Debbi A. Morrissette

Serotonergic Drugs for Depression and Beyond

The current generation of antidepressant drugs acts predominantly by targeting the serotonin transporter (SERT). The original trend to do this selectively (e.g., with SSRIs or selective serotonin reuptake inhibitors) has given way to combining various additional pharmacologic mechanisms with SERT inhibition, including dual actions by single drugs (e.g., SNRIs or serotonin norepinephrine reuptake inhibitors), or by augmenting SSRIs with a second drug of a different mechanism (e.g., bupropion with dopamine and norepinephrine reuptake inhibition; trazodone with 5HT2A antagonism; mirtazapine with 5HT2A/5HT2C/5HT3/alpha2 antagonism; buspirone or some atypical antipsychotics with 5HT1A partial agonism; other atypical antipsychotics with 5HT2C/5HT7 antagonism and other mechanisms). Novel drugs in development include those that combine multiple simultaneous pharmacologic mechanisms in addition to SERT inhibition within the same molecule, such as vilazodone (combining 5HT1A partial agonism with SERT inhibition), triple reuptake inhibitors (combining norepinephrine and dopamine reuptake inhibition with SERT inhibition), and vortioxetine, a multimodal antidepressant combining actions at the G protein receptor mode (5HT1A and 5HT1B partial agonism and 5HT7 antagonism), at the ion channel mode (5HT3 antagonism) as well as the neurotransmitter transporter mode (SERT inhibition). These various strategies that build upon SERT inhibition provide promise for novel therapeutic approaches to depression, including the possibility of targeting residual symptoms not well treated by SERT inhibition alone, and reducing side effects, such as sexual dysfunction.

California State Hospital Violence Assessment and Treatment (Cal-VAT) guidelines

Here we provide comprehensive guidelines for the assessment and treatment of violence and aggression of various etiologies, including psychotic aggression and impulsive aggression due to schizophrenia, mood disorders, ADHD, or trauma, and predatory aggression due to psychopathy and other personality disorders. These guidelines have been developed from a collection of prescribing recommendations, clinical trial results, and years of clinical experience in treating patients who are persistently violent or aggressive in the California Department of State Hospital System. Many of the recommendations provided in these guidelines employ off-label prescribing practices; thus, sound clinical judgment based on individual patient needs and according to institution formularies must be considered when applying these guidelines in clinical practice.

Modulating the serotonin system in the treatment of major depressive disorder-ERRATUM

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.

Treating the violent patient with psychosis or impulsivity utilizing antipsychotic polypharmacy and high-dose monotherapy

Insufficient treatment of psychosis often manifests as violent and aggressive behaviors that are dangerous to the patient and others, and that warrant treatment strategies which are not considered first-line, evidence-based practices. Such treatment strategies include both antipsychotic polypharmacy (simultaneous use of 2 antipsychotics) and high-dose antipsychotic monotherapy. Here we discuss the hypothesized neurobiological substrates of various types of violence and aggression, as well as providing arguments for the use of antipsychotic polypharmacy and high-dose monotherapy to target dysfunctional neurocircuitry in the subpopulation of patients that is treatment-resistant, violent, and aggressive. In this review, we focus primarily on the data supporting the use of second-generation, atypical antipsychotics both at high doses and in combination with other antipsychotics.

Twisting the night away: a review of the neurobiology, genetics, diagnosis, and treatment of shift work disorder.

Although not all individuals who work outside of standard daytime hours develop physical and psychiatric issues, there is a substantial portion of shift workers who develop shift work disorder. Shift work disorder is due to a misalignment between an individuals endogenous circadian rhythms and environmental stimuli, and can have potentially serious consequences to an individuals health and quality of life. This article reviews the neurobiological and genetic underpinnings of shift work disorder, and describes how desynchronization of the molecular clock may lead to both physical and psychiatric illnesses. Diagnostic tools and treatment guidelines to address the circadian misalignment, excessive sleepiness, and insomnia experienced by patients with shift work disorder are also discussed.

Should High Dose or Very Long-Term Antipsychotic Monotherapy Be Considered Before Antipsychotic Polypharmacy?

Standard doses of all antipsychotics target 60–80% occupancy of dopamine D2 receptors. However, many patients do not respond adequately in 2–6 weeks to standard doses of one or more antipsychotics given as sequential monotherapies, as suggested by contemporary treatment guidelines for schizophrenia. The reasons for such inadequate treatment responses are several, and include both pharmacokinetic and pharmacodynamic failures. That is, some patients at standard doses do not attain 60–80% D2 occupancy. Factors accounting for this include not only noncompliance, but also failure to absorb, rapid metabolism, CYP450 2D6 polymorphisms, and others. In addition, some patients at standard doses attain 60–80% D2 occupancy but do not respond adequately to this. Common problems among such patients are hostility, aggression, assaultiveness and violence as well as continued positive symptoms of psychosis. At least two approaches may be considered for such pharmacokinetic and pharmacodynamic failures: namely, high dose monotherapy, and very long treatment times when feasible. High doses of a single agent are actually better studied than antipsychotic polypharmacy with two or more antipsychotics, especially for certain agents, and provides an approach that is potentially simpler, safer and more effective for overcoming both pharmacokinetic and pharmacodynamic treatment failures, and allows a strategy to optimize antipsychotic treatment without polypharmacy. In addition, certain patients have very late onset improvements, measured in months or years, and very long term treatment data for antipsychotics in schizophrenia are beginning to emerge for patients who are not in urgent management situations as an alternative to antipsychotic polypharmacy.

Do no harm: a paradigm shift in the unchecked use of antidepressants

The following true case scenario is one that the new paradigm shift in recognizing and treating mixed features of major depressive episodes is poised to prevent. Asking about subsyndromal symptoms of mania/hypomania, as well as asking about family history, will potentially alter clinical practice and change outcomes for many lives. The Case. A 17-year-old male presents to his primary care provider with symptoms of depression (anhedonia, feelings of worthlessness, etc.), and he is placed on antidepressant monotherapy and sent on his way. Approximately 2 months later, the patient experiences a full-blown manic episode with suicidal ideation. He is hospitalized, and a more appropriate treatment (in this case, an antipsychotic with mood-stabilizing properties) is initiated. However, this 17-year-old patient has already lost his job, his long-term girlfriend, and his chance at entering college with his peer group, all as a result of his manic episode. As it turns out, the mother of the patient had been diagnosed with bipolar disorder I, and the patient himself had at times exhibited subsyndromal symptoms of hypomania (including irritability, distractibility, and racing thoughts). His first-line clinician had never asked about family history or assessed for anything beyond symptoms of unipolar depression, and the patient did not know the importance of mentioning these things. The solution could have been a short conversation about family history and a fewminutes spent filling out a simple questionnaire while in the waiting room to possibly avoid this devastating outcome—a young life seemingly damaged right as it was beginning. With our newly published guidelines for diagnosis and treatment of mood disorders all along the spectrum, we (myself along with the top mood-disorder experts from around the world) are advocating that every patient who presents with symptoms of depression be thoroughly screened for family history of bipolar disorders and symptoms of (hypo)mania. I would argue that our guidelines not be viewed as something to instruct the diagnosis and treatment of some “obscure” mixed depression (rarely encountered and only for the most advanced psychiatric professionals to deal with), but as guidelines for what to do whenever a patient with seemingly “unipolar” depression comes to us for help. These newly developed guidelines do not necessarily suggest that an antidepressant should never be used—for many (approximately half) of the patients with symptoms of depression, the antidepressant class of medications is relatively effective and safe. What we argue is that antidepressant monotherapy be earned—meaning that, before any patient is placed on an antidepressant, we have done all in our power to ensure that any symptoms of (hypo)mania and positive family history have been aggressively ruled out. And in cases where antidepressant monotherapy is initiated, continuous and frequent monitoring for the emergence of (hypo)manic symptoms is our obligation to the patients (and their families) who are trusting us with their care. The mixed depression guidelines may be especially critical when it comes to the pediatric population. One indication that depression may actually NOT be unipolar in nature is young age of onset. When any patient under the age of 18 presents with symptoms of depression, mixed features or bipolarity should actually be expected and screened for thoroughly, intensely, and with no stone left unturned. If evidence that symptoms fall outside the realm of unipolar are suspected, antidepressant monotherapy should probably not be the treatment of choice. Not only may antidepressant monotherapy spark a switch to mania and possible emergence of suicidality, but the evidence indicates that, with the exception of fluoxetine, antidepressants DON’T WORK when it comes to pediatric depression. The potential risks therefore far outweigh any potential benefits. As frightening as it may seem to place such young patients on such “dangerous” * Address for correspondence: Debbi Ann Morrissette, Senior Medical Writer, Neuroscience Education Institute, 5900 La Place Court, Suite 120, Carlsbad, California 92008, USA. (Email: dmorrissette@neiglobal.com) CNS Spectrums, page 1 of 2.

Drug information update. Unconventional treatment strategies for schizophrenia: polypharmacy and heroic dosing

The majority of patients respond to antipsychotic monotherapy at standard doses, but a subset of patients will require more heroic measures that include antipsychotic polypharmacy and high-dose monotherapy. Indeed, research has shown that roughly 30% of patients with psychosis are prescribed multiple antipsychotic medications. We discuss the potential benefits and challenges of these approaches and provide a rationale for why and when they should be utilised.

Strategies for optimizing medication adherence in schizophrenia

Medication nonadherence is a common problem in the treatment of schizophrenia. The consequences of nonadherence are numerous and can be quite serious, including increased risk of rehospitalization and suicide. There are numerous factors that affect a patients decision and ability to take medication, including medication efficacy and tolerability, treatment regimen, cognitive deficits, and the patients relationship with the treatment team. Fortunately, there are several strategies that may increase treatment adherence, including individualization of medication selection and dosing strategy to maximize efficacy and minimize adverse side effects, utilization of long-acting injectable depot formulations that eliminate the need for the patient to remember daily oral medication, and psychosocial approaches that emphasize the benefits of staying well.