ABSTRACT
PURPOSE OF REVIEW: Insomnia is a common type of sleep disorder defined by an ongoing difficulty initiating or maintaining sleep or nonrestorative sleep with subsequent daytime impairment. The sleep disturbances in insomnia usually manifest as difficulty in falling asleep, maintaining the continuity of sleep, or waking up too early in the morning well before the desired time, irrespective of the adequate circumstances to sleep every night. Insomnia can significantly impact daytime functioning resulting in decreased workplace productivity, proneness to errors and accidents, inability to concentrate, frequent daytime naps, and poor quality of life.The treatment of insomnia should involve a multi-disciplinary approach, focusing on implementing behavioral interventions, improving sleep hygiene, managing psychological stressors, hypnotic treatment, and pharmacological therapy. The most effective therapies utilize cognitive behavioral therapy in conjunction with pharmacotherapy to minimize the needed dose and any resulting side effects. Non-benzodiazepine hypnotics such as zolpidem, eszopiclone, zaleplon are the most used as adjunctive treatment. One of the most used of these hypnotics is zolpidem. However, zolpidem has a wide variety of adverse effects and has some special considerations noted in the literature. RECENT FINDINGS: Zolpidem has been associated with an increased risk of falls in hospitalized patients with an OR of 4.28 (P <0.001) when prescribed short-term for insomnia. The relative risk (RR) for hip fractures in patients taking zolpidem was described as 1.92 (95% CI 1.65-2.24; P<0.001), with hip fractures being the most commonly seen. A case series of 119 inpatients aged 50 or older demonstrated that a majority (80.8%) of ADRs were central nervous system (CNS)-related such as confusion, dizziness, and daytime sleepiness. A systematic review of 24 previous studies of sleepwalking associated with zolpidem demonstrated that the association was not dependent on age, dose, medical history, or even a history of sleepwalking at any time before zolpidem use. Suicide attempts and completion have been successfully linked with zolpidem use (OR 2.08; 95% CI 1.83-2.63) in patients regardless of the presence of comorbid psychiatric illness. There have been multiple cases reported of seizures following the withdrawal of zolpidem. Most cases have demonstrated that withdrawal seizures occurred in patients taking daily dosages of around 450-600mg/day, but some reported them as low as 160mg/day. Rebound insomnia has been a concern to prescribers of zolpidem. Sleep onset latency has been demonstrated to be significantly increased on the first night after stopping zolpidem (13.0 minutes; 95% CI 4.3-21.7; P<0.01). Women had a non-significantly higher mean plasma concentration than men after 8 hours for the 10mg IR (28 vs. 20 ng/mL) and the 12.5mg MR (33 vs. 28ng/mL). The FDA has classified zolpidem as a category C drug based on adverse outcomes seen in animal fetal development. In the mothers exposed to zolpidem, there was an increased incidence of low birth weight (OR = 1.39; P<0.001), preterm delivery (OR 1.49; P<0.001), small for gestational age (SGA) babies (OR = 1.34; P<0.001), and cesarean deliveries (OR =1.74; P<0.001). The rate of congenital abnormalities was not significantly increased with zolpidem (0.48 vs 0.65%; P = 0.329). SUMMARY: Insomnia is linked to fatigue, distractibility, mood instability, decreased satisfaction, and overall decreased quality of life. Optimal therapy can aid patients in returning to baseline and increase their quality of life. Zolpidem is a helpful drug for the treatment of insomnia in conjunction with cognitive-behavioral therapy. When prescribed to elderly patients, the dose should be adjusted to account for their slower drug metabolism. Still, zolpidem is considered a reasonable choice of therapy because it has a lower incidence of residual daytime sleepiness and risk of falls when compared to other drugs. The most concerning adverse effects, which are often the most publicized, include the complex behaviors that have been seen in patients taking Zolpidem, such as sleeping, hallucinations, increased suicidality, driving cars while asleep, and even a few cases of committing homicide. Even so, zolpidem could be a suitable pharmacological treatment for insomnia. Decisions for whether or not to prescribe it and the dosage should be made on a case-by-case basis, considering both the psychical and psychiatric risks posed to the patient with insomnia versus if the patient were to take zolpidem to treat their condition.
ABSTRACT
Purpose of Review: Antipsychotics are the standard of care when it comes to the treatment of Schizophrenia, and they are often used in Bipolar as well. Their use can come with adverse effects such as extrapyramidal movements, metabolic complications as well as cardiovascular complications such as a prolonged QT interval. Treatment for these side effects ranges from the treatment of the complications up to the cessation of the medication, which could come at the expense of the user's stability. Both schizophrenia and bipolar disorder have an increased risk of suicide and increased morbidity. The purpose of this review presents the background, evidence, and indications for the use of the new second-generation antipsychotic Cariprazine, which has a primary function as a D3 and D2 partial agonist, with higher selectivity for the D3 receptor type. Recent Findings: Schizophrenia is currently teated by dopamine antagonists and/or 5HT modulators, each with their own set of side effects. Bipolar disorder is mostly treated with mood stabilizers. Studies looking at the efficacy and safety of cariprazine have shown in two phase II trials and phase III trials the decrease in PANSS scores in schizophrenia. The most common adverse effects were akathisia, insomnia, constipation, and other extrapyramidal side effects. A unique side effect of Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following daily oral administration for 13 weeks and/or 1 year and retinal degeneration in rats following daily oral administration for 2 years. Another study showed that cariprazine had significant efficacy in preventing relapse in patients with schizophrenia. The time to the loss of sustained remission was significantly longer (P = .0020) for cariprazine compared to placebo (hazard ratio = 0.51) during the double-blind treatment. 60.5% of patients treated with cariprazine and 34.9% of patients treated with placebo sustained remission through the final visit (odds ratio [OR] = 2.85; P = .0012; number needed to treat [NNT] = 4. Another Phase IIIb study looked at negative symptoms and used the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), and it found that the use of cariprazine, from baseline to week 26, led to a greater least-squares mean change in PANSS-FSNS than did risperidone. Another study looked at the quality of life years with the treatment of cariprazine and showed those treated with cariprazine had superior quality of life compared to those treated with risperidone. In terms of bipolar disorder, it showed a decrease in depressive symptoms as measured by decreased MADRs scores with a dose of 3.0mg/day. A phase II study looked at the use of cariprazine in mania or mix states and showed cariprazine significantly decreased YMRS scores compared to placebo, least-square mean difference of -6.1 (p < 0.001). The metabolic parameters demonstrated comparable changes except for fasting glucose in which cariprazine was associated with elevations in glucose levels compared to placebo (p < 0.05). Another phase III study showed significant differences in YMRS total score mean change between cariprazine versus placebo-treated group. Changes in metabolic profiles in all mentioned studies were minimal. Summary: Cariprazine, in recent studies, has shown some promise in being able to treat both bipolar disorder in manic, depressed, and mixed states as well as schizophrenia. Side effects noted as adverse events in these studies are similar in profile to the medications that were developed in the past. With better relapse prevention, cariprazine could be a reasonable alternative clozapine.
