A major challenge in the treatment of major depressive episodes associated with bipolar disorder is differentiating this illness from major depressive episodes associated with major depressive disorder. Mistaking the former for the latter will lead to incorrect treatment and poor outcomes. None of the classic antidepressants, serotonin specific reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors have ever received regulatory approval as monotherapies for the treatment of bipolar depression. At present, there are only 3 approved medication treatments for bipolar depression: olanzapine/fluoxetine combination, quetiapine (immediate or extended release), and lurasidone (monotherapy or adjunctive to lithium or valproate). All 3 have similar efficacy profiles, but they differ in terms of tolerability. Number needed to treat (NNT) and number needed to harm (NNH) can be used to quantify these similarities and differences. The NNTs for response and remission for each of these interventions vs placebo range from 4 to 7, and 5 to 7, respectively, with overlap in terms of their 95% confidence intervals. NNH values less than 10 (vs placebo) were observed for the spontaneously reported adverse events of weight gain and diarrhea for olanzapine/fluoxetine combination (7 and 9, respectively) and somnolence and dry mouth for quetiapine (3 and 4, respectively). There were no NNH values less than 10 (vs placebo) observed with lurasidone treatment. NNH values vs placebo for weight gain of at least 7% from baseline were 6, 16, 58, and 36, for olanzapine/fluoxetine combination, quetiapine, lurasidone monotherapy, and lurasidone combined with lithium or valproate, respectively. Individualizing treatment decisions will require consideration of the different potential adverse events that are more likely to occur with each medication. The metric of the likelihood to be helped or harmed (LHH) is the ratio of NNH to NNT and can illustrate the tradeoffs inherent in selecting medications. A more favorable LHH was noted for treatment with lurasidone. However, OFC and quetiapine monotherapy may still have utility in high urgency situations, particularly in persons who have demonstrated good outcomes with these interventions in the past, and where a pressing clinical need for efficacy mitigates their potential tolerability shortcomings. In terms of maintenance therapy, adjunctive quetiapine is the only agent where the NNT vs lithium or valproate alone is less than 10 for both the prevention of mania and the prevention of depression.

Treatment resistance, along with its sibling partial response, remains a common phenomenon in schizophrenia, complicating the disability burden inherent in the disease. Antipsychotic medications are the mainstay of treatment, and treatment resistance has mainly been defined in terms of poor response to antipsychotic medication. At the same time, clozapine, the most effective antipsychotic, remains underutilized at the expense of exposing patients to polypharmacy. We review known causes of disability in schizophrenia, how they impact various areas of everyday functioning, and discuss potential treatment options including but not limited to pharmacological approaches aimed at maximizing treatment response and reducing treatment resistance.

The medications used to treat narcolepsy are targeted toward alleviating symptoms such as excessive sleepiness and cataplexy. The cause of this neurological sleep disorder is still not completely clear, though a destruction of hypocretin/orexin neurons has been implicated. The destruction of these neurons is linked to inactivity of neurotransmitters including histamine, norepinephrine, acetylcholine, and serotonin, causing a disturbance in the sleep/wake cycles of narcoleptic patients. Stimulants and MAOIs have traditionally been used to counteract excessive daytime sleepiness and sleep attacks by inhibiting the breakdown of catecholamines. Newer drugs, called wake-promoting agents, have recently become first-line agents due to their better side-effect profile, efficacy, and lesser potential for abuse. These agents similarly inhibit reuptake of dopamine, but have a novel mechanism of action, as they have been found to increase neuronal activity in the tuberomamillary nucleus and in orexin neurons. Sodium oxybate, a sodium salt of gamma-hydroxybutyrate (GHB), is another class that is used to treat many symptoms of narcolepsy, and is the only U.S. Food and Drug Administration (FDA)-approved medication for cataplexy. It has a different mechanism of action than either stimulants or wake-promoting agents, as it binds to its own unique receptor. Antidepressants, like selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have also been used, as similar to stimulants, they inhibit reuptake of specific catecholamines. In this article, we seek to review the mechanisms behind these classes of drugs in relation to the proposed pathophysiology of narcolepsy. Appropriate clinical strategies will be discussed, including specific combinations of medications that have been shown to be effective.

Since currently available antipsychotic medications predominantly treat hallucinations, delusions, disorganized thoughts and behavior, and related agitation/aggression, attention has traditionally been focused on managing positive symptoms. However, prominent negative symptoms and clinically relevant cognitive impairment affect approximately 40% and 80% of people with schizophrenia, respectively. Moreover, negative and cognitive symptoms are closely related to functional outcomes, and contribute substantially to the overall illness burden. Therefore, approaches to describe, measure, and manage these symptom domains are relevant. This article summarizes the phenomenology, prevalence, assessment, and treatment of negative and cognitive symptoms in patients with schizophrenia, including pharmacologic and nonpharmacologic management strategies that can be used in clinical care now, as well as pharmacologic approaches that are being tested. Currently, no approved treatments targeting negative or cognitive symptomatology in schizophrenia are available. It is hoped that progress in the understanding of the neurobiology of these important symptom domains of schizophrenia will help develop effective treatment strategies in the future. However, until this goal is achieved, clinicians should avoid therapeutic nihilism. Rather, the severity and impact of negative and cognitive symptoms should be determined, quantified, and monitored. Further, psychosocial treatments have shown therapeutic benefits. Thus, cognitive behavioral therapy, cognitive remediation, social skills training, and computer-assisted training programs should be offered in conjunction with antipsychotic treatment. Several non-antipsychotic augmentation strategies can be tried off-label. Treatment plans that incorporate currently available management options for negative and cognitive symptomatology in patients with schizophrenia should be adapted over time and based on the individual’s needs, with the aim to enhance overall outcomes.

Learning Objective: Discuss the theory of modulation of receptor activity or the blockade of the reuptake of multiple neurotransmitter systems for the future treatment of MDD.

Major depressive disorder (MDD) is a serious and often crippling psychiatric illness with a high risk of relapse and treatment resistance. In this article, we discuss the role of the serotonergic system in MDD including our current understanding of how various serotonin (5HT) receptors modulate monoamine neurotransmission and behavior. We also discuss how pharmacologic interventions, including novel and existing antidepressants and atypical antipsychotics, may be utilized to adjust serotonergic neurotransmission and provide more effective treatments for patients with MDD.