The second generation antipsychotics are a complex class of psychiatric medications, applicable to a diverse range of both FDA approved treatment indications and off-label uses. This variety stems largely from the unique pharmacodynamic profile of each agent, and often necessitates the employment of unique dosing strategies across the treatment of the varied psychiatry disorders, including schizophrenia, bipolar mania and depression, major depressive disorder, and autism. Despite the shared mechanism of dopamine D2 and serotonin-2a dual receptor blockade, which mediates the antipsychotic and antimanic properties of the second generation antipsychotics, the unique pharmacodynamic signature of each agent is subsequently responsible for the additional and varied antidepressant, anxiolytic, hypnotic, and tolerability� profile observed with each drug. Using an evidence based approach, this comprehensive handbook aims to highlight and discuss data relevant to treatment indications, off-labels uses, and dosing strategies of the 11 currently FDA approved second generation antipsychotics, with a strong emphasis on the pharmacodynamic profiles of these drugs. With the advent of three relatively new antipsychotics (lurasidone in 2011, brexpiprazole in 2015, and cariprazine in 2015), this text will serve as an excellent reference for practicing physicians, research investigators, and medical students alike. This review addresses not only these clinical applications, but provides physicians with the tools necessary to optimize treatment based upon patient diagnosis, proper antipsychotic selection, and implementation of an appropriate dosing strategy, thereby striking an essential balance between treatment efficacy and patient tolerability.

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Second and Third Generation Antipsychotics

A Comprehensive Handbook

By Ryan S. O'Dell

AuthorHouse

List of Tables, ix, 
List Of Abbreviations, xi, 
Foreword, xiii, 
Introduction, xv, 
Chapter 1: THE '-DONES', 1, 
1. Risperidone, 2, 
2. Paliperidone, 8, 
3. Ziprasidone, 10, 
4. Iloperidone, 15, 
5. Lurasidone, 18, 
Chapter 2: THE '-PINES', 22, 
6. Olanzapine, 23, 
7. Quetiapine, 27, 
8. Asenapine, 31, 
Chapter 3: THE '-PIPS' AND '-RIPS', 34, 
9. Aripiprazole, 35, 
10. Brexpiprazole, 39, 
11. Cariprazine, 43, 
Discussion, 47, 
References, 51, 
Tables, 79,

CHAPTER 1

THE '-DONES'

RISPERIDONE

The first modern atypical antipsychotic, risperidone, was approved for the treatment of schizophrenia in 1993. It is currently approved for both the acute and maintenance treatment of schizophrenia (in adults and adolescents aged 13-17 years), the acute phase of bipolar I disorder (mania or mixed episode) either as monotherapy or adjunct treatment with lithium or valproate, and irritability associated with autistic disorder (Table 1). This drug is absorbed consistently after ingestion, with an oral bioavailability of 70.0% and a peak plasma concentration within 1-2 hours (Table 4). With respect to dosing strategies in adults with schizophrenia, a typical initial dose is 1.0-2.0 mg/day, with a target dose of 4.0-6.0 mg/day and a maximum dose of 16.0 mg/ day (Table 1). Adolescents should be started at 0.5 mg/day and titrated to a daily dose of 3.0 mg/day. Dosing adjustments should not occur at intervals less than 24 hours and at increments of 1.02.0 mg for adults and 0.5-1.0 mg for adolescents. There are no current guidelines for to the long-term use of risperidone (beyond 8 weeks) in adolescents with schizophrenia. However, a recent open-label, multicenter study demonstrated risperidone maintenance treatment was efficacious and well tolerated over 6 to 12 months in adolescents with schizophrenia.

In adults with bipolar mania, initiation doses are typically higher and utilize a loading strategy (2.0-3.0 mg/day with a maximum dose of 6.0 mg/day; Table 1). In pediatric populations, a starting dose of 0.5 mg/day with a target of 2.5 mg/ day and maximum dose of 6.0 mg/day is recommended. As these recommendations were based on short-term, 3-week trials of antimanic efficacy, there are no current guidelines or approvals for the use of risperidone as maintenance therapy for bipolar mania.

Lastly, in regard to the treatment of irritability and aggression associated with autism (5-18 years of age), lower initiation doses of 0.25 mg/day (patients < 20.0 kg) and 0.5 mg/day (patients > 20.0 kg) are recommended (Table 1). The titration strategy is slow, with a minimum of four days at the starting dose, with increases in increments of 0.25-0.5 mg at 14-day intervals. Average efficacious doses range between 0.5 mg/day and 2.5 mg/ day, with a maximum daily dose of 3 mg/day.

For all treatment indications, the dosing of risperidone (or any atypical antipsychotic) should be individualized and should demonstrate a careful balance between symptom alleviation and patient tolerability. Once clinical efficacy has been maintained, physicians must always consider a gradual taper or further titration of the dosage to optimize this balance between symptom efficacy and safety. Based upon clinical trials and clinical experience, it therefore appears that higher doses of risperidone are required for the treatment of psychotic or manic symptoms, while lower doses can be used to curb irritation in children with autism. This antipsychotic attenuation is most likely due to higher (> 65.0%) D2 receptor occupancy and antagonism in the mesolimbic pathway at higher doses, while at lower doses, there is little receptor occupancy and therefore less antipsychotic effect. This is a property common to all SGAs.

Although not approved for the treatment of depression or anxiety, there exists a fair amount of evidence supporting the efficacy of risperidone in these psychiatric illnesses. The doses are often lower, suggesting that D2 receptor antagonism is not the responsible mechanism. The efficacy of risperidone in the treatment of MDD was first described in case reports, and there are currently five randomized, placebo-controlled trials suggesting low-dose risperidone as successful augmentation therapy in treatment resistant depression. The oldest of these studies in 2006 demonstrated that low-dose risperidone augmentation (0.25-2.0 mg/ day) to citalopram (40.0-60.0 mg/day) in patients with treatment resistant depression improved both the relapse rate (56.1% vs. 64.1%) and median time to relapse (97 days vs. 56 days). In this study, patients were treated with 4-6 weeks of citalopram monotherapy, followed by 4-6 weeks of open-label risperidone augmentation, and finally a 24-week double-blind continuation phase. A smaller but similarly designed trial also found a trending, but non-significant decrease in the relapse rate (56.0% vs. 65.0%) with low-dose risperidone augmentation . In 2007, a six-week trial of risperidone augmentation (1.0-2.0 mg/day) demonstrated a statistically significant reduction in depressive symptoms, an increase in both response rate and remission, and improvements in Hamilton rating scale for depression (HAM-D) scores. A randomized crossover study in 2008 also suggested that low-dose risperidone (0.5-2.0 mg/day) was especially efficacious in the treatment of suicidality. Finally, the most recent of these five studies (2009) provided further evidence for the use of low-dose risperidone (0.5-3.0 mg/day) as a therapeutic option for treatment resistant depression, demonstrating both faster responses and improved quality of life in a short-term, 4-week augmentation trial. Mechanistically, 5-HT2a antagonism (similar to that seen with the antidepressants nefazodone and trazodone) may explain this antidepressant efficacy.

Other, less well-controlled investigations have also demonstrated such antidepressive efficacy of low-dose risperidone. For example, a recent study demonstrated significant improvements in both depressive and psychotic symptoms when risperidone (2.0 mg/day) was used as an adjunct (to citalopram or venlafaxine XR) for the short-term treatment of MDD with psychotic features. In addition, there was similar efficacy with either quetiapine (300.0 mg/day) or olanzapine (15.0 mg/day) adjunctive therapy. However, larger controlled trials are needed to compare the long-term efficacy and tolerability of risperidone in the treatment of MDD, both with and without psychotic features. Finally, a small, open-label study suggested risperidone augmentation to sertraline improved symptoms in patients with sertraline-resistant depression and promoted increased levels of brain derived neurotrophic factor (BDNF). It is plausible that increased levels of BDNF, a known mediator of neuronal growth, differentiation, and synaptogenesis, alleviates depressive symptoms through improved neuronal connections and/or neurotransmission. Abnormalities in BDNF signaling have also been linked to the etiologies of both schizophrenia and mood disorders , further suggesting that the use of pharmacologic agents which modify BDNF signaling (i.e. low-dose risperidone) may prove helpful in these disorders.

In regard to the treatment of anxiety disorders, early investigations suggested low-dose adjunctive risperidone (0.5-1.5...

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