What clinicians need to know about intranasal esketamine for treatment-resistant depression?

OBJECTIVE: To review the usefulness of esketamine for treatment-resistant depression. METHOD: Pivotal trials of intranasal esketamine in treatment-resistant depression were synthesized as a narrative review. RESULTS: Esketamine is postulated to act through antagonism of N-methyl-D-aspartate (NMDA) glutamate receptors, but opioidergic effects may also be involved. Unlike intravenous ketamine, esketamine is given intranasally (under clinical observation), usually in addition to an oral antidepressant. Trials compared esketamine plus antidepressant versus placebo plus antidepressant. At 4 weeks, remission was 37% higher with esketamine/antidepressant than placebo/antidepressant. Speed of response and improvement in suicidality were comparable. In stable remitters on esketamine/antidepressant, 45% relapsed when esketamine was withdrawn over the following 6 months (whereas 25% relapsed on esketamine/antidepressant). Response appears less likely in patients with multiple antidepressant failures. Adverse effects include dissociation, dizziness, nausea, sedation, and headache but no psychosis. Hypertension affected 13%, especially older patients. Dose frequency is twice-weekly for 4 weeks, then weekly/fortnightly thereafter. No abuse has been reported. Unsubsidised cost may be beyond the reach of many Australians. CONCLUSION: Intranasal esketamine plus antidepressant has been approved by regulators as moderately effective and acceptably tolerable for treatment-resistant depression. Cost is a drawback. Use often needs to be long-term and vigilance for abuse is essential.

Association between long-term use of prolactin-elevating antipsychotics in women and the risk of breast cancer: What are the clinical implications?

BACKGROUND: Some antipsychotic drugs elevate prolactin, and hyperprolactinaemia is associated with an increased risk of breast cancer. Women with schizophrenia have an increased incidence of breast cancer, but also multiple risk factors for the condition. METHOD: This paper will critically review recent epidemiological studies concerning antipsychotics and breast cancer from a psychiatric perspective. RESULTS: Two recent epidemiological studies have found an association between use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders. Prolactin-elevating drugs include paliperidone, risperidone, amisulpride and haloperidol, whilst prolactin-sparing antipsychotics included aripiprazole, brexpiprazole, cariprazine and quetiapine. In the two studies, estimated increased risks of breast cancer were disconcertingly high (up to 62%), but a third recent study found only a weak dose-response association. There are extensive methodological complications in this research, including the extent to which studies measure other risk factors for breast cancer and disagreement about the extent of prolactin elevation by some antipsychotics. CONCLUSION: Although causation between prolactin elevating antipsychotics and breast cancer in women has not been demonstrated, recent epidemiological reports are worrying. For women on antipsychotics, informed consent should ideally include discussion of breast cancer concerns within the wider context of treatment benefits and risks.

Lemborexant, an orexin receptor antagonist sedative-hypnotic: Is it useful for insomnia in psychiatric disorders?

OBJECTIVE: Lemborexant, an orexin receptor antagonist similar to suvorexant, has been approved for the treatment of sleep onset and/or maintenance insomnia. Lemborexant is reviewed and compare to suvorexant from a psychiatric perspective. CONCLUSION: Rapidly absorbed (peak 1-3 h), lemborexant has a half-life of 17-19 h (suvorexant half-life 12 h). It is metabolized by CYP3A4/5, with no significant effects of age, sex or weight. Trials for insomnia indicate sustained efficacy beyond 6 months. Lemborexant has not been trialled in major psychiatric disorders. Commenced at 5 mg, lemborexant can then be increased to 10 mg, taken at least 7 h before planned awakening. Adverse effects are higher at 10 mg: somnolence occurs in about 10% while headache and nightmares affect 2-5%, approximately similar to 40 mg suvorexant (recommended suvorexant dose 20 mg). Sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms, complex sleep behaviours and emergence of depression/suicidal ideation can occur. Neither tolerance to sedation nor withdrawal effects on discontinuation have been observed. Whether the differences between lemborexant and suvorexant are clinically relevant is unclear. Like suvorexant, lemborexant appears to be effective in longer-term use for insomnia, but until efficacy and safety are adequately investigated in major mental disorders, clinicians need to monitor patient experience closely.

Cariprazine: A new partial dopamine agonist with a familiar profile.

OBJECTIVE: Cariprazine is the third partial dopamine agonist now available in Australia. This paper will review the properties, evidence and likely clinical place of cariprazine. CONCLUSION: Cariprazine is a partial agonist with high affinity at dopamine D2 and D3 receptors, partial agonism at 5HT1a receptors, moderate 5HT2a and H1 antagonism and no anticholinergic activity. It is rapidly absorbed, is unaffected by food, achieves a peak plasma level in 4-8 hours and has high bioavailability. The half-life of cariprazine and its metabolites is long (7-8 days); steady state occurs in 4-8 weeks. It is hepatically metabolized via 3A4 cytochrome enzymes. Cariprazine is an effective antipsychotic in acute schizophrenia in both short and longer placebo-controlled studies. Cariprazine appears to have small advantages in negative symptoms of schizophrenia. While not approved for bipolar disorder, cariprazine is effective in mania and mixed states but requires doses higher than current maximums recommended. Cariprazine causes more akathisia than aripiprazole or brexpiprazole but is less prone to insomnia, weight gain and sedation. Risks for hyperprolactinaemia and QTc prolongation are low. Cariprazine is another 'metabolically-friendly' antipsychotic for schizophrenia, with advantages for those with negative symptoms, mood symptoms or problems with adherence.

Comparison of inpatients who were readmitted within 28 days of discharge with those not readmitted: an audit at an Australian private psychiatric hospital.

OBJECTIVE: To compare inpatients who had been readmitted within 28 days of discharge with patients not readmitted within the same period in a private psychiatric hospital. METHOD: Of 118 readmissions within 28 days in 2017 (7% of admissions), 50 were randomly selected and matched by age and gender with control patients who had not been readmitted within 28 days. Differences in demographics, diagnosis, length of stay and number of admissions in the previous 12 months were examined. RESULTS: Readmitted cases were 64% female, were aged 49.8 ± 18.2 years (range 19-89), 40% were in relationships and 24% were receiving disability support. Most patients were suffering an episode of depression. Cases had higher rates of multiple psychiatric diagnoses (p < .001) and physical disorders (p < .05). There were no significant differences between cases and controls on psychiatric diagnoses. Cases had a longer length of stay in their previous admission (p < .01) and a higher number of admissions in the preceding 12 months (p < .05) compared to controls. CONCLUSION: This study indicates that inpatients readmitted within 28 days of discharge were more likely to have multiple diagnoses, physical co-morbidity and relapsing conditions than patients who were not readmitted.

Characteristics, diagnoses and risk profiles of inpatients readmitted within 28 days of discharge to an Australian private psychiatric hospital.

OBJECTIVE: The objective of this study was to perform a clinical and risk audit of private hospital inpatients who had been readmitted within 28 days of a preceding admission. METHOD: Of 118 readmissions within 28 days in 2017 (7% of all admissions), 50 were randomly selected for audit. Characteristics, illness severity and clinical risk profiles were ascertained at discharge from the index admission and at readmission. RESULTS: Cases were 64% female, age 49.9 ± 18.2 years (range 19-89), 40% in relationships and 24% on disability support. At readmission, 88% posed danger to self due to effects of illness, 46% had high suicide risk and 40% had high physical risk. Illness was rated as severe in 58%, while 40% were rated markedly ill. Relapse or exacerbation of major depression was a cause of readmission in 78%, relapse of alcohol/substance use requiring readmission in 22% and relapse of psychosis in 20%. Index admission length of stay of cases did not differ from that of all hospital admissions. CONCLUSION: Most readmitted patients were suffering severe exacerbation of depression, were acutely suicidal and were otherwise at high risk of harm. If these patients had been denied readmission on the basis of insurer funding disincentives, catastrophic outcomes may well have occurred.

Characteristics, diagnoses, illness course and risk profiles of inpatients admitted for at least 21 days to an Australian private psychiatric hospital.

OBJECTIVES:: To perform a clinical and risk audit of private hospital inpatients staying in hospital at least 21 days. METHODS:: Of 492 admissions for ≥21 days in 2016, 40 were randomly selected for audit. Characteristics, illness severity and course using the Clinical Global Impression severity (CGI-S) subscale and improvement (CGI-I) subscale, and clinical risk profiles were ascertained at admission, day 15 and discharge by two psychiatrists. RESULTS:: The cases were 65% female, age 50.0±16.2 years (range 24-86), 43% in relationships, and 28% on disability support. The length of stay was 29±7 days. On admission 88% were severely or markedly ill on the CGI-S subscale. Thirty-nine of 40 cases had ≥3 psychiatric diagnoses: 93% depression, 48% bipolar, 15% schizophrenia. High risk was present in suicide risk (48%), illness-induced dysfunction risk (78%) and physical risk (28%). By day 15, 63% were not improved or marginally worse. Suicide ratings were unimproved. By the time of discharge, illness severity and risk ratings were significantly reduced. CONCLUSION:: Private hospital inpatients staying ≥21 days were predominantly female and had severe, diagnostically complex illnesses and high risk ratings. Most were still seriously unwell after 15 days. Patients improved significantly by the time of discharge (though were by no means recovered), indicating that the duration of hospitalisation was appropriate.

Milnacipran: serotonin-noradrenaline reuptake inhibitor approved for fibromyalgia may be a useful antidepressant.

OBJECTIVE: Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) approved for treatment of fibromyalgia in Australia, but is used for depression in Europe and elsewhere. This paper will briefly review milnacipran and its utility in psychiatry for the treatment of depression. CONCLUSION: Milnacipran is a dual reuptake inhibitor of noradrenaline and serotonin, with greater effect on noradrenaline than serotonin, in contrast to the related drugs venlafaxine, desvenlafaxine and duloxetine. Rapidly absorbed irrespective of food, milnacipran has a half-life of approximately 8 hours, reaches steady state in 2 days and is excreted renally. Milnacipran helps a minority of patients with fibromyalgia by reducing pain and fatigue. It is also an effective antidepressant with efficacy comparable to venlafaxine and duloxetine, and a side effect profile characteristic of SNRIs. The dose range is 50-200 mg, in divided doses. Milnacipran may be useful for patients with depression and pain, and endogenous depression characterised by anergia, psychomotor retardation and hypersomnia. Caution is necessary in the presence of heart disease, hypertension, renal impairment, epilepsy, glaucoma, bipolar disorder, and bleeding tendency. Milnacipran is likely to be a useful late antidepressant option in treatment-resistant patients, as well as those with chronic pain, anergia and hypersomnia.

Paliperidone palmitate three-month depot formulation: a helpful innovation with practical pitfalls.

OBJECTIVE: Paliperidone palmitate is now available as a three-month depot injection. This paper will review the pharmacokinetics, pharmacodynamics, efficacy and tolerability, as well as practical issues and pitfalls for clinicians with this innovative treatment for schizophrenia. CONCLUSION: The three-month depot formulation of paliperidone for the treatment of schizophrenia is not a new compound. The nanocrystalline structure of the three-month formulation is larger and takes longer to disperse than the one-month formulation, hence its extended depot action. As expected, it is non-inferior to one-month depot paliperidone, and superior to placebo, for the treatment of schizophrenia. The side effect profile of three-month paliperidone is identical to the one-month formulation. The relapse rate on treatment is low, and the median time to relapse after ceasing the drug is 395 days. An understanding of half-life and kinetics is crucial for clinicians using this compound, and the loading strategy is important to ensure effectiveness. There are significant challenges: ensuring timely administration and switching a three-month depot treatment to another antipsychotic may be problematic. Paliperidone palmitate three-month depot injection represents an advance for both convenience and effectiveness in the long term psychopharmacological treatment of schizophrenia.

Brexpiprazole: a new leaf on the partial dopamine agonist branch.

OBJECTIVES: Brexpiprazole is a new dopamine partial agonist antipsychotic in the same class as aripiprazole. This paper will briefly review brexpiprazole and compare it with aripiprazole. CONCLUSIONS: Brexpiprazole and aripiprazole are both partial agonists at dopamine D2, and serotonin 5-HT1A and antagonists at serotonin 5-HT2A and noradrenergic α1B receptors. However, the two drugs are significantly different in potencies at various receptors; neurochemical profiles predict that brexpiprazole may be comparable with aripiprazole in its antipsychotic efficacy but may cause less akathisia, extrapyramidal side effects (EPS) and activation. In pivotal trials brexpiprazole demonstrated antipsychotic efficacy in short and long-term studies; it was also found to be an effective adjunct in patients with major depression resistant to antidepressants. Akathisia can occur early in treatment with brexpiprazole, as can minor weight gain and prolactin elevation. Indirect data extrapolations from pivotal studies suggest that brexpiprazole and aripiprazole have comparable efficacy but brexpiprazole may cause less akathisia. Like aripiprazole, brexpiprazole has been approved in the USA for use in schizophrenia and antidepressant-resistant depression. Although much more clinical experience is needed, brexpiprazole appears to be distinct from aripiprazole and a promising new 'metabolically-friendly' antipsychotic option for treatment of psychoses and mood disorders.

Suvorexant: scientifically interesting, utility uncertain.

OBJECTIVE: Suvorexant, a new hypnotic, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance, and is used long-term. This paper will briefly review suvorexant. RESULTS: Orexin is a hypothalamic peptide which promotes wakefulness. By blocking orexin receptors, suvorexant induces sleep. Peaking 2 h after ingestion, it has a half-life of 12 h and is hepatically metabolized mainly by CYP3A. Kinetics are not affected by age but concentrations are higher in females and obese patients. There may be interactions with benzodiazepines, antidepressants and antipsychotics. Suvorexant is available in 15 mg and 20 mg doses at which benefits are moderate: after three months' treatment users fell asleep 6 min faster and slept 16 min longer than those on placebo. Studies with 40 mg showed greater benefits but more side effects: next day somnolence, fatigue, xerostomia and peripheral oedema. Hallucinations, sleep paralysis and somnambulism occur rarely. Tolerance, withdrawal and rebound do not generally occur at recommended doses. CONCLUSION: Suvorexant has not been trialled against other hypnotics, is expensive and its utility for insomnia in patients with psychiatric disorders is unknown. Currently, use of suvorexant could be considered where more established treatments are inappropriate.

Lurasidone: an antipsychotic with antidepressant effects in bipolar depression?

OBJECTIVE: Lurasidone is a new serotonin-dopamine antagonist atypical antipsychotic which also appears to be effective in bipolar depression. This paper will briefly review the evidence concerning lurasidone. CONCLUSIONS: Lurasidone is an antagonist at dopamine D2, serotonin 5-HT2 and 5-HT7, and partial agonist at 5HT1a receptors; it has no anticholinergic or antihistaminic activity. Rapidly absorbed, it has a half-life of 18 ± 7 hours, will reach steady state in five days and is taken at night with food (absorption is halved on an empty stomach). It is hepatically metabolised with some potential for interactions. Lurasidone is an effective antipsychotic in acute schizophrenia, and non-inferior to quetiapine but not risperidone in 12-month studies. Lurasidone may cause mild sedation, nausea, agitation, insomnia and akathisia (especially at initiation). Risks for weight gain, hyperprolactinaemia and QTc prolongation are low. Lurasidone has demonstrated antidepressant efficacy both as monotherapy and in addition to lithium or valproate in bipolar depression, of a comparable degree to that seen with the combination of olanzapine and fluoxetine. Lurasidone appears to be a "metabolically-friendly" antipsychotic for schizophrenia where weight gain and hyperprolactinaemia are of concern, and may also prove useful in bipolar depression (although not approved for this condition in Australia).

Aripiprazole long-acting injection: promising but more evidence needed.

OBJECTIVE: Aripiprazole long acting injection (ALAI) is now available, and this paper aims to assist clinicians in deciding when to use ALAI. CONCLUSION: Aripiprazole is a partial dopamine agonist with low sedation, relatively favourable metabolic profile and a tendency to lower, rather than raise, prolactin. Available for over a decade, aripiprazole has been increasingly recognised by many clinicians as a useful option in the treatment of psychoses. ALAI is a suspension of crystalline aripiprazole in water which takes 5-7 days to reach steady state after an initial intramuscular injection. Monthly injections achieve steady state in four months. Studies have demonstrated that ALAI is effective in aripiprazole-responsive patients. ALAI was generally well tolerated, but more prone to cause extrapyramidal side-effects than the oral form. ALAI has not been compared with other depots. Although the recommended starting dose is 400 mg, it is likely that there will be significant inter-individual dose variation. Dose optimisation in each patient will be necessary for best effectiveness and tolerability. ALAI is currently appropriate for aripiprazole-responsive patients who need a depot, but clinicians are likely to try ALAI in patients who have been on other depots, particularly in whom weight gain and hyperprolactinaemia have been problematic.

Should ketamine be used for the clinical treatment of depression?

OBJECTIVE: There has been widespread interest from the public and media in the potential of ketamine as a novel treatment for depression. This paper reviews whether current evidence supports the use of ketamine for the clinical treatment of depression. CONCLUSIONS: Clinical trials have investigated the use of intravenous ketamine for the treatment of depressive symptoms over the past 15 years. However, there remain many unanswered questions regarding its effectiveness, safety, and the route, dose and regimen for repeated administration. Experts have also raised concerns regarding ketamine's adverse effects, abuse potential and the risk of addiction. At this stage, the use of ketamine in the treatment of depression remains in the realm of research settings.

Vortioxetine: A multimodal antidepressant or another selective serotonin reuptake inhibitor?

OBJECTIVE: The treatment of depressive disorders remains unsatisfactory for many patients with regard to efficacy and tolerability. Vortioxetine has been registered by regulatory authorities for the treatment of major depressive disorder. This paper aims to provide clinicians with a brief overview of vortioxetine and its place in treatment. CONCLUSIONS: Vortioxetine is a serotonin reuptake inhibitor with additional serotonergic receptor effects of uncertain significance; hence, its classification as 'multimodal'. The half-life is about 2.75 days and steady state requires about 14 days. Metabolism is hepatic and involves cytochromes 2D6 and 3A4/5. Antidepressant efficacy in major depressive disorder has been established in registration studies, but the effectiveness of vortioxetine in 'real world' patients and in comparison to other antidepressants needs further investigation. The recommended dose range is 5-20 mg. Nausea, constipation and vomiting are the most common side effects. Sexual dysfunction may occur at higher doses but there appears to be low risk of weight gain and sedation. There is still much to learn about this drug, particularly whether it has unique characteristics in comparison to existing antidepressants. At present, vortioxetine can be considered as an antidepressant option in patients with established major depressive disorder who have not responded adequately to other antidepressants.

Management of antidepressant-induced sexual dysfunction.

OBJECTIVE: Antidepressant-induced sexual dysfunction is a common, troublesome complication of antidepressant treatment that patients often fail to report, which can have major consequences, including non-adherence to treatment with resultant relapse of depressive illness. The aim of this paper is to review the extent, causation and evidence-based management of antidepressant-induced sexual dysfunction to inform clinical practice. CONCLUSIONS: The preponderance of evidence suggests that antidepressant s can be divided into high risk (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors) and low risk (agomelatine, bupropion, moclobemide and reboxetine) categories with regard to propensity for antidepressant-induced sexual dysfunction, although there is disagreement, particularly about mirtazapine, and methodological issues militate against definitive findings. Antidepressant-induced sexual dysfunction is dose-dependent to an extent, but patient vulnerability factors are also relevant. There are significant differences in antidepressant-induced sexual dysfunction between men and women. It is important to ask antidepressant -treated patients about sexual dysfunction as few self-report; this may well contribute to antidepressant non-adherence. Consider using an antidepressant with low risk of antidepressant-induced sexual dysfunction for initial treatment. When antidepressant-induced sexual dysfunction has developed, try to persuade the patient to wait in case tolerance develops. Then consider changing to a lower risk or use of high/low risk antidepressant combinations but pharmacological expertise is required. Adjunctive sildenafil can help in both sexes.

Evaluation of treatment in 35 cases of bipolar suicide.

OBJECTIVE: The aim of the present study was to evaluate clinical factors relevant to suicide prevention (including treatment) in cases of bipolar suicide with available therapeutic histories. METHOD: Victorian Coroner's Office data enabled identification of suicides that occurred between March 1993 and December 2001. Cases involving sufficient clinical notes to enable diagnosis of DSM-IV bipolar disorder and review of treatment were de-identified and assessed by an expert clinical panel. RESULTS: From 3752 suicides, 35 eligible bipolar subjects (22 men, 13 women) aged 40.3 +/- 1.8 years were identified. Duration of illness was 11.9 +/- 1.1 years. A total of 86% had made at least one previous suicide attempt, and 83% were in the depressed phase of illness. A total of 63% manifested psychosis at some time during lifetime illness. Fourteen per cent were inpatients, and 26% suicided within 6 weeks of hospital discharge. The panel's retrospective risk assessment concluded that only 48% of cases could have been assessed as high risk. In the 4 weeks prior to suicide, treatment was rated as not reaching benchmark standards in 60% of cases. Electroconvulsive therapy had been given to 11%, lithium to 43% (but definitely therapeutic in only 11%), 31% had never been treated with lithium, and psychosocial interventions did not reach adequate standards in 57% during the previous year. CONCLUSIONS: In the majority of bipolar suicide cases in the present case series the subjects did not receive treatment at or above a benchmark standard, often due to illness and situational factors, but also possibly due to inadequate clinical interventions. Strategies to improve treatment may reduce suicide in bipolar disorder.

Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder. Randomised, controlled, open-label study.

BACKGROUND: The efficacy and safety of long-acting injectable risperidone have not been compared with those of an oral atypical antipsychotic. AIMS: To compare long-acting risperidone and oral olanzapine in 377 patients with DSM-IV schizophrenia or schizoaffective disorder. METHOD: Patients were randomised to receive long-acting risperidone (25 mg or 50 mg every 14 days) or olanzapine (5-20 mg/day). RESULTS: In the 13-week phase, long-acting risperidone was at least as effective as (not inferior to) oral olanzapine. In the 12-month phase, significant improvements in the Positive and Negative Syndrome Scale (PANSS) total and factor scores from baseline to month 12 and end-point were seen in both groups of patients. Few patients discontinued treatment because of an adverse event. CONCLUSIONS: Both treatments were efficacious and well tolerated.

Beyond the evidence: is there a place for antidepressant combinations in the pharmacotherapy of depression?

Up to 45% of patients with debilitating and potentially lethal depressive illness do not achieve remission with initial drug treatment. Using combinations of antidepressants as an early option for treatment-resistant depression has become increasingly common. Before trying combination therapy, it is essential first to ensure diagnosis is correct, and then to optimise antidepressant monotherapy, using an effective dose for an adequate period. Subsequently, augmentation of antidepressants with lithium and triiodothyronine should be considered, as these strategies are strongly supported by numerous clinical trials. Electroconvulsive therapy is the most effective treatment for severe depression. There is little evidence to support use of antidepressant combinations. Risk of toxicity and drug interactions mandate that combinations be used as a last resort, and only in specialist settings.

Clinical experience with atypical antipsychotics in an acute inpatient unit: focus on quetiapine.

Objective. To evaluate dosing and time to efficacy of atypical antipsychotics in an acute inpatient unit. Methods. Admissions during 2001 were reviewed. Patients primarily treated with an atypical antipsychotic (including those simultaneously commenced on a mood stabiliser and/or antidepressant or receiving benzodiazepines) were evaluated. Non-acute patients, those without medical records or transferred to other hospitals were excluded. Medication details were noted. Results. A total of 137 patients were evaluated; 56 (41%) had received risperidone, 38 (28%) olanzapine, and 37 (27%) quetiapine. Mean doses (mg/day) at discharge were risperidone 4.1±2.3, olanzapine 22.5±10.2, quetiapine 576±472. Dose ranges (mg/day) were risperidone 0.5-12, olanzapine 5-40, quetiapine 50-1800. No differences between atypicals in time to efficacy/concomitant anticholinergics/mood stabilisers were observed. Benzodiazepine use was more frequent with risperidone and olanzapine than quetiapine. No serious side effects with any drug were noted. Quetiapine was rapidly titrated in 20 patients (up to 400 mg on Day 1). In 18 of these, acute disturbance was controlled. Two patients were switched for lack of efficacy, one due to persistent tachycardia, and five for concern about early postural hypotension. Conclusion. These data provide further evidence concerning dose and dose range of atypicals required for optimal clinical outcome. More rapid initiation with quetiapine may be of benefit to some patients in the acute inpatient setting.