More than two dozen pharmacological treatments are currently available for depression, working by more than a half dozen mechanisms, yet there remain many unmet therapeutic needs. Available antidepressants act directly on monoamine mechanisms, influencing receptors and transporters for serotonin, norepinephrine, and/or dopamine. Truly novel therapeutic targets beyond the monoamines have not emerged in the past few decades. Advances have been mostly in improved tolerability, and as a result, limitations in efficacy persist for all agents in the antidepressant class. Specifically, far too few patients, perhaps only a third, attain a full remission of symptoms, and those who have had many episodes of depression are not likely to sustain any remission for more than a few months. Thus, there is the urgent need for antidepressants with improved efficacy. Although the “holy grail” of antidepressant treatment has long been rapid onset of action, the reality is that more robust and sustained efficacy, even if delayed, is the unmet need of today. This is unlikely to be met by targeting the same monoamine transporters and receptors where current antidepressants act, so novel therapeutic targets must be identified if there is to be novel therapeutic efficacy of more robust and sustained antidepressant action.

Other issues in the treatment of depression include the increasing confusion between unipolar and bipolar depression, particularly at onset of first depressive episodes, as well as the confusion between treatment-resistant unipolar depression versus difficult-to-treat rapid cycling, mixed episodes of bipolar depression. Treatments for bipolar depression such as anticonvulsants and atypical antipsychotics are increasingly being used for bipolar and treatment-resistant cases. Future therapeutics may usefully exploit these mechanisms, and treatment of difficult cases in the future will likely involve use of multiple simultaneous mechanisms, either with multiple drugs or with multifunctional drugs.

There is also concern that depression may be a progressive illness, with unipolar depression progressing to treatment-resistant depression or even to bipolar spectrum disorder, and bipolar disorder progressing to rapid cycling and mixed treatment-resistant bipolar episodes. Future treatments of depression may not only have the potential to treat current symptoms and prevent their relapse, but also to halt progression and thus be disease-modifying, altering the course of untreated or inadequately treated illness.

Figuring out how to treat schizophrenia in different patients can be challenging. Different “pharmacies” are presented in this chapter that can be useful in the search for an effective treatment plan. Practical switching strategies are also presented that will aid in properly changing medications in patients when different treatments are required.

Likewise, a patient might not present with the full panoply of symptoms and might thus require specific treatment. Thus it is beneficial to know which medications are more efficacious at treating different symptom dimensions.

Olanzapine and clozapine have the highest risk of weight gain and therefore cardiometabolic disease, and should only be used as third-line treatment. Some of the conventional antipsychotics might actually carry less risk of cardiometabolic side effects, but more research is required.

If sedation is wanted, then compounds such as quetiapine, clozapine, olanzapine, or asenapine should be used. Augmentation with a benzodiazepine can also lead to sedation.

Generally, it is preferable to (1) not rush the discontinuation of the first antipsychotic, (2) not allow gaps between two antipsychotic treatments, and (3) not start the second antipsychotic at full dose.

Even though the patient will be simultaneously taking two medications for a short period of time, this is acceptable as it can decrease side effects and the risk of rebound symptoms, and it can hasten the successful transition to the second drug.

While polypharmacy is sometimes a necessity in hard-to-treat cases, an adequate monotherapy trial of a second drug should be the first option.

When patients are agitated, it may be beneficial to augment with a benzodiazepine just for a short time when the nonsedating antipsychotic is initiated. Thus the benzodiazepine is used as a “lead in” to the nonsedating anti-psychotic.

Once the nonsedating antipsychotic has been titrated to its full dose, then the benzodiazepine can be slowly tapered. Additionally, during the maintenance phase of the antipsychotic it can be helpful to use a benzodiazepine as a “top up” when needed by the patient.

This switching strategy may be best for patients who are switching due to lack of adequate control of symptoms by their sedating antipsychotic. For those who are switching due to intolerability, the temporary polypharmacy of three agents may lead to side effects.

Overview

This book aims to visually explain the underlying pathophysiology of schizophrenia, give an overview of the receptor profiles of conventional and atypical antipsychotics, and to provide information on best treatment approaches. The book is divided into five chapters for ease of reading and referencing. Chapter 1, “Neurobiology of Schizophrenia and Mood Disorders,” focuses on the known and hypothetical causes underlying the pathophysiology of schizophrenia and mood disorders. Chapter 2, “Multifunctionality of Antipsychotics,” is divided into multiple parts, focusing on the different receptor profiles and properties of antipsychotic medications. Chapter 3, “Side Effects of Antipsychotics: Metabolic Issues and Sedation,” explains the importance of monitoring patients initiated on antipsychotic medication. Chapter 4, “Individual Antipsychotic Drugs,” describes each antipsychotic medication currently available in terms of their approval, side effects profile, dosing tips, and drug interactions. Finally, Chapter 5, “Schizophrenia Pharmacy and Switching Strategies,” presents different ways to treat the various symptoms of schizophrenia and describes ways to switch between different antipsychotic agents. The visual component of this minibook is designed to allow the reader to easily grasp concepts.

Target Audience

This activity was designed for healthcare professionals, including psychiatrists, neurologists, primary care physicians, nurses, pharmacists, and others who treat patients with psychiatric conditions.

Statement of Need

The following unmet needs regarding antipsychotics were revealed following a vigorous assessment of activity feedback, expert faculty assessment, literature review, and through new medical knowledge:

• • The neurobiology underlying schizophrenia is based on the dopamine hypothesis, but many other neurotransmitter systems are also involved. It is important to understand the interaction among these neurotransmitter systems in order to get the full picture of the underlying causes of schizophrenia.

• • Many of the neurotransmitter systems involved in schizophrenia are also involved in mood disorders, and thus could be targeted by drugs effective in schizophrenia. A better understanding of the neurobiology of mood disorders can lead to a more precise choice of medication.

• • The pharmacological agents used to treat schizophrenia affect neurobiological systems in specific ways; understanding the relationship between the medications and the underlying pathophysiology of schizophrenia is essential in order to select appropriate treatment for a patient.

The serendipitous discovery in the 1950s that the antihistamine chlorpromazine can relieve symptoms of psychosis led to the discovery of conventional antipsychotics. Their ability to block D2 receptors was recognized by the 1970s. Since then, much research has been done to improve antipsychotic medications. This chapter explores the different classes of antipsychotics, explains their mechanisms of action, and describes how they affect the brain circuitry in schizophrenia and in mood disorders.

Additional properties have been integrated into the newer medications to improve therapeutic efficacy and prevent/reduce drug-related side effects. This table provides an overview of the different types of antipsychotics used to date.

This D2 antagonism will lead to a reduction in both the hyperactivity of this pathway and the positive symptoms linked to it.

However, the mesolimbic DA pathway is not the only pathway affected by D2 antagonists.

As the PFC does not have a high density of D2 receptors, the worsening of negative symptoms might also result from a deficient mesolimbic DA pathway.

In order to treat both positive and negative symptoms it is important to decrease DA activity in the mesolimbic pathway and increase DA tone in the mesocortical pathway. Dopamine function in schizophrenia is not simply “too high” or “too low;” it might be “out of tune.” Thus today's psychopharmacologist needs to learn how to tune the system adequately.

A lack of DA in this pathway results in movement disorders such as rigidity, akinesia, bradykinesia, and tremor, all hallmarks of Parkinson's disease.

A surplus of DA in this pathway, on the other hand, results in hyperkinetic movement disorders such as chorea and dyskinesia. Blockade of D2 receptors, such as with a conventional antipsychotic, prevents DA from binding there and can lead to motor side effects that are often collectively termed extrapyramidal side effects (EPS).

Every year, 5% of patients on conventional antipsychotics will develop tardive dyskinesia (25% of patients will be affected by 5 years), and for a disorder that starts in the early 20s, these odds are not acceptable.

Removing the conventional antipsychotic in time can prevent the occurrence of tardive dyskinesia, as this will allow the D2 receptors to lose their sensitivity and downregulate.

• • The underlying pathophysiology of schizophrenia remains to be fully elucidated.

• • Dopamine, glutamate, and serotonin are three of the most important neurotransmitter systems involved in schizophrenia and in the mechanism of action of conventional and atypical antipsychotics.

• • Each antipsychotic has a unique receptor profile, important in the alleviation of symptoms and induction of side effects.

• • Atypical antipsychotics can have cardiometabolic risks, and thus patients need to be monitored when treatment is initiated.

• • Today's psychopharmacologist has many choices when it comes to choosing an antipsychotic and can individualize treatment with the goals of maximizing treatment and minimizing side effects.

• • It is necessary for psychopharmacologists to understand the art of switching between different antipsychotics, as patients will most likely have to try different medications in order to reach an optimal treatment plan.

This chapter will go over the metabolic issues and other side effects associated with the different classes of antipsychotics, and explain how an informed psychopharmacologist can ascertain that side effects are minimized and optimal treatment is maximized. Whereas Chapter 4 will expand upon the effects that antipsychotics have on the brain—or the pharmacodynamics of antipsychotics—this chapter includes a section that explains the pharmacokinetics of antipsychotics, namely how brain and body interactions affect the drugs. These are important concepts to understand in order to maximize treatment and minimize side effects.

Specifically, 5HT2C and H1 antagonism is linked to weight gain, and M3 receptor antagonism can alter insulin regulation. Receptor “X” may increase insulin resistance, resulting in elevated fasting plasma triglyceride levels. Some patients might be more prone than others to experience increased cardiometabolic risk on certain atypical antipsychotics.

When hyperinsulinemia leads to pancreatic beta cell failure, pre-diabetes and then diabetes ensue. The presence of diabetes increases a patient's risk for cardiovascular events and premature death.

When patients have dyslipidemia, are pre-diabetic or diabetic, or are obese, it is necessary to obtain their fasting glucose levels, blood pressure, and waist circumference measurements just before starting treatment with antipsychotics and throughout treatment. It may be best in these patients to avoid or switch from antipsychotics that exhibit a higher risk of cardiometabolic side effects.

If, on the other hand, blockade of 5HT and DA receptors has antimanic and antipsychotic efficacy, thus leading to good patient outcome, it would be best to use an antipsychotic that has a 5HT/DA profile, but lacks efficacy at M1, H1, or alpha 1 receptors.

Other patients might become tolerant to the sedating side effects of their medication. Careful monitoring to develop individualized treatment is necessary in determining the best possible treatment plan for each patient.

Various antidepressants such as paroxetine, fluoxetine, duloxetine, and high doses of sertraline are inhibitors of cytochrome P450 2D6; thus they could theoretically raise the levels of the previously mentioned antipsychotics as these are substrates for the same enzyme. However, this is not usually clinically significant.

This chapter will describe each antipsychotic medication currently available in terms of side effect profile, dosing tips, and drug interactions. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated. Thus it is important to remain up-to-date on the specifics of each antipsychotic. This chapter will also introduce some of the new medications that are in development.

Even though it is very effective, clozapine is not considered a fi rst-line agent as it can lead to the potentially life-threatening side effect agranulocytosis. Weight increase and the concomitant risk of developing metabolic complications are greatest with clozapine.

Risperidone is also available as an intramuscular, long-term depot formulation that lasts two weeks. Risperidone does increase prolactin levels, but there appears to be less risk of weight gain with risperidone, as well as less cardiometabolic risk, than with some other atypical antipsychotics, at least in some patients.

Paliperidone may theoretically improve depression due to its alpha 2 antagonist properties but has not been extensively studied. It might however be associated with weight gain, insulin resistance, and diabetes as well as prolactin elevation, similarly to risperidone.

Paliperidone is the first atypical antipsychotic that has recently been approved as a once-monthly formulation for the acute and maintenace treatment of schizophrenia in the United States.

The 5HT1D antagonist actions combined with the 5HT and NE reuptake blocking properties might contribute to the absence of weight gain induction by ziprasidone, as well as its potential antidepressant and anxiolytic properties.

Similarly to ziprasidone, aripiprazole causes little to no weight gain, most likely because it lacks 5HT2C and histamine H1 properties. Additionally, aripiprazole does not seem to induce dyslipidemia, increase fasting triglyceride levels, or increase insulin resistance. Thus aripiprazole has a lower cardiometabolic risk.

Another side effect of zotepine is its tendency to increase QTc prolongation. Due to its norepinephrine reuptake inhibition, zotepine has the potential for antidepressant actions.

Although loxapine usually does not lead to weight gain, it might present a cardiometabolic risk. Loxapine has an intramuscular formulation, and its metabolite amoxapine is a tricyclic antidepressant.

This chapter introduces the neurobiology that is thought to underlie the symptoms of schizophrenia. The dopamine hypothesis of schizophrenia has been accepted for a long time, especially as the first antipsychotics were shown to block dopamine D2 receptors. This theory posits that dopamine is overactive in some brain areas, and underactive in other brain areas. This chapter shows that it might be more accurate to say that dopamine is neither “too high” nor “too low” but “out of tune.” In addition, ideas about the involvement of glutamate and serotonin have gained momentum in the pathophysiology of schizophrenia, and this chapter aims to give an overview of how these three neurotransmitter systems may come together to induce both the positive and negative symptoms of schizophrenia.

As various antipsychotics have been used in the treatment of mood disorders, this chapter will also go through the hypothetical neurobiology of disorders, such as mania and depression. Beside dopamine and serotonin, norepinephrine is also one of the main players in mood disorders, and will therefore be discussed here.

This brief neurobiological overview of the neurotransmitter systems impacted by antipsychotics will also aid in understanding the occurrence of side effects of different antipsychotics.

In schizophrenia, the neurotransmitter dopamine (DA) is theoretically dysregulated, and as a result various brain areas are overactive, underactive, or otherwise “out of tune,” resulting in the generation of positive and negative symptoms.

Specifically, it has been hypothesized that hyperactivity of this pathway accounts for the delusions and hallucinations observed in schizophrenia. This hypothesis is known both as the “DA hypothesis of schizophrenia” and perhaps more precisely as the “mesolimbic DA hyperactivity hypothesis of positive symptoms of schizophrenia.”

This DA deficit could result from ongoing degeneration due to glutamate excitotoxicity or from a neurodevelopmental impairment in the glutamatergic system. Loss of motivation and interest, anhedonia, and lack of pleasure as observed in schizophrenia result not only from a malfunctioning mesocortical DA pathway but also from a deficient mesolimbic DA pathway.

Although these two pathways are unaffected in schizophrenia, they do play an intricate part in the development of side effects, as they will not remain untouched by drugs interacting with DA neurons throughout the brain.