Antipsychotic agents

Antipsychotic agents.

This chapter will explore antipsychotic drugs, with an emphasis on treatments for schizophrenia. These treatments include not only conventional antipsychotic drugs, but also the newer atypical antipsychotic drugs that have largely replaced the older conventional agents. Atypical antipsychotics are really misnamed, since they are also used as treatments for both the manic and depressed phases of bipolar disorder, as augmenting agents for treatment-resistant depression, and “off-label” for various other disorders, such as treatment-resistant anxiety disorders. The reader is referred to standard reference manuals and textbooks for practical prescribing information, such as drug doses, because this chapter on antipsychotic drugs will

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Figure 5-1. . ThroughoutQualitative and semi-quantitative representation of receptor binding properties this chapter, the receptor binding properties of the atypical antipsychotics are represented both graphically and semi-quantitatively. Each drug is represented as a blue sphere, with its most potent binding properties depicted along the outer edge of the sphere. Additionally, each drug has a series of colored boxes associated with it. Each colored box represents a different binding property, and binding strength is indicated by the size of the box and the number of plus signs. Within the colored box series for any particular antipsychotic, larger boxes with more plus signs (positioned to the left) indicate stronger binding affinity, while smaller boxes with fewer plus signs (positioned to the right) represent weaker binding affinity. The series of boxes associated with each drug are arranged such that the size and positioning of a box reflect the binding potency for a particular receptor. The vertical dotted line cuts through the dopamine 2 (D ) receptor binding box, with binding properties that are more2 potent than D on the left and those that are less potent than D on the right. All binding properties are based on2 2 the mean values of published K (binding affinity) data ( ). The semi-quantitative depictioni http://pdsp.med.unc.edu

used throughout this chapter provides a quick visual reference of how strongly a particular drug binds to a particular receptor. It also allows for easy comparison of a drug’s binding properties with those of other atypical antipsychotics.

emphasize basic pharmacologic concepts of mechanism of action and not practical issues such as how to prescribe these drugs (for that information see for example Stahl’s Essential

, which is a companion to this textbook).Psychopharmacology: the Prescriber’s Guide

Antipsychotic drugs exhibit possibly the most complex pharmacologic mechanisms of any drug class within the field of clinical psychopharmacology. The pharmacologic concepts developed here should help the reader understand the rationale for how to use each of the different antipsychotic agents,

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based upon their interactions with different neurotransmitter systems ( ). Such interactionsFigure 5-1 can often explain both the therapeutic actions and the side effects of various antipsychotic medications and thus can be very helpful background information for prescribers of these therapeutic agents.

Conventional antipsychotics

What makes an antipsychotic “conventional”?

In this section we will discuss the pharmacologic properties of the first drugs that were proven to effectively treat schizophrenia. A list of many conventional antipsychotic drugs is given in .Table 5-1 These drugs are usually called antipsychotics, but they are sometimes also called conventional

antipsychotics, or antipsychotics, or antipsychotics. The earliestclassical typical first-generation effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations more than

Table 5-1 Some conventional antipsychotics still in use

60 years ago, rather than from scientific knowledge of the neurobiological basis of psychosis, or of the mechanism of action of effective antipsychotic agents. Thus, the first antipsychotic drugs were discovered by accident in the 1950s when a drug with antihistamine properties (chlorpromazine) was serendipitously observed to have antipsychotic effects when this putative antihistamine was tested in schizophrenia patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions

in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action.

Early in the testing process, chlorpromazine and other antipsychotic agents were all found to cause “neurolepsis,” known as an extreme form of slowness or absence of motor movements as well as behavioral indifference in experimental animals. The original antipsychotics were first discovered largely by their ability to produce this effect in experimental animals, and are thus sometimes called “neuroleptics.” A human counterpart of neurolepsis is also caused by these original (i.e., conventional) antipsychotic drugs and is characterized by psychomotor slowing, emotional quieting, and affective indifference.

Figure 5-2. . Conventional antipsychotics, also called first-generation antipsychotics or typicalD antagonist2 antipsychotics, share the primary pharmacological property of D antagonism, which is responsible not only for2 their antipsychotic efficacy but also for many of their side effects. Shown here is an icon representing this single pharmacological action.

D receptor antagonism makes an antipsychotic conventional2

By the 1970s it was widely recognized that the key pharmacologic property of all “neuroleptics” with antipsychotic properties was their ability to block dopamine D receptors ( ). This action has2 Figure 5-2

proven to be responsible not only for the antipsychotic efficacy of conventional antipsychotic drugs, but also for most of their undesirable side effects, including “neurolepsis.”

The therapeutic actions of conventional antipsychotic drugs are hypothetically due to blockade of D2 receptors specifically in the mesolimbic dopamine pathway ( ). This has the effect ofFigure 5-3

reducing the hyperactivity in this pathway that is postulated to cause the positive symptoms of psychosis, as discussed in ( and ). All conventional antipsychotics reduceChapter 4 Figures 4-12 4-13 positive psychotic symptoms about equally well in schizophrenia patients studied in large multicenter trials if they are dosed to block a substantial number of D receptors there ( ).2 Figure 5-4

Unfortunately, in order to block adequate numbers of D receptors in the mesolimbic dopamine2 pathway to

Figure 5-3. . In untreated schizophrenia, the mesolimbicMesolimbic dopamine pathway and D antagonists2 dopamine pathway is hypothesized to be hyperactive, indicated here by the pathway appearing red as well as by the excess dopamine in the synapse. This leads to positive symptoms such as delusions and hallucinations. Administration of a D antagonist, such as a conventional antipsychotic, blocks dopamine from binding to the D2 2 receptor, which reduces hyperactivity in this pathway and thereby reduces positive symptoms as well.

Figure 5-4. . All known antipsychoticsHypothetical thresholds for conventional antipsychotic drug effects bind to the dopamine 2 receptor, with the degree of binding determining whether one experiences therapeutic and/or side effects. For most conventional antipsychotics, the degree of D2 receptor binding in the mesolimbic pathway needed for antipsychotic effects is close to 80%, while D2 receptor occupancy greater than 80% in the dorsal striatum is associated with extrapyramidal side effects (EPS) and in the pituitary is associated with hyperprolactinemia. For conventional antipsychotics (i.e,. pure D2 antagonists) it is assumed that the same number of D2 receptors is blocked in all brain areas. Thus, there is a narrow window between the threshold for antipsychotic efficacy and that for side effects in terms of D2 binding.

quell positive symptoms, one must simultaneously block the same number of D receptors2 throughout the brain, and this causes undesirable side effects as a “high cost of doing business” with conventional antipsychotics ( through ). Although modern neuroimaging techniquesFigures 5-5 5-8 are able to measure directly the blockade of D receptors in the dorsal (motor) striatum of the2 nigrostriatal pathway, as shown in , for conventional antipsychotics it is assumed that theFigure 5-4 same number of D receptors is blocked in all brain areas, including the ventral limbic area of2 striatum known as the nucleus accumbens of the mesolimbic dopamine pathway, the prefrontal cortex of the mesocortical dopamine pathway, and the pituitary gland of the tuberoinfundibular dopamine pathway.

Neurolepsis

D receptors in the mesolimbic dopamine system are postulated to mediate not only the positive2 symptoms of psychosis, but also the normal reward system of the brain, and the nucleus accumbens is widely considered to be the “pleasure center” of the brain. It may be the final common pathway of all reward and reinforcement, including not only normal reward (such as the pleasure of eating good food, orgasm, listening to music) but also the artificial reward of substance abuse. If D receptors are2 stimulated in some parts of the mesolimbic pathway, this can lead to the experience of pleasure. Thus, if D receptors in the mesolimbic system are blocked, this may not only reduce positive2 symptoms of schizophrenia, but also block reward mechanisms, leaving patients apathetic, anhedonic, lacking motivation, interest, and joy from social interactions, a state very similar to that of negative symptoms of schizophrenia. The near shutdown of the mesolimbic dopamine pathway necessary to improve the positive symptoms of psychosis ( ) may contribute to worseningFigure 5-4 of anhedonia, apathy, and negative symptoms, and this may be a partial explanation for the high incidence of smoking and drug abuse in schizophrenia.

Antipsychotics also block D receptors in the mesocortical DA pathway ( ), where DA may2 Figure 5-5

already be deficient in schizophrenia (see through ). This can cause or worsenFigures 4-14 4-16

negative and cognitive symptoms even though there is only a low density of D receptors in the2 cortex. An adverse behavioral state can be produced by conventional antipsychotics, and is sometimes called the “neuroleptic-induced deficit syndrome” because it looks so much like the negative symptoms produced by schizophrenia itself, and is reminiscent of “neurolepsis” in animals.

Extrapyramidal symptoms and tardive dyskinesia

When a substantial number of D receptors are blocked in the nigrostriatal DA pathway, this will2 produce various disorders of movement that can appear very much like those in Parkinson’s disease; this is why these movements are sometimes called drug-induced

Figure 5-5. . In untreated schizophrenia, theMesocortical dopamine pathway and D antagonists2 mesocortical dopamine pathways to dorsolateral prefrontal cortex (DLPFC) and to ventromedial prefrontal cortex (VMPFC) are hypothesized to be hypoactive, indicated here by the dotted outlines of the pathway. This hypoactivity is related to cognitive symptoms (in the DLPFC), negative symptoms (in the DLPFC and VMPFC), and affective symptoms of schizophrenia (in the VMPFC). Administration of a D antagonist could further reduce2 activity in this pathway and thus not only not improve such symptoms but actually potentially worsen them.

parkinsonism. Since the nigrostriatal pathway is part of the extrapyramidal nervous system, these motor side effects associated with blocking D receptors in this part of the brain are sometimes also2 called extrapyramidal symptoms, or EPS ( and ).Figures 5-4 5-6

Worse yet, if these D receptors in the nigrostriatal DA pathway are blocked chronically ( ),2 Figure 5-7

they can produce a hyperkinetic movement disorder known as tardive dyskinesia. This movement disorder causes facial and tongue movements, such as constant chewing, tongue protrusions, facial grimacing, and also limb movements that can be quick, jerky, or choreiform (dancing). Tardive dyskinesia is thus caused by long-term administration of conventional antipsychotics and is thought to be mediated by changes, sometimes irreversible, in the D receptors of the nigrostriatal DA2 pathway. Specifically, these receptors are hypothesized to become supersensitive or to “upregulate” (i.e., increase in number), perhaps in a futile attempt to overcome drug-induced blockade of D2 receptors in the striatum ( ).Figure 5-7

About 5% of patients maintained on conventional antipsychotics will develop tardive dyskinesia every year (i.e., about 25% of patients by 5 years), not a very encouraging prospect for a lifelong illness starting in the early twenties. The risk of developing tardive

Figure 5-6. . The nigrostriatal dopamine pathway isNigrostriatal dopamine pathway and D antagonists2 theoretically unaffected in untreated schizophrenia. However, blockade of D receptors, as with a conventional2 antipsychotic, prevents dopamine from binding there and can cause motor side effects that are often collectively termed extrapyramidal symptoms (EPS).

dyskinesia in elderly subjects may be as high as 25% within the first year of exposure to conventional antipsychotics. However, if D receptor blockade is removed early enough, tardive dyskinesia may2 reverse. This reversal is theoretically due to a “resetting” of these D receptors by an appropriate2 decrease in the number or sensitivity of them in the nigrostriatal pathway once the antipsychotic drug that had been blocking these receptors is removed. However, after long-term treatment, the D2 receptors apparently cannot or do not reset back to normal, even when conventional antipsychotic drugs are discontinued. This leads to tardive dyskinesia that is irreversible, continuing whether conventional antipsychotic drugs are administered or not.

Is there any way to predict those who will be harmed with the development of tardive dyskinesia after chronic treatment with conventional antipsychotics? Patients who develop EPS early in treatment may be twice as likely to develop tardive dyskinesia if treatment with a conventional antipsychotic is continued chronically. Also, specific genotypes of dopamine receptors may confer important genetic risk factors for developing tardive dyskinesia with chronic treatment using a conventional antipsychotic. Risk of new cases of tardive

Figure 5-7. . Long-term blockade of D receptors in the nigrostriatal dopamine pathway canTardive dyskinesia 2 cause upregulation of those receptors, which may lead to a hyperkinetic motor condition known as tardive dyskinesia, characterized by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing) as well as quick, jerky limb movements. This upregulation may be the consequence of the neuron’s futile attempt to overcome drug-induced blockade of its dopamine receptors.

dyskinesia, however, can diminish considerably after 15 years of treatment, presumably because patients who have not developed tardive dyskinesia despite 15 years of treatment with a conventional antipsychotic have lower genetic risk factors for it.

A rare but potentially fatal complication called the “neuroleptic malignant syndrome,” associated with extreme muscular rigidity, high fevers, coma, and even death, and possibly related in part to D2 receptor blockade in the nigrostriatal pathway, can also occur with conventional antipsychotic agents.

Prolactin elevation

Dopamine D receptors in the tuberoinfundibular DA pathway are also blocked by conventional2 antipsychotics, and this causes plasma prolactin concentrations to rise, a condition called hyperprolactinemia ( ). This is associated with conditions called galactorrhea (i.e., breastFigure 5-8 secretions) and amenorrhea (i.e., irregular or lack of menstrual periods). Hyperprolactinemia may thus interfere with fertility, especially in women. Hyperprolactinemia might lead to more rapid demineralization of bones, especially in postmenopausal women who are not taking estrogen replacement therapy. Other possible problems associated with elevated prolactin levels may include sexual dysfunction and weight gain, although the role of prolactin in causing such problems is not clear.

The dilemma of blocking D dopamine receptors in all dopamine pathways2

It should now be obvious that the use of conventional antipsychotic drugs presents a powerful dilemma. That is, there is no doubt that conventional antipsychotic medications exert dramatic therapeutic actions upon positive symptoms of schizophrenia by blocking hyperactive dopamine neurons in the mesolimbic dopamine pathway. However, there are dopamine pathways in theseveral brain, and it appears that blocking dopamine receptors in of them is useful ( ),only one Figure 5-3 whereas blocking dopamine receptors in the remaining pathways may be harmful (Figures 5-4 through ). The pharmacologic5-8

Figure 5-8. . The tuberoinfundibular dopamineTuberoinfundibular dopamine pathway and D antagonists2 pathway, which projects from the hypothalamus to the pituitary gland, is theoretically “normal” in untreated schizophrenia. D antagonists reduce activity in this pathway by preventing dopamine from binding to D2 2 receptors. This causes prolactin levels to rise, which is associated with side effects such as galactorrhea (breast secretions) and amenorrhea (irregular menstrual periods).

quandary here is what to do if one wishes simultaneously to dopamine in the mesolimbicdecrease dopamine pathway in order to treat positive psychotic symptoms theoretically mediated by hyperactive mesolimbic dopamine neurons and yet dopamine in the mesocortical dopamineincrease pathway to treat negative and cognitive symptoms, while leaving dopaminergic tone unchanged in both the nigrostriatal and tuberoinfundibular dopamine pathways to avoid side effects. This dilemma may have been addressed in part by the atypical antipsychotic drugs described in the following sections, and is one of the reasons why the atypical antipsychotics have largely replaced conventional antipsychotic agents in the treatment of schizophrenia and other psychotic disorders throughout the world.

Muscarinic cholinergic blocking properties of conventional antipsychotics

In addition to blocking D receptors in all dopamine pathways ( through ), conventional2 Figures 5-3 5-8

antipsychotics have other important pharmacologic

Figure 5-9. . Shown here is an icon representing a conventional antipsychoticConventional antipsychotic drug. Conventional antipsychotics have pharmacological properties in addition to dopamine D antagonism. The2 receptor profiles differ for each agent, contributing to divergent side-effect profiles. However, some important characteristics that multiple agents share are the ability to block muscarinic cholinergic receptors, histamine H1 receptors, and/or -adrenergic receptors.1

properties ( ). One particularly important pharmacologic action of some conventionalFigure 5-9 antipsychotics is their ability to block muscarinic M -cholinergic receptors ( through ).1 Figures 5-9 5-11

This can cause undesirable side effects such as dry mouth, blurred vision, constipation, and cognitive blunting ( ). Differing degrees of muscarinic cholinergic blockade may alsoFigure 5-10 explain why some conventional antipsychotics have a lesser propensity to produce extrapyramidal side effects (EPS) than others. That is, those conventional antipsychotics that cause more EPS are the agents that have only anticholinergic properties, whereas those conventional antipsychoticsweak that cause fewer EPS are the agents that have anticholinergic properties.stronger

How does muscarinic cholinergic receptor blockade reduce the EPS caused by dopamine D2 receptor blockade in the nigrostriatal pathway? The reason seems to be based on the fact that dopamine and acetylcholine have a reciprocal relationship with each other in the nigrostriatal pathway ( ).Figure 5-11

Figure 5-10. . In this diagram, the icon of aSide effects of muscarinic cholinergic receptor blockade conventional antipsychotic drug is shown with its M anticholinergic/antimuscarinic portion inserted into1 acetylcholine receptors, causing the side effects of constipation, blurred vision, dry mouth, and drowsiness.

Figure 5-11

A. . Dopamine and acetylcholine have a reciprocalReciprocal relationship of dopamine and acetylcholine relationship in the nigrostriatal dopamine pathway. Dopamine neurons here make postsynaptic connections with the dendrite of a cholinergic neuron. Normally, dopamine suppresses acetylcholine activity (no acetylcholine being released from the cholinergic axon on the right).

B. . This figure shows what happens to acetylcholine activityDopamine, acetylcholine, and D antagonism2 when dopamine receptors are blocked. As dopamine normally suppresses acetylcholine activity, removal of dopamine inhibition causes an increase in acetylcholine activity. Thus if dopamine receptors are blocked at the D receptors on the cholinergic dendrite on the left, then acetylcholine becomes overly active, with enhanced2 release of acetylcholine from the cholinergic axon on the right. This is associated with the production of extrapyramidal symptoms (EPS). The pharmacological mechanism of EPS therefore seems to be a relative dopamine deficiency and a relative acetylcholine excess.

C. . One compensation for the overactivity that occurs whenD antagonism and anticholinergic agents2 dopamine receptors are blocked is to block the acetylcholine receptors with an anticholinergic agent (M1 receptors being blocked by an anticholinergic on the far right). Thus, anticholinergics overcome excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by conventional antipsychotics. This also means that extrapyramidal symptoms (EPS) are reduced.

Dopamine neurons in the nigrostriatal dopamine pathway make postsynaptic connections with cholinergic neurons ( ). Dopamine normally acetylcholine release fromFigure 5-11A inhibits postsynaptic nigrostriatal cholinergic neurons, thus suppressing acetylcholine activity there (Figure

). If dopamine can no longer suppress acetylcholine release because dopamine receptors are5-11A

being blocked by a conventional antipsychotic drug, then acetylcholine becomes overly active ( ).Figure 5-11B

One compensation for this overactivity of acetylcholine is to block it with an anticholinergic agent ( ). Thus, drugs with anticholinergic actions will diminish the excess acetylcholine activityFigure 5-11C

caused by removal of dopamine inhibition when dopamine receptors are blocked ( and Figures 5-10 ). If anticholinergic properties are present in the same drug with D blocking properties, they5-11C 2

will tend to mitigate the effects of D blockade in the nigrostriatal dopamine pathway. Thus,2 conventional antipsychotics with potent anticholinergic properties have lower EPS than conventional antipsychotics with weak anticholinergic properties. Furthermore, the effects of D blockade in the2 nigrostriatal system can be mitigated by co-administering an agent with anticholinergic properties. This has led to the common strategy of giving anticholinergic agents along with conventional antipsychotics in order to reduce EPS. Unfortunately, this concomitant use of anticholinergic agents does not lessen the ability of the conventional antipsychotics to cause tardive dyskinesia. It also causes the well-known side effects associated with anticholinergic agents, such as dry mouth, blurred vision, constipation, urinary retention, and cognitive dysfunction ( ).Figure 5-10

Other pharmacologic properties of conventional antipsychotic drugs

Still other pharmacologic actions are associated with the conventional antipsychotic drugs. These include generally undesired blockade of histamine H receptors ( ) causing weight gain and1 Figure 5-9

drowsiness, as well as blockade of -adrenergic receptors causing cardiovascular side effects such1 as orthostatic hypotension and drowsiness. Conventional antipsychotic agents differ in terms of their ability to block these various receptors represented in . For example, the popularFigure 5-9 conventional antipsychotic haloperidol has relatively little anticholinergic or antihistaminic binding activity, whereas the classic conventional antipsychotic chlorpromazine has potent anticholinergic and antihistaminic binding. Because of this, conventional antipsychotics differ somewhat in their side-effect profiles, even if they do not differ overall in their therapeutic profiles. That is, some conventional antipsychotics are more sedating than others, some have more ability to cause cardiovascular side effects than others, some have more ability to cause EPS than others.

A somewhat old-fashioned way to subclassify conventional antipsychotics is “low potency” versus “high potency” ( ). In general, as the name implies, low-potency agents require higher dosesTable 5-1 than high-potency agents, but, in addition, low-potency agents tend to have more of the additional properties discussed here than do the so-called high-potency agents: namely, low-potency agents have greater anticholinergic, antihistaminic, and antagonist properties than high-potency agents,1 and thus are probably more sedating in general. A number of conventional antipsychotics are available in long-acting depot formulations ( ).Table 5-1

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