Bipolar disorder is characterized by episodes of mania, hypomania, and depression. Recurrences of manic or (more frequently) depressive symptoms are common. About 15-20% of patients with bipolar disorder die by suicide.

Three extended-release injectable formulations of second-generation antipsychotic drugs — two of risperidone (Rykindo, Uzedy) and one of aripiprazole (Abilify Asimtufii) — have been approved by the FDA for treatment of schizophrenia in adults. Rykindo and Abilify Asimtufii are also approved for maintenance treatment of bipolar I disorder in adults. Other extended-release injectable formulations of risperidone and aripiprazole have been available in the US for years (see Table 1).

The FDA has approved the second-generation antipsychotic drug cariprazine (Vraylar — Abbvie) for adjunctive treatment of major depressive disorder (MDD) in adults. Cariprazine was previously approved for treatment of schizophrenia and bipolar depression, and for acute treatment of manic or mixed episodes associated with bipolar I disorder.

The FDA has approved a sublingual film formulation of the alpha-2 adrenergic receptor agonist dexmedetomidine (Igalmi — BioXcel Therapeutics) for acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults. It is the first alpha-2 agonist and the only sublingual film to be approved for this indication. Dexmedetomidine has been available for many years in an injectable formulation (Precedex) for sedation in the intensive care unit and to facilitate procedures such as mechanical ventilation.

Invega Hafyera (Janssen), a long-acting, extended-release (ER) formulation of the second-generation antipsychotic paliperidone palmitate, has been approved by the FDA for twice-yearly IM treatment of schizophrenia in adults who have been adequately treated with another injectable ER formulation of the drug (Invega Sustenna or Invega Trinza). It is the first drug to become available in the US for twice-yearly treatment of schizophrenia.

The FDA has approved Lybalvi (Alkermes), a fixed-dose combination of the second-generation antipsychotic olanzapine (Zyprexa, and generics) and samidorphan, a new opioid antagonist, for treatment of adults with schizophrenia or with manic or mixed episodes of bipolar I disorder. The addition of samidorphan is intended to mitigate the weight gain that occurs with olanzapine. This is the first FDA approval for samidorphan.

The FDA has approved lumateperone (Caplyta — Intracellular Therapies), an oral second-generation antipsychotic, for once-daily treatment of schizophrenia in adults. It is the 13th second-generation antipsychotic drug to be approved by the FDA for this indication.

The FDA has approved Cinvanti (Heron), an IV emulsion formulation of the substance P/neurokinin-1 (NK1) receptor antagonist aprepitant, for prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in adults. Aprepitant is also available in oral capsule and suspension formulations (Emend, and generics), and fosaprepitant, a prodrug of aprepitant, is available in an IV formulation (Emend for injection).

Oral antipsychotic drugs used for treatment of schizophrenia, schizoaffective disorder, delusional disorder, and other manifestations of psychosis or mania are listed in Table 1. Parenteral antipsychotic drugs used for treatment of these disorders are listed in Table 2.

Bipolar disorder is characterized by intermittent episodes of mania and/or depression. Even with maintenance treatment, recurrences of manic or (more frequently) depressive episodes are common. Some of the drugs and dosages recommended here have not been approved by the FDA for use in bipolar disorder.

The FDA has approved cariprazine (Vraylar – Actavis), an oral, once-daily, second-generation antipsychotic, for treatment of schizophrenia and for acute treatment of manic or mixed episodes associated with bipolar I disorder.

The FDA has approved two new long-acting injectable formulations of second-generation antipsychotics for treatment of schizophrenia: aripiprazole lauroxil (Aristada – Alkermes), which is given once every 4-6 weeks, and paliperidone palmitate (Invega Trinza – Janssen), which is given once every 3 months. Once-monthly injectable formulations of aripiprazole (Abilify Maintena) and paliperidone palmitate (Invega Sustenna) were approved earlier.

The FDA has approved the oral, once-daily, second-generation antipsychotic brexpiprazole (Rexulti – Otsuka/Lundbeck) for treatment of schizophrenia and as an adjunct to antidepressants for treatment of major depressive disorder (MDD). Aripiprazole (Abilify), a structurally similar second-generation antipsychotic also comarketed by Otsuka (with BMS), recently became available generically.

Pharmacological treatment of insomnia includes prescription drugs, non-prescription medications, and "natural" remedies. Behavioral approaches such as cognitive behavioral therapy, which are not discussed here, are also used. Pharmacologic treatment and behavioral therapy are often combined.

Adults with a body mass index (BMI) between 25 and 29.9 kg/m² are considered overweight. Those with a BMI ≥30 are considered obese. Losing even a small amount of weight and increasing physical activity can prevent some of the complications of obesity, particularly type 2 diabetes. Diet and exercise are the preferred methods for losing weight, but long-term failure rates are high. Several drugs have been approved by the FDA for weight reduction, but adherence is poor, adverse effects are common, and patients usually regain the lost weight when the drug is stopped. Bariatric surgery can produce substantial weight loss and significantly reduce obesity-related comorbidities; long-term data on its safety are encouraging, but still limited. Guidelines for the management of overweight or obese adults have recently been published.

The FDA has approved an inhalation powder formulation of loxapine (Adasuve – Teva), a first-generation antipsychotic long available in an oral formulation, for treatment of acute agitation related to schizophrenia or bipolar I disorder in adults. Adasuve is the first inhaled drug to be approved for this indication.

Alzheimer's disease (AD) is the most common cause of dementia, but cognitive loss is also associated with other neurological conditions such as Parkinson's disease, dementia with Lewy bodies, and vascular dementia. Mild cognitive impairment (MCI) is generally defined as cognitive decline greater than expected for an individual's age and educational level, but not interfering with activities of daily living; it may be a transitional state between the cognitive changes of normal aging and dementia.

Drugs are not the only treatment for psychiatric illness. Psychotherapy remains an important component in the management of these disorders, and cognitive behavioral therapy (CBT) can be used for many of them as well. Electroconvulsive therapy (ECT) has a long history of efficacy and safety when drugs are ineffective or cannot be used.

Pharmacological treatment of insomnia includes prescription drugs, non-prescription medications and "natural" remedies. Behavioral changes are often needed as well.

Augmentation with a second-generation (atypical) antipsychotic is a treatment option for patients with major depressive disorder (MDD) whose symptoms persist following antidepressant monotherapy. Aripiprazole (Abilify), olanzapine in a fixed-dose combination with fluoxetine (Symbyax), and extended-release quetiapine (Seroquel XR) have been approved by the FDA for such use.

The FDA has approved lurasidone (Latuda - Sunovion), a new second-generation antipsychotic, for oral treatment of schizophrenia in adults.

The antipsychotic drugs listed in Table 1 on the next page are more effective for treating the “positive symptoms” of schizophrenia (hallucinations and delusions) than the “negative symptoms” (apathy, social withdrawal, and blunted affect). Some symptoms of schizophrenia and acute psychoses may improve rapidly after treatment with antipsychotic drugs, but chronic schizophrenia improves slowly over many weeks and some patients may continue to improve for months. Most patients with chronic schizophrenia require prolonged maintenance therapy, but the risk of tardive dyskinesia and adverse metabolic effects must be kept in mind.

Drugs are not the only treatment for mood disorders. Psychotherapy remains an important component in the management of these disorders, and electroconvulsive therapy (ECT) has a long history of efficacy and safety when drugs are ineffective, poorly tolerated or cannot be used. Some drugs are recommended here for indications that have not been approved by the FDA.

The FDA has approved the marketing of iloperidone (Fanapt – Vanda), a second-generation antipsychotic, for treatment of schizophrenia. Iloperidone is chemically related to risperidone (Risperdal, and others).

Asenapine (Saphris - Schering-Plough), a dibenzo-oxepino pyrrole, has been approved by the FDA in a sublingual tablet formulation for acute treatment of schizophrenia and manic or mixed episodes associated with bipolar disorder. It is the sixth second-generation antipsychotic approved by the FDA for use in bipolar disorder.

The majority of patients with insomnia do not have a predisposing psychiatric disease. Rather, untreated insomnia may be a risk factor for development of psychiatric problems such as depression or anxiety.

A recently published retrospective cohort study in patients 30-74 years old has led to headlines in the media warning that use of atypical antipsychotic drugs doubles patients’ risk of sudden cardiac death. Typical antipsychotics have long been associated with this risk. In this study, however, the incidence of sudden cardiac death was similar with typical and atypical antipsychotics: about 1 in 340 person-years among the patients who took typical (first generation) antipsychotics such as haloperidol (Haldol, and others) and 1 in 360 personyears among those who took atypical (second-generation) drugs such as olanzapine (Zyprexa), compared to 1 in 700 patient-years among otherwise similar nonusers of antipsychotic drugs. The risk increased with the dose of the drug and also with the age of the patient; the authors state that they did not include patients younger than 30 because sudden cardiac death is very rare in the younger age group.1

Second-generation drugs are less likely than first generation drugs to cause extrapyramidal symptoms, tardive dyskinesia and neuroleptic malignant syndrome, but more likely to cause weight gain and other metabolic abnormalities.2 Aripiprazole (Abilify)3 is least likely to prolong the QT interval, which is one of the mechanisms that could be responsible for the small increase in the absolute risk of sudden death among patients who take antipsychotic drugs.

In a patient with a good indication for its use, the consequences of not taking an antipsychotic drug may be greater than the risks of taking one.

1. WA Ray et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225.
2. Drugs for psychiatric disorders. Treat Guidel Med Lett 2006; 4:35.
3. Second-generation antipsychotics — aripiprazole revisited. Med Lett Drugs Ther 2005; 47:81.

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Drugs are not the only treatment for psychiatric illness. Psychotherapy remains an important component in the management of these disorders, and cognitive behavioral therapy (CBT) is used for many of them as well. Electroconvulsive therapy (ECT) has a long history of efficacy and safety when drugs are ineffective or cannot be used.

Aripiprazole (Abilify - Bristol-Myers Squibb/Otsuka), a second-generation (atypical) antipsychotic drug, was approved by the FDA in 2002 for treatment of schizophrenia and more recently for bipolar disorder as well. It has been promoted as causing fewer adverse effects than other antipsychotics, without sacrificing efficacy.

The FDA has reported that 5106 elderly patients with dementia treated with atypical (second generation) antipsychotics in 17 randomized controlled trials had a higher mortality rate (4.5% vs. 2.6%) than those receiving placebo. Most of the deaths were due to cardiovascular and infectious causes (such as pneumonia). The drugs used in the trials were aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal). As the increase in mortality was considered a class effect, the FDA advisory also included ziprasidone (Geodon), clozapine (Clozaril) and the olanzapine/fluoxetine combination (Symbyax). The manufacturers of all of these drugs will be required to add a "black box" warning to their labeling.

An extended-release formulation of carbamazepine, available since 1997 for treatment of epilepsy, has now been approved under a new name, Equetro, for acute mania and mixed episodes of bipolar disorder. Although the drug was effective in some patients for up to 6 months, it has not been approved for maintenance treatment. Carbamazepine has not been shown to be more effective than lithium or valproate, and it can cause serious adverse effects.

The fixed-dose combination of olanzapine and fluoxetine (Symbyax - Lilly) has been approved by the FDA for treatment of depressive episodes associated with bipolar disorder. Olanzapine alone (Zyprexa), which is mainly used as an antipsychotic (Medical Letter 2003; 45:102), is FDA-approved for treatment of acute manic episodes and for maintenance treatment of bipolar disorder. Fluoxetine alone (Prozac, and others), which is mainly used as an antidepressant (Medical Letter 2003; 45:93), has no specific approval for use in bipolar disorder.

A recent supplement to the Journal of Clinical Psychiatry, titled "The Expert Consensus Guideline Series: Optimizing Pharmacologic Treatment of Psychotic Disorders," concluded that most experts endorsed use of second-generation (atypical) antipsychotics rather than first-generation drugs, with risperidone (Risperdal - Janssen) the top choice for first episodes, multiple episodes or switches from another drug (JM Kane et al, J Clin Psychiatry 2003; 64 suppl 12:5). The supplement was sponsored by Janssen.

The number of drugs marketed for psychiatric indications has increased sharply in recent years. The recommendations in this article are based on the results of controlled trials and on the experience and opinions of Medical Letter consultants. Interactions with other drugs can be found in The Medical Letter Handbook of Adverse Drug Interactions, 2003.

Aripiprazole (Abilify - Bristol-Myers Squibb/Otsuka), a quinolinone derivative, has been approved by the FDA for treatment of schizophrenia.

Ziprasidone (Geodon - Pfizer), a benzisothiazolyl piperazine, has been approved by the FDA for oral treatment of schizophrenia. An intramuscular formulation will probably be available in the near future.

The number of new drugs marketed for psychiatric indications has increased sharply in recent years. The recommendations in this article are based on the results of controlled trials and on the experience and opinions of Medical Letter consultants. Interactions with other drugs can be found in The Medical Letter Handbook of Adverse Drug Interactions, 1997.