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13. Antipsychotics: Overview
Keywords
AntipsychoticsDopamine-2 receptorMechanism of actionFirst-generation antipsychoticsSecond-generation antipsychoticsThird-generation antipsychoticsNeurotoxicityNeuroprotectionEssential Concepts
All current antipsychotics marketed for schizophrenia share varying degrees of dopamine-2 (D2) receptor blockade as the presumed main mechanism of action. However, the next generation of antipsychotics may no longer follow this rule.
Primary symptom targets of antipsychotics are positive symptoms (disorganization, delusions, and hallucinations) and agitation, with limited efficacy for other symptom clusters (negative symptoms, cognition).
For historical reasons, antipsychotics are grouped into first-generation antipsychotics – “typical” or conventional antipsychotics, which are all characterized by extrapyramidal symptom (EPS) liability – and second- and third-generation antipsychotics (with reduced EPS risk, hence “atypical” antipsychotics).
Second-generation antipsychotics (clozapine, iloperidone, lurasidone, olanzapine, risperidone, and paliperidone, quetiapine, ziprasidone) and third-generation antipsychotics (aripiprazole, brexpiprazole, cariprazine) should not be considered interchangeable, as each drug has a unique receptor profile beyond shared 5-HT-2 – D2 antagonism, resulting in different side effects.
The main risks for first-generation antipsychotics are neurologic side effects (dystonias, akathisia, Parkinsonism, and tardive dyskinesia). For most second- and third-generation antipsychotics, metabolic problems (weight gain, dyslipidemia, and hyperglycemia) have emerged as major problems in long-term management, in addition to ongoing concerns about neurological side effects.
Non-dopaminergic antipsychotics are under development as they would be devoid of undesirable effects related to dopamine blockade.
In preclinical models, antipsychotics have both neuroprotective and neurotoxic properties. Tardive dyskinesia is an example of neurotoxicity, but the clinical implications of many other observations (e.g., cortical thinning in imaging studies) remain unclear.
“The greater the ignorance, the greater the dogmatism.” [1]
-Sir William Osler, Father of Modern Medicine, 1849–1919
Antipsychotics are the mainstay of treatment for schizophrenia. Lumped together into one group based on dopamine blockade, there are clear differences between antipsychotics with regard to side effects, particular among the newer antipsychotics. All antipsychotics are about equally effective for non-refractory patients with schizophrenia. For pedagogical reasons, I have maintained the historical distinction between first-, second-, and third-generation antipsychotics which mostly reflects the time period when they were approved. This chapter introduces dopamine blockade as mechanism of action for all current antipsychotics and derives clinical points related to this basic property (e.g., dosing). Motor and non-motor side effects are then covered in greater detail in the next two chapters (Chaps. 14 and 15, respectively). Clozapine and long-acting antipsychotics have their own chapters (Chaps. 17 and 18, respectively).
Mechanism of Action
All currently marketed antipsychotics for schizophrenia block D2 receptors, albeit with different affinities. Dopamine blockade in the mesolimbic system is believed to be responsible for the clinical efficacy of antipsychotics. Unfortunately, antipsychotics do not have enough regional specificity and cause extrapyramidal symptoms from D2 blockade in the nigrostriatal motor system and prolactin elevation in the tuberoinfundibular system. Drug development has thus far failed to develop an antipsychotic that does not interact with the dopamine system, although a pure serotonergic agonist, pimavanserin, is approved for psychosis in Parkinson’s disease [2] and clinicians have started to use it for other forms of psychosis [3]. The next generation of antipsychotics may very well include an antipsychotic that does not target dopamine receptors, at least not directly and would be expected to be devoid of motor side effects.
Antipsychotics only treat symptoms believed to be related to a hyperdopaminergic state (“dopamine storm”) in mesolimbic brain areas: positive symptoms (disorganization, delusions, and hallucinations) and agitation [4]. Since dopamine release is part of the biological mechanism behind tagging events as personally important for us, antipsychotics may be particularly effective for those symptoms where unconstrained dopamine release creates a state of aberrant salience: where everything becomes meaningful and connected to us – a state of self-referential thinking which is the core of paranoia [5]. On the other hand, symptoms of schizophrenia associated with other brain networks may be adversely affected by dopamine blockade (e.g., motivational systems and cognition). In addition to their acute efficacy for positive symptoms, antipsychotics can prevent psychotic relapse [6]. Just as antipsychotics are not a treatment for all aspects of the syndrome of schizophrenia, antipsychotics are not a treatment specific for schizophrenia: they are also effective for delirium, for mania, for depression, for anxiety, or for insomnia. In that sense, antipsychotics are broad-spectrum psychotropics (like broad-spectrum antipsychotics).
Key Point
Antipsychotics are not a treatment for all symptoms of schizophrenia which is a syndrome. They are effective for the positive symptoms of schizophrenia and to prevent relapse. Other symptom clusters are either not effectively treated (e.g., cognitive symptoms) or even worsened with dopamine blockade (e.g., negative symptoms).
Receptors and side effects
Receptor | Side effect | Clinical manifestations |
|---|---|---|
Alpha-1 | Hypotension | Syncope |
Dopamine-2 | Extrapyramidal side effects | Akathisia, dystonia, Parkinsonism Tardive dyskinesia |
Hyperprolactinemia | Amenorrhea, galactorrhea Sexual side effects Osteoporosis | |
Histamine-1 | Sedation | Secondary negative symptoms |
Weight gain | Obesity, metabolic syndrome | |
Muscarinic | Anticholinergic side effects | Confusion, dry mouth, constipation, blurred vision, tachycardia, urinary retention |
Clozapine, iloperidone, and quetiapine are the antipsychotics with the least “tightness” of binding to D2 (i.e., fastest dissociation from the receptor, with easy displacement by endogenous dopamine) and hence are the least likely to cause EPS, even at high doses [8]. All antipsychotics are full D2 antagonists with the exception of the more recent aripiprazole, brexpiprazole, and cariprazine which are partial agonists at D2 (i.e., function as an antagonist in the presence of dopamine).
One word on nomenclature: first-generation (or conventional) antipsychotics (FGAs) are old medications that were approved in the 1950s and 1960s. All are effective, and all cause EPS. FGAs are also referred to as “typical” antipsychotics to differentiate them from the “atypical” antipsychotic clozapine, which was the first antipsychotic that did not cause EPS, hence “atypical.” Up until clozapine, the efficacy of antipsychotics was believed to be tied to their propensity to cause EPS. With clozapine, efficacy and EPS became dissociated. Its value was proven in a seminal trial in 1988 when John Kane showed superior efficacy in treatment-refractory patients over typical antipsychotics [9]. Since then, many other atypical or second- and third-generation antipsychotics have been marketed, beginning with risperidone in 1993. Antipsychotic is the term preferred over neuroleptic. This current nomenclature based on “generations” is unsatisfactory and more a reflection on history and attempts to market antipsychotics (“new” implying better) [10]. Importantly, all antipsychotics are about equally effective for non-refractory patients with schizophrenia, at least at the group level. It is also misleading to assume that only first-generation antipsychotics induced EPS, while second-generation are mostly free of EPS [11]. Antipsychotics, particularly those lumped together in the bin of second-generation antipsychotics, have very little in common: they are widely different drugs with regard to side effect profiles and tolerability. Moreover, antipsychotics despite their name have a much broader range of applicability, beyond their core efficacy for positive symptoms and aggression, as noted above. A science-based nomenclature for antipsychotics based on the mechanism of action has been proposed but has not found its way into the clinic yet [12]. It is only for pedagogical purposes that I continue to use the terms first-, second, and third-generation antipsychotics.
Key Point
There is no one definition of what renders an antipsychotic “atypical” [13]. A broad definition of “atypicality” merely denotes the absence of extrapyramidal side effects across its dose range. Put differently, a neuroleptic is considered typical if it causes EPS at usual clinical doses (which is what you would expect from a “neurolpetic” – a “neuron-grabber” that stiffens mice when administered during drug discovery). More narrow definitions of atypicality include in addition to the lack of EPS the absence of hyperprolactinemia and, importantly, broadened efficacy (which may be mediated by receptors other than dopamine [14]). Clozapine remains the only truly atypical antipsychotic if the most narrow definition is applied.
For most antipsychotics, once-a-day dosing would be appropriate with regard to efficacy because the serum half-life of the antipsychotic does not reflect drug action on the brain (initiation-adaptation hypothesis [15]). Tolerability and safety considerations, however, may make more frequent necessary. More frequent dosing can be used if one wants to take advantage of the ataractic properties that many antipsychotics possess (e.g., quetiapine), but nightly dosing works for most patients. The safe starting dose and rapidity of titration depend on the clinical situation (e.g., age, gender, ethnicity, first-episode vs. multi-episode patient, acute vs. maintenance treatment phase). As a rule of thumb, start at the low end of the dose range for outpatients and increase the dose slowly. More aggressive dosing is possible in supervised inpatient settings.
First-Generation Antipsychotics
The first-generation antipsychotics (FGAs) can be broadly classed into low-potency antipsychotics, medium-potency antipsychotics, and high-potency agents. The prototype of a low-potency FGA is chlorpromazine (brand name Thorazine, after Thor, the one with the hammer), the first antipsychotic approved by the Food and Drug Administration (FDA) in 1954. Low-potency FGAs are not selective for the dopamine receptor; sedation, orthostatic hypotension, and anticholinergic side effects, as well as metabolic problems, are characteristic. Haloperidol and fluphenazine are high-potency agents, which are highly selective for the D2 receptor; predictably, side effects are largely restricted to the motor system (and the pituitary). The medium-potency FGAs, perphenazine and loxapine, have a side effect profile that falls in between chlorpromazine and haloperidol with regard to EPS and sedation. Perphenazine has had a renaissance after its good efficacy and tolerability were demonstrated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE ; see Chap. 16 for more information on this seminal trial) in which it was chosen as the FGA comparator medication. Loxapine may be an overlooked mid-potency antipsychotic that fell out of use not because of ineffectiveness or difficult side effects but simply because newer medications displace older ones, at least in a market-driven society. It may behave like a second-generation antipsychotic [16] but without pronounced metabolic liability; consider giving it a try for maintenance treatment, at a dose of 25–50 mg/day. (For loxapine developed as an aerosol for the treatment of agitation, see Chap. 10.) Several FGAs with prominent cardiac side effects (thioridazine, mesoridazine) are no longer marketed.
Key Point
For antipsychotic efficacy, about 65% of (striatal) D2 receptors need to be blocked [17]. Pushing the dose of tightly bound antipsychotics, such as all FGAs, beyond this point will not increase efficacy but will merely lead to EPS once a threshold of 80% occupancy is exceeded [18].
Dosing of selected first-generation antipsychotics
CPZ-Eqa (mg) | Dosing rangeb (mg/day) | Maximum dose (mg/day)c | |
|---|---|---|---|
Low-potency | |||
Chlorpromazine | 100 | 300–600 | 800 |
Mid-potency | |||
Loxapine | 10 | 25–100d | 200 |
Perphenazine | 10 | 8–32e | 42 |
High-potency | |||
Trifluoperazine | 5 | 15–30 | 35 |
Fluphenazine | 2 | 5–10 | 20 |
Haloperidol | 2 | 5–10 | 20 |
Pushing the dose of FGAs reliably increases EPS but does no translate into further efficacy. Use the “neuroleptic threshold,” which is the point at which you just begin to see EPS on exam for cogwheeling (and which corresponds to 80% D2 occupancy), to determine the optimal dose; exceeding the patient’s neuroleptic threshold does not increase efficacy [21]. The recommended CPZ-Eq correspond to the neuroleptic threshold doses.
The major long-term morbidity concern with FGAs is tardive dyskinesia. Haloperidol has a rather complex metabolism that includes the formation of a neurotoxic pyridinium analog (HP+) which has been proposed to explain its higher risk for tardive dyskinesia [22]. Haloperidol and fluphenazine are the only first-generation antipsychotics that are available in the United States as long-acting depot injections (“decanoates”) (see Chap. 18 on LAIs).
Tip
I suggest that you become familiar with at least one from each group of FGAs. Be very familiar with the high-potency haloperidol because of its known efficacy and toxicities and availability for parental use (in the emergency department and the medical hospital). Medium-potency agents if dosed carefully (e.g., perphenazine) remain an interesting treatment choice due to overall good tolerability. The occasional patient still takes chlorpromazine, and it can be a useful adjunctive option (also for second-line use in the emergency department).
Second-Generation Antipsychotics
Dosing of second-generation antipsychotics
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