Самидорфан и оланзапин

Topline results from a phase 2 study show that treatment with a novel oral antipsychotic was as effective as treatment with the antipsychotic olanzapine (multiple brands) with far less weight gain in patients with schizophrenia, the company developing the drug announced today.
The drug currently known as ALKS 3831, from Alkermes, combines samidorphan, a novel, potent mu-opioid antagonist, with olanzapine.

Positive Topline Phase 2 Results for Novel Schizophrenia Drug

Механизм неврологических побочных эффектов сульфаниламидов

The team drew from previous research showing that blocking the activity of a certain enzyme (sepiapterin reductase) affects the levels of an important molecule called tetrahydrobiopterin (BH4) in cells. BH4 is critical for the production of neurotransmitters like serotonin and dopamine, and BH4 deficiency causes similar neurological problems to those associated with sulfonamide side effects. 

The EPFL scientists showed for the first time that sulfonamides actually bind to the part of the enzyme that makes BH4. Using a high-throughput drug screening system, the researchers identified ten sulfonamides that strongly inhibit the enzyme. Taking advantage of the expertise of Florence Pojer at EPFL's Global Health Institute, the scientists were able to solve the enzyme's molecular structure and determine how sulfonamides bind to it.

 New Understanding Of The Neurological Side Effects Of Sulfonamide Antibiotics

Сравнение лития и флуоксетина у больных БАР

Background
Controversy exists over antidepressant use in rapid-cycling bipolar disorder.
Aims

Exploratory analysis of safety and efficacy of fluoxetine v. lithium monotherapy in individuals with rapid- v. non-rapid-cycling bipolar II disorder.

Method

Randomised, double-blind, placebo-controlled comparison of fluoxetine v. lithium monotherapy in patients initially stabilised on fluoxetine monotherapy (trial registration NCT00044616).

Results

The proportion of participants with depressive relapse was similar between the rapid- and non-rapid-cycling groups (P = 0.20). The odds of relapse were similar between groups (P = 0.36). The hazard of relapse was similar between groups (hazard ratio 0.87, 95% CI 0.40–1.91). Change in mania rating scores was similar between groups (P = 0.86). There was no difference between groups in the rate of syndromal (P = 0.27) or subsyndromal (P = 0.82) hypomania.

Conclusions

Depressive relapse and treatment-emergent mood conversion episode rates were similar for lithium and fluoxetine monotherapy and placebo during long-term, relapse-prevention therapy of rapid- and non-rapid-cycling bipolar II disorder.

Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder

Полиморфизм CYP2D6 и приверженность лечению антидепрессантами

Early discontinuation of antidepressant drugs (ADPs) therapy is common, occurring in about 30% of patients by week 6.1, 2 Among the most relevant reasons for ADP discontinuation are adverse drug reactions and lack of improvement,3 which can be explained by interindividual variability in drug metabolism. Thus, discontinuation of amitriptyline or fluoxetine, two of the most commonly used ADPs worldwide, which are mainly metabolized by CYP2D6, could be related to CYP2D6 genetic polymorphism.

...

Despite the limitations of the present study (naturalistic observation, non-fixed dose, lack of evaluation of drug plasma concentrations and efficacy), a relationship between CYP2D6 polymorphism and early discontinuation of fluoxetine or amitriptyline monotherapy treatment was observed. There were differences across CYP2D6 groups in the rate of ADP discontinuation at week 4 (P < 0.01;Table 1). Overall, the rates of ADP discontinuation were 25, 36 and 46% at weeks 4, 8 and 12, respectively; no patient returned after dropout. All UMs discontinued treatment within the first 4 weeks, whereas no PM did so within 12 weeks.

 CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients

Клозапин, нейтропения и гранулоцитарный фактор, стимулирующий рост клеток

Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

 Granulocyte Colony Stimulating Factor (G-CSF) can allow treatment with clozapine in a patient with severe Benign Ethnic Neutropaenia (BEN): a case report

Бетагистин как корректор увеличения массы тела при приёме оланзапина

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug’s antagonistic affinity to histamine H1 receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H1 receptor agonist and H3 receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H3 receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H1 receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.

 Reducing olanzapine-induced weight gain side effect by using betahistine: a study in the rat model

Литий-индуцированный гиперпаратиреоз

Approximately 15% to 20% of patients receiving long-term lithium treatment show elevated calcium levels, although only a few of these patients also have significant elevations of PTH levels and clinical symptoms of hyperparathyroidism. Interestingly, lithium-associated clinical hyperparathyroidism is almost always caused by a single parathyroid adenoma rather than 4-gland hyperplasia.
...
Neuropsychiatric symptoms associated with primary hyperparathyroidism include anxiety as well as cognitive and psychotic presentations. However, the most common presentation is depression with associated apathy. In a prospective study of 34 patients with hyperparathyroidism, Velasco and colleagues6 found that approximately one-third of participants had no psychiatric symptoms, one-third had affective symptoms (with or without paranoia), and one-third had cognitive impairment. Affective symptoms were most common in patients with modest elevations in electrolyte levels, while cognitive deficits were more often related to higher calcium concentrations.

 Hyperparathyroidism Resulting From Lithium Treatment Remains Underrecognized

Генетические маркеры метаболических осложнений при приёме антипсихотиков второго поколения

Using DNA analysis, the researchers found that 8% of all study participants had the MTHFR C677T gene variant. Those with the variant who also used SGAs were significantly more likely to have metabolic syndrome than the children receiving SGAs but without the variant (OR, 5.75; P < .05).
The children with the gene variant also had higher diastolic blood pressure (P = .005) and higher fasting plasma glucose (P < .05).
"This is the first report of an underlying biological factor predisposing children to complications associated with SGA medication use. However, we need to do more research before this can be translated into clinical practice," said Dr. Panagiotopoulos.
She noted that because it is known that the MTHFR gene is involved in metabolizing the B-vitamin folate, the investigators are currently taking a more detailed dietary history from these children and conducting a study to answer "what's going on?" with the population's nutritional intake.

New Predictors May Determine Metabolic Risk in Kids on Atypicals

Литий как препарат выбора для долгосрочной терапии БАР

Lithium is linked to thyroid and parathyroid abnormalities, weight gain, and an increased risk for reduced urinary concentrating ability, but the jury is still out on whether it causes birth defects, new research suggests.
The systematic review and meta-analysis of 385 randomized, controlled trials and observational studies also found scant evidence that lithium produced a clinically significant reduction in renal function in most patients and that the risk of end-stage renal failure among users of the drug is low.
"Lithium is the most effective long-term therapy for bipolar disorder, protecting against both depression and mania and reducing the risk of suicide and short-term mortality," Professor John R. Geddes, MD, University of Oxford and Warneford Hospital, Oxford, United Kingdom, and colleagues write.
"Because lithium has always been an unpatented, cheap drug, it is not commercially promoted and the potential for adverse effects has been a substantial deterrent to use," they write.
There have been concerns about lithium’s effect on renal function and its purported teratogenicity. Despite these concerns, there has not been an "adequate synthesis of the evidence for adverse effects," the authors note.

Lithium's Safety Examined

Предупреждение нежелательных эффектов лекарственных препаратов в психиатрии

How to prevent adverse drug events

Пролонгированная инъекционная форма рисперидона вызывает больше побочных эффектов

Long-acting, injectable risperidone, the first second-generation antipsychotic available in the United States in this formulation, is no better than oral antipsychotics for the treatment of unstable schizophrenia, a new study published in the March 3 issue of the New England Journal of Medicine suggests.

In a randomized study of more than 300 Veterans Affairs (VA) patients, investigators found injectable risperidone did not significantly decrease hospitalization rates or improve symptoms, social function, or quality of life compared with those treated with "clinicians' choice" of oral antipsychotics. The risperidone-treated group also reported more adverse effects.

No Benefit, More Side Effects With Injectable Risperidone

Оксибутинин в качестве корректора гипергидроза вызванного приёмом антидепрессантов

Patient A is a 59-year-old man with a history of recurrent episodes of panic disorder, for which he had used paroxetine, venlafaxine, and escitalopram as well as high doses of oxazepam in the past. He was admitted to the hospital because of a severe depressive episode with suicidal ideation. The depression was successfully treated with clomipramine, 100 mg/day, which was effective for the treatment of panic attacks as well. Although he sweated all over his body, he was willing to continue clomipramine monotherapy after discharge. Lowering the dosage did not change the situation, nor did treatment with cognitive-behavioral therapy. Finally, a trial with oxybutynin, 2.5 mg b.i.d., relieved the hyperhidrosis completely, without any side effects.

Patient B is a 60-year-old man with recurrent severe depressive episodes with psychotic symptoms and agitation. Typical for his disorder are the rapid onset of relapse and the severity of agitation, which in the past required hospitalization and seclusion. In the latest episode he was treated with clomipramine, 75 mg/day, and olanzapine, 15 mg/day, but he suffered from severe hyperhidrosis. A switch from olanzapine to haloperidol did not change the hyperhidrosis. Later, 800 mg/day of lithium was successfully added for the treatment of his depressive symptoms. Oxybutynin, 5 mg t.i.d., was added to his treatment and relieved his hyperhidrosis without side effects.

There are several preferential strategies to treat hyperhidrosis, such as lowering the dosage or altering the dosing schedule, changing clothing or food habits, or regulating anxiety (2). In the present two cases, these strategies were unsuccessful and oxybutynin maintenance treatment was introduced. With its rapid, short-term effect (within an hour), oxybutynin could also be considered "as needed" in specific social situations. One should be careful in dosing to avoid anticholinergic side effects such as constipation, urinary retention, and blurred vision. Although placebo-controlled research is necessary, the cases reported here suggest that adding oxybutynin to antidepressants can be a simple and effective treatment option for hyperhidrosis.

Oxybutynin for Antidepressant-Induced Hyperhidrosis

Вилазодон: механизм действия и побочные эффекты

Vilazodone is the first approved drug that is both a combination selective serotonin reuptake inhibitor (SSRI) and a partial agonist of serotonergic (5HT1A) receptors. Its mechanism of action "is not fully understood but is thought to be related to its enhancement of serotonergic activity in the central nervous system through selective inhibition of serotonin reuptake," according to a press release from Clinical Data, which holds worldwide marketing rights for the drug.

In 2 randomized, double-blind trials in adults with MDD, vilazodone 40 mg once daily was shown to be significantly superior to placebo at improving depressive symptoms, as measured by a mean change in the Montgomery-Asberg Depression Rating Scale total score from baseline to week 8. Patients in the study were titrated up to the 40-mg dose over the course of 2 weeks.

In safety studies involving 2177 patients diagnosed with MDD, the most common adverse events were diarrhea, nausea, vomiting, and insomnia. In all, 7.1% of patients who received vilazodone discontinued treatment because of an adverse reaction compared with 3.2% of control patients. The drug was not associated with change in body weight over 8 weeks, and there were no reported drug-related abnormalities in hepatic or cardiac parameters or vital signs, the company says.

Психоз при потенцировании дулоксетина арипипразолом

"Ms. L" was a 49-year-old woman with chronic depression and postoperative cellulitis following a bunion excision. She was evaluated on the medical unit. She endorsed depressive symptoms, auditory hallucinations, and suicidal thoughts. The patient had previously attempted suicide twice by drug overdose. Her most recent suicide attempt was 7 months prior. Previous responses to sertraline and citalopram were poor. At the time of assessment on the medical unit, she was receiving duloxetine (40 mg twice daily), aripiprazole (1 mg/day), clonazepam (1 mg twice daily), and amoxicillin/clavulanate (850 mg twice daily).

The patient was started on duloxetine 7 months before. Ten days prior to admission, her primary care physician had started her on aripiprazole (2 mg/day) for augmentation. She denied a history of psychotic symptoms and drug or alcohol abuse as well as a family history of psychosis.

Three days after starting aripiprazole, Ms. L reported auditory hallucinations. She was paranoid regarding her ex-husband. She described command hallucinations from the devil, who meant to harm her, and could also hear God's voice encouraging her not to listen to the devil. She experienced concurrent onset of suicidal ideation with no plan. She was fully oriented, with no evidence of confusion. Aripiprazole was reduced to 1 mg/day, which led to amelioration of her hallucinations. However, her suicidal thoughts and paranoid beliefs persisted.

The psychiatric consultant decided to discontinue aripiprazole, leading to rapid and complete resolution of the patient's psychotic symptoms and suicidal ideation. Her ongoing depression was managed with duloxetine (60 mg twice daily).

New-Onset Psychosis and Emergence of Suicidal Ideation With Aripiprazole

Механиз атипичного действия антипсихотиков, fast off

Background: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics’ mechanism of action and how it differs from that of the more typical drugs. Method: This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. Results: Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. Conclusion: Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. Relevance: The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.

Atypical Antipsychotics: Mechanism of Action

Монотерапия рисперидоном в сравнении с терапией комбинацией низких доз рисперидона и галоперидола

Monotherapy is recommended for schizophrenia treatment, but the risk-benefit issue of antipsychotic drug combination (except for clozapine) remains unclear. Risperidone, an atypical antipsychotic drug, has a lower incidence of extrapyramidal syndrome but higher risks of prolactinemia and metabolic syndrome than haloperidol, a typical agent. This study compared efficacy and safety of risperidone monotherapy versus low-dose risperidone plus low-dose haloperidol in schizophrenia. In this 6-week, double-blind study, patients were randomized to the combination group (2-mg/d risperidone plus 2-mg/d haloperidol, n = 46) or the monotherapy group (4-mg/d risperidone, n = 42). Efficacy assessments included Clinical Global Impression-Severity, Positive and Negative Syndrome Scale and subscales, Calgary Depression Scale, Global Assessment of Functioning, and Medical Outcomes Study Short-Form 36. Safety was rigorously monitored. Response was defined as 30% reduction in the Positive and Negative Syndrome Scale total score. The 2 treatment groups were similar in (1) demographic and clinical characteristics at baseline, (2) response rate, and (3) improvement in various psychopathological measures and quality of life at end point. The monotherapy group had a higher increase in prolactin levels (P = 0.04) and Simpson-Angus Scale scores (P = 0.04) and a higher percentage of biperiden use (P = 0.045). There were no significant between-group difference in changes in weight, vital signs, corrected QT interval, liver/renal function, fasting glucose level, and lipid profiles. The findings suggest that risperidone monotherapy may yield higher prolactin levels than a combination of low-dose risperidone plus low-dose haloperidol. The 2 treatment groups are similar in efficacy, life quality, and other safety profiles. Future long-term studies are warranted.

A randomized, double-blind comparison of risperidone versus low-dose risperidone plus low-dose haloperidol in treating schizophrenia.

Эффективность приёма антипсихотика через день

Objective: In the treatment of schizophrenia, all currently available oral antipsychotics are administered at least once daily, with strict adherence strongly encouraged to minimize risk of relapse. Based on a better understanding of the brain kinetics of antipsychotics, we have proposed a variation of this approach, “extended” dosing, which allows for intermittent but regular dosing.

Method: We carried out a randomized, double-blind, placebo-controlled trial evaluating 35 individuals with DSM-IV–defined schizophrenia who had been stabilized on antipsychotic therapy. Over a 6-month interval, 18 subjects received their medication as usual (daily), while 17 received their antipsychotic therapy every second day (extended). Outcome measures included clinical scales to assess symptoms (Brief Psychiatric Rating Scale [the primary outcome measure], Calgary Depression Scale), illness severity (Clinical Global Impressions-Severity of Illness scale), and relapse (ie, rehospitalization) rates. Side effects were also assessed, including movement disorders (Barnes Akathisia Scale, Simpson-Angus Scale, Abnormal Involuntary Movement Scale) and weight. The study was conducted from February 2003 to July 2007.

Results: Individuals in the extended dosing group were not at greater risk of symptom exacerbation, relapse, or rehospitalization; indeed, more rehospitalizations occurred in those receiving regular dosing. At the same time, though, there was no indication that side effects were significantly reduced in the extended dosing group.

Conclusions: These results challenge the long-standing dogma that oral antipsychotics must be administered daily in stabilized patients with schizophrenia. Further studies with larger samples are needed to replicate these findings, as well as to elucidate whether postulated clinical advantages can be established and determined to outweigh potential risks.

“Extended” Antipsychotic Dosing in the Maintenance Treatment of Schizophrenia: A Double-Blind, Placebo-Controlled Trial

Нейротоксичность лития при нормальных концентрациях

To the Editor: Lithium is used with great success in the treatment and prophylaxis of bipolar disorders, unipolar recurrent depression, and endogenous depression that is resistant to conventional treatment. It is also known to be neurotoxic at higher serum levels. In rare cases patients develop symptoms of intoxication even with normal lithium levels.

Case Report

A 61-year-old man with history of bipolar disorder that was managed with lithium for more than 20 years presented with complaints of psychomotor slowdown, unsteady gait, memory deficits, restlessness, sleep disorder, and severe tremor in his hand that prevented him from eating or drinking properly. These symptoms had begun in the previous week. There was no recent history of fever, respiratory, gastrointestinal, or urinary complaints. He was medicated with lithium, 800 mg/day, and fluvoxamine, 200 mg/day, and the dosage of his medication had remained unchanged over the last year.

Neurological examination showed psychomotor slowdown, inattention, temporal disorientation, severe episodic memory impairment, motor and verbal perseveration, slurred speech, and hypophonia. Symmetrical global and segmental bradykinesia and lead-pipe rigidity, as well as tremor at rest, intention, and posture, were also evident. His gait was abnormal with shuffling small steps and a hunched-forward upper body.

An analytic study revealed no abnormalities, including CBC, renal, thyroid and hepatic function, and PCR. Lithium serum levels were normal (1.0 mmol/liter).

EEG showed diffuse slow background activity, mainly at 5–6 Hz, with periods of greater lentification at 3 Hz, which is compatible with moderate to severe encephalopathy. A brain CT was normal. The patient was admitted and lithium was stopped. There was remarkable clinical improvement over the next days, and he was discharged at day 5, asymptomatic and on valproic acid (300 mg/day).

Lithium Neurotoxicity at Normal Serum Levels

Дисфагия при приёме палиперидона

Paliperidone-Induced Dystonic Dysphagia

Normally, after eating, your body uses carbohydrate as the main energy source. After a long time hungry, it switches to fat. Zyprexa made the body use fat all the time

SUMMARY: A class effect, to varying degrees; and eating less may not help.


1. Food intake was the same between controls and Zyprexaers. You get these effects even if you eat the same.

2. This effect is shared by other atypicals, in a predictable fashion:


In the fed state, Zyprexa and Clozaril do a massive conversion to fat utilization, Risperdal a medium, and sulpiride minimal covnersion.

In the fasting state:

Geodon has a lesser effect than Zyprexa, and appears to normalize; Abilify and Haldol seem close to normal.

3. These effects are consistent with Lilly's own studies that the majority of weight gain happens in the first month, and not suddenly after a year of use.

4. There is still a hunger component to weight gain that is separate from the metabolic effect. Some drugs will make you hungry, change your metabolism, or some mixture of the two. Hunger appears to be a H1 mediated process (Seroquel, Zyprexa, Clozaril, Remeron, Paxil>Prozac, etc.)

5. The immediate clinical consequence of this information is probably (paradoxically) to tell the patients to eat less sugar.

Unless you dramatically cut fat out of your diet, the body will still churn through what fat you do eat at the expense of carbohydrate. Better, and easier, to reduce the carb load that lingers in your body (and likely ultimately gets stored.)

Why Zyprexa (And Other Atypical Antipsychotics) Make You Fat