD was diagnosed, and clozapine 300 mg daily introduced, leading to significant improvement in bipolar symptoms but worsening in OC symptoms. Treatment of OCD with fluoxetine and with cognitive-behavioral therapy (CBT) was unsuccessful. Introduction of aripiprazole 20 mg daily led to decided improvement of OC-symptoms. After one year, clozapine was gradually tapered down to 150 mg daily without reappearance of bipolar symptoms but further improvement of OC-symptoms.

Treatment of OCD-bipolar co-morbidity is difficult given the risk of manic switch with antidepressants and the risk of benzodiazepine dependence. CBT could represent an alternative, however, it did not show any efficacy in our patient. Worsening of OCD under clozapine is described in the literature. Adjunction of aripiprazole to clozapine seems an interesting therapeutic option: it diminishes OC symptoms without destabilizing the patient's mood state.

The authors have not supplied their declaration of competing interest.

Depression and hypercholesterolemia are two of the most commonly treated conditions in the developed countries, while the lipid–lowering agents and antidepressants are among the most widely prescribed drugs in the world. There is a common concern that selective serotonin reuptake inhibitors (SSRIs) can trigger statin adverse effects, especially myopathy. However, the supporting evidence originates from studies in-vitro and big epidemiological studies. Recent pharmacokinetic insights indicate that the magnitude of pharmacokinetic interaction between SSRIs and statins is likely to be below the threshold for clinical significance.

Explorative study on pharmacokinetic effects of SSRIs on statin drugs.

We performed a detailed literature review through PubMed, EMBASE and Cochran's Library to assess the clinical relevance of combined SSRIs and statin use. To address pharmacokinetic interactions between two drug groups, we focused on:

– cytochrome P450 enzyme metabolism of statins;

– CYP enzyme inhibition by SSRIs;

– SSRIs–statin drug interactions;

– non-CYP pharmacokinetic pathways.

With regard to pharmacokinetic drug interactions and the risk of statin related myopathy, escitalopram, citalopram, and paroxetine are to be safe in co-therapy with all statins. Rosuvastatin and pravastatin are almost certain to be safe in co-therapy with all SSRIs. Fluoxetine and sertraline are also likely to be safe, even when combined with atorvastatin, simvastatin, and lovastatin.

Though the absolute risk of concomitant use of SSRIs with statins seems to be negligible, even this risk can be minimized by using lower statin doses and monitoring the patient.

The authors have not supplied their declaration of competing interest.

Psychotropic agents have been implicated in the cause of hyponatremia, including the majority of selective serotonin reuptake inhibitors (SSRIs). The reported incidence of hyponatremia caused by SSRIs varies widely up to 40%. Important risk factors are older age and concomitant use of diuretics. Though there are numerous retrospective studies available, an update of current knowledge SSRI induced hyponatremia is warranted.

To review the incidence, risk factors, mechanism, times of onset and resolution, and treatment of hyponatremia associated with selective serotonin-reuptake inhibitors (SSRIs).

An English language literature search was conducted using Pubmed, EMBASE and Cochrane library (December 1980–December 2015) using the search terms selective serotonin-reuptake inhibitor, hyponatremia, syndrome of inappropriate secretion of antidiuretic hormone, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

Numerous case reports, observational studies, and case-controlled studies, as well as one prospective clinical trial, have reported hyponatremia associated with SSRI use, with an incidence of 15%. Risk factors for the development of hyponatremia with SSRIs include older age, female gender, and concomitant use of diuretics, low body weight, and lower baseline serum sodium concentration. Predisposing factors, such as volume status, diuretic use, or concomitant use of other agents known to cause SIADH, may predispose to the development of hyponatremia. In published reports, hyponatremia developed within the first few weeks of treatment and resolved within 2 weeks after therapy was discontinued.

Practitioners should be on the alert for this potentially life-threatening adverse event, especially in older adults.

The authors have not supplied their declaration of competing interest.

The authors have not supplied their declaration of competing interest.

The creation of new lithium compounds with antioxidant activity is relevant problem for psychiatry. The aim of this work was study of the protective effect of lithium salts against ethanol-induced oxidative damage to proteins and lipids of human blood plasma in vitro.

We used lithium ascorbate and lithium carbonate 0.6 mmol/L which correspond to the therapeutic dose (in terms of lithium ions). Antioxidant carnosine (β-Ala-L-His) was used as comparison drug. We used the blood of 12 healthy donors. The heparinized blood samples were incubated in presence of tested preparations for one hour at 37 °C. The final ethanol concentration in samples was 0.5%. Oxidative modification of proteins was determined as the level of carbonylated proteins with 2.4–dinitrophenilhydrazine, lipid peroxidation products–as the level of TBA-reactive products by spectrometry. Statistical analysis was performed with “Statistika 10” program.

The addition of ethanol in the blood led to a significant increase in carbonylated proteins and TBA-reactive products in the plasma (carbonylated proteins: without ethanol 0.26 ± 0.01 nmol/mg of protein; with ethanol 0.33 ± 0.02 nmol/mg; TBA-reactive products: without–3.2 ± 0.1 nmol/mL; with–4.0 ± 0.2 nmol/mL, P < 0.05). In the presence of carnosine such increase of oxidized products of biomolecules is not observed, i.e. carnosine had a protective effect against ethanol-induced oxidative damage. Lithium ascorbate showed a protective effect like carnosine. Lithium carbonate revealed no detectable influence on biomolecules in the conditions of our experiment.

Lithium ascorbate has a protective effect on blood plasma proteins and lipids under ethanol-induced oxidative damage of biomolecules.

The authors have not supplied their declaration of competing interest.

The polypharmacy is a very controversial subject; it brings together problems of interaction between drugs, side effects, and rationality of co-prescriptions, pharmaco-economic aspects. The long acting is useful to solve adherence to treatment but they are often prescribed in polytherapy.

The aim of this studies is to compare long-acting haloperidol, fluphenazine, risperidone and paliperidone regard to prescribing associations and pharmaco-economy. Also we want to consider for each long-acting which and how many drugs are associated and the implications in terms of pharmaco-economics. We examined all prescriptions (126 patients) over a period of 12 months in a mental health center, identifying which long acting had the best pharmaco-economic profile.

Despite being the less prescribed and not being associated with other psychiatric drugs, paliperidone palmitate shows the best pharmaco-economic profile.

The costs of a drug are in relationship not only with unit price but also with the question of safety in order to oppose the overmedication.

The authors have not supplied their declaration of competing interest.

The authors have not supplied their declaration of competing interest.

Case presentation of a middle aged lady Mrs. C.K., who developed tardive dyskinesia (TD) after a trial of an SSRI.

A 49-year-old Australian aboriginal lady, presented with involuntary movement of her face (bucco-linguo masticatory), movements after a 3 months trial of sertraline (maximum dose of 100 mg daily) for her depressive illness. There was no history of trials with anti-psychotics or any other medications, which may have caused the oral dyskinesias. Routine examinations including cognitive testing, EEG and MRI revealed no pathological findings. Her sertraline was ceased and she was commenced on mirtazapine 15 mg at night, which was hiked to 30 mg after 1 week and continued on this dose over the next 3 months. She exhibited good improvement in her depressive symptoms and a significant attenuation of her TD's. Involuntary movement scale rating: she was rated on the abnormal involuntary movement scale (AIMS) and showed gradual improvement in the severity of her orofacial dyskinetic movement. Her scores were–initial presentation (scored 22/36); at 4 weeks (9/36); 8 weeks (6/36) and at 16 weeks (4/36).

Although TD's are seen in approximately 1 to 5% of mental health patients treated with anti-psychotics (and some other medications like Levodopa, Metochlorpromide, etc.), research studies on SSRI's causing TD's are rare and few (Leo et al., 1996; Gerber et al., 1998).

To alert and educate clinicians about a relatively rare adverse-effect of SSRI producing an involuntary movement disorder.

The author has not supplied his/her declaration of competing interest.

One of the most common, and many times hidden, secondary effects of antidepressants drugs use is sexual dysfunction (SD). It has been noted that as many as 20% of patients will discontinue treatment with an SSRI, with one-third of these patients doing so due to adverse reactions.

A review was conducted aiming to clarify the pathogenesis of sexual dysfunction in depressed patients or taking antidepressants and how to prevent and manage it. The literature search was conducted in PubMed data reviewing articles dating between 2015 and 2016.

(1) the sexual response cycle is negatively affected in individuals suffering from major depressive disorder, even before initiation of any psychotropic medication. The serotonergic system plays a largely inhibitory role on sexual desire, orgasm, and ejaculation with involvement of the hippocampus and amygdala. Tricyclic antidepressants increase the level of prolactin and indirectly suppress the level of testosterone. (2) Bupropion and vortioxetine are the only antidepressants that have level 1 evidence supporting that they either have a more favorable SD profile. (3) SD with vortioxetine was not statistically higher when compared with placebo, and was statistically lower compared with other SSRIs or SNRIs. (4) There is evidence that antidepressants that are also 5–HT1A receptor agonists (e.g. vortioxetine and vilazodone) may facilitate sexual performance.

In case of SD pharmacologic and non-pharmacologic options are available. Vortioxetine seems to be a good pharmacologic option, with better NNH than SNRI and less SD.

The authors have not supplied their declaration of competing interest.

Over the last decade a number of effective maintenance treatments for bipolar disorder (BPD) have been developed. Lithium remains the best-established option, but valproic acid, lamotrigine, olanzapine, and quetiapine are also effective maintenance drugs. However, oral administration contributes to lower adherence rates with these drugs. In the United States and Europe, aripiprazole is approved for the acute management of manic and mixed episodes and maintenance in BPD. It presents the advantage of a low risk of metabolic side effects, sexual dysfunction, and sedation, which can facilitate treatment adherence and help improve clinical outcomes.

The authors present an illustrative case on which aripiprazol long acting injection monotherapy was effective as maintenance treatment in a patient with long history of BPD with several hospital inpatient admissions and very poor therapeutic adherence.

Case report based on the patient's file. Narrative review of articles available in PubMed about the use of aripiprazol in BPD.

For this patient, aripiprazol long acting injection has proved to be an excellent choice for long-term treatment of BPD. The once-a-month injection promotes therapeutic adherence, which in this case was combined with involuntary outpatient treatment, ensuring therapeutic compliance.

Aripiprazol has been shown to be safe and effective in the maintenance treatment in BPD. It shows similar efficacy and a superior tolerability profile when compared with other well-established treatments. Further studies are needed, warranted by its potential advantages, particularly on patients with poor insight and adherence.

The authors have not supplied their declaration of competing interest.

Bipolar disorder is a chronic psychiatric illnesses characterized by alternating episodes of mania/hypomania and major depression, or with mixed features. Acute exacerbations and maintenance treatment with appropriate pharmacotherapy are mandatory. Long-term treatment with mood-stabilizing medications is typically required. The incidence of bipolar disorders in women during the primary reproductive years is very high, and the episodes of mania or depression are thought to occur in an estimated 25%–30% of women with bipolar disorder during pregnancy.

Provide a clinically focused review of the available information on the effectiveness and safety of the different pharmacotherapies in the treatment of bipolar disorder during pregnancy.

A bibliographic review is made of the pregnancy in bipolar disorder, based on the data published in PubMed.

Clinical decision making about the use of mood stabilizers and atypical anti-psychotics by pregnant women can be conceptualized as balancing the competing risks imposed by withholding or stopping pharmacotherapeutic treatment against that of continuing or initiating pharmacotherapy during pregnancy. Some of the most effective pharmacotherapies have been associated with the occurrence of congenital malformations or other adverse neonatal effects in offspring. There is few information about the safety profile and clinical effectiveness of atypical anti-psychotic drugs when used to treat bipolar disorder during pregnancy.

Treating women with bipolar disorders during pregnancy is a challenge. There are no uniformly effective or risk-free treatment options. Fully informed decision-making requires the review of the risks of both untreated maternal bipolar disorder and risks associated with potentials interventions.

The authors have not supplied their declaration of competing interest.

Perampanel (PER) is a new selective, non-competitive AMPA glutamate receptor antagonist. PER is generally well tolerated, with dizziness, somnolence, headache, and fatigue as the most common treatment-emergent adverse events, however neuropsychiatric adverse reactions; particularly irritability and aggressiveness can be expected.

We describe a patient who developed and acute confusional state presumably related to treatment with PER.

At the conclusion, the participants should be able to remember that PER is associated with psychiatric side effects.

Collect the data of the clinical history of the patient, who was admitted in the acute psychiatry ward of our hospital.

A 32-year-old woman diagnosed with pharmacoresistant juvenile myoclonic epilepsy, was referred to the emergency department because of severe behavioral disturbances, insomnia, irritability and aggressivity after increasing the dose of PER from 6 to 12 mg. Physical exploration, drug screen and blood tests were all normal. No abnormalities were found in CT, EEG and MRI, and then she was referred to psychiatric ward. At her admission, she presented fluctuations of her mental state and level of consciousness. She was diagnosed with acute confusional syndrome induced by PER, and consequently PER was stopped and risperidone was initiated. In the 4th week symptomatology remitted.

Anti-epileptic drug's (AEDs) are associated with psychiatric side effects. Patients with epilepsy have higher risk develop psychiatric symptoms and behavioral disturbances. There is evidence to suggest that AMPA receptors are involved in the pathogenesis of psychiatric conditions. Such mechanisms could be responsible of the psychiatric symptoms observed. Neuropsychological profiles of AEDs are important considerations for treatment selection, particularly in children and adolescents.

The authors have not supplied their declaration of competing interest.

Drug-drug interactions (DDIs) are known to lead to treatment failure.

In most European countries there are no data on DDIs in patients within correctional facilities.

The main aim of this paper is to present the most frequent DDIs in the biggest Slovenian male, Slovenian correctional facility Dob to avoid serious DDIs in future.

A retrospective study was carried between September 2015 and June 2016 on 141 patients on substitution treatment (methadone, suboxone and buprenorphine) and 125 other prisoners with mental disorders in need for psychiatric treatment were included. All study data were extracted from the patients’ medical files of the psychiatric dispensary in the prison Dob. DDIs were determined by different interaction classes with Lexicomp Online™ 19.0 version and only X (major interactions and should be avoided) and D (minor interactions and avoid if it is possible) were included.

Together 220 patients were included. Number of patients with at least 1 interaction, were 139 (63.2%). Number of patients with at least 1 X interaction, were 59 (26.8%). Number of patients with more than one (1) X interactions was 15 (6.8%). More than half of the patients (56.4%) were treated by hypnotics and 38.4% with benzodiazepines. The most frequent X DDIs were: buprenorphine, methadone and sulpride with antipsychotics (clozapine and quetiapine) and antidepressants (e.g. escitalopram, fluoxetine).

In patients treated with methadone and buprenorphine there are frequent DDIs resulting in contraindications for prescribed combination of drugs. If an antidepressant is to be used in patients prescribed methadone and buprenorphine, sertraline is recommended.

The authors have not supplied their declaration of competing interest.