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Current and novel approaches to antipsychotics

Interview with Holger Arthur


Antipsychotic drugs have been around since the 1950s and are a cornerstone in the treatment of schizophrenia and other psychotic disorders. Advances in drug development have over the years made them more tolerable with fewer side effects. Yet one question remains; has the effectiveness improved? Furthermore, clinicians tend to use these drugs with a great variability in terms of choice of drug, dosing and whether to use them in combinations or not. In order to learn more about the field, I have interviewed Holger Arthur, psychiatrist in Stockholm with a long experience of treating psychotic syndromes.

The variety of drugs used for the treatment of psychosis is indeed enormous and it seems to me that there are no clear steps in which different drugs are used. What are your thoughts about how physicians choose which drug?

This is a complex and a bit controversial question, but it needs to be addressed to provide patients with optimal treatment in the various phases of psychotic illness. This explains why national clinical guidelines are too general. The diversity of recommendations could also be explained with different treatment traditions in general versus forensic psychiatry and with various economic conditions in different countries.

In psychiatric hospital care, physicians focus on safe and quick treatment for the shortest possible length of hospital stay, and in outpatient care, the doctor focuses on rehabilitation and functional improvement (activities of daily living and work training).

This means that there is a need for antipsychotic drugs with different effect profiles (we have more than 30 compounds to choose from), but many doctors see the switch of drugs in outpatient care as hazardous (exacerbation and new side effects) and therefore hesitate to change medication.

The second-generation antipsychotics (SGA) have been around for decades now. Is there still a place for first-generation antipsychotics (FGA)?

Well, after 40 years with the FGA´s associated with considerable motor, metabolic and cognitive side effects (due to serotonergic, histaminergic, cholinergic and adrenergic receptor affinity) we could prescribe the first SGA´s (remoxipride, risperidone, and amisulpride and some years later, still in the '90s, olanzapine). Striatal dopamine D2 receptor blockade was now supplemented with serotonin 5HT-2 blockade and fewer off target effects.

Still, it seems that many doctors feel safe using FGA`s (e.g. haloperidol, zuclopenthixol) in emergency situations in the hospital setting, even if nowadays olanzapine is widely used, despite metabolic side effects in the long run. My recommendation is that already during hospital care, it is important to prepare for outpatient care, I mean to consider a switch to alternative antipsychotics to improve the patient's ability to manage on their own at home and in society. Here one must consider that haloperidol is associated with serious side effects at high doses or with long-term use (irreversible motor side effects and neurotoxicity, which was reported in Swedish animal studies 30 years ago by Gunne and Häggström. Also, the Cochrane Institute declared in 2002 at the Biennial Winter Workshop on Schizophrenia. Davos, Switzerland that haloperidol should no longer be used as a reference substance in clinical trials aimed at introducing new antipsychotics. Two years later the first partial agonist, aripiprazole was approved by the European Medicines Agency.

Holger Arthur and Serafen in Stockholm City Centre, former Serafimerlasarettet, Sweden's first hospital established in 1752.


Would you consider the partial agonists the third generation of AP's (TGA)? For what patients should they be used?

When we talk about striatal dopamine D2 and D3 partial agonists we have aripiprazole and cariprazine, and eventually brexpiprazole in Europe. They all have a favorable side effect profile if you "start slow and go low", especially in older adults. Aripiprazole, after 17 years on the market, is now widely used, also in adolescents and increasingly as a long-acting injectable. Furthermore, there is now enough data and clinical experience to prescribe aripiprazole during pregnancy. Due to different mechanisms of action, these partial agonists are suggested to be used as addon medication with an SGA in treatment-resistant schizophrenia and the D3 partial agonist cariprazine in patients with psychosis and substance use disorder (as nucleus accumbens, a part of the limbic system, is involved in the regulation of motivation and reward).

These TGA´s are also approved as adjunctive therapy, in combination with antidepressant medication, for the treatment of major depressive disorder. Additionally, aripiprazole can treat bipolar I disorder (acute treatment of manic and mixed episodes or maintenance treatment), Tourette's disorder, and irritability due to autistic disorder. In the emergency department the injection form of aripiprazole (the aqueous solution, not Maintena), as well as intramuscular olanzapine and ziprasidone, is used for treating acute agitation caused by schizophrenia or bipolar disorder, without causing somnolence. In a prospective observational study of consecutive patients, we found these SGA´s to be as effective as zuclopenthixol acetate, but sometimes these newer compounds needed to be injected twice.

Psychosis is a very broad concept, ranging from more secondary and mood-related symptoms to more primary ones in the schizophrenic spectrum. Do you have any reflections on what drugs to use in different forms of psychotic syndromes?

In patients with core symptoms of schizophrenia without excitement components (uncooperativeness, poor impulse control, hostility, suspiciousness) I recommend paliperidone or aripiprazole as the first choice, both of which can be used as long-acting injectables, the sooner the better. In a state of agitation or even aggressive behavior, I choose olanzapine in the acute phase of illness, and if necessary, also a fast-acting benzodiazepine, but only in the hospital setting. When the patient presents predominant negative symptoms, I choose cariprazine or aripiprazole and if depressive symptoms, lurasidone could be a good choice, or possibly a combination with a serotonin reuptake inhibitor. When I give lectures to the medical students I usually say: “Make it easy, treat what you see”, i.e. medicate the condition that you find.

Are there any head-to-head comparisons studying the efficacy of antipsychotics?

There are way too few head-to-head randomized controlled trials. Efficacy differences between antipsychotics are shown, but most of them are gradual rather than discrete. In the large studies without the patient categories separated, the differences in side-effects are more marked. If more accurate sub-analyses of study data were performed, it could be possible to find subpopulations of psychosis patients with significant effects in specific domains.

An easy way to choose medication is the principle of "accelerating or braking", i.e. treatment of energy loss (apathy, anhedonia, avolition) or on the other hand reduction of hyperactivity/excitement components (positive or manic symptoms). In an outpatient setting a tranquilizing/sedating antipsychotic (in any case at high dosage) preferably should be used only temporarily, e.g. olanzapine, quetiapine or zuclopenthixol, and the maintenance treatment can then be a more activating antipsychotic, e.g. cariprazine, aripiprazole or lurasidone.

Since I have been involved in pharmacogenetic studies at Huddinge University Hospital I would like to point out that pharmacokinetics and drug interactions are important to consider in our effort to optimize drug treatment. The choice of medication may therefore include the possibility of plasma concentration measurements. A recommended range (“a therapeutic window”) is available for many antipsychotics, although effects may be achieved at lower concentrations (especially for clozapine).

There is a substantial variation between dose and plasma concentration between individuals. The dose corrected concentration (with the same comparable dose) of an antipsychotic (CYP2D6 substrate) may differ 20- fold with oral medication and 6-fold with intramuscular injections when comparing patients being poor versus ultrarapid metabolizers. Therefore, a tip is to take a blood sample for drug concentration measurement at steady-state before discharge from the hospital to obtain a “feel-good value” when the patient has responded well without side-effects and the medication adherence is as good as one might expect.

Even if the relationship between the dose and the plasma drug concentration is proportional (mainly explained by genetically determined drug metabolism), a limitation of this therapeutic drug monitoring technique (TDM) is that the relationship between drug concentration and pharmacodynamic effects is more unpredictable. Receptor interaction and receptor response are parameters to take in account and they vary significantly, just as metabolic capacity over the years with a chronic psychosis.

Nevertheless, or I would say, therefore, in the outpatient setting, this TDM value (optimal plasma concentration for the individual) could be useful throughout the treatment process to strengthen the patient's motivation for medication and optimize treatment outcomes.

Despite all efforts, we see that patients sometimes, after a few years, become treatment refractory. Is there a place for combination therapy in the treatment of psychosis – and why?

Polypharmacy (without multimorbidity) has been a hot topic for a long time as the risk of adverse effects increases with higher numbers of medications, especially in the elderly. Drug-drug interactions can be both pharmacodynamic (e.g. serotonergic syndrome) or pharmacokinetic (combination of an antidepressant and a neuroleptic, when both are CYP2D6-substrates). At present the focus is on metabolic, cardiac, and hormonal side effects, so be sure to check the drug interaction function of the computerized medical record!

Combination treatment with two antipsychotics could be successful if compounds with different mechanisms of action are being used, e.g. aripiprazole or cariprazine as augmentation of clozapine.

Is there evidence for augmentation treatment using other drugs than AP's for the treatment of psychotic symptoms?

There is some evidence or at least reports of using lithium, valproate or other anticonvulsants as augmentation in treatment-resistant schizophrenia. On the other hand, more promising is that scientists these days focus on glutamate receptor modulators, while the dopamine synthesis in the striatum is not elevated in treatment-resistant schizophrenia, but the glutamate level is shown to be elevated in the prefrontal cortex and anterior cingulate cortex.


Genetic polymorphism of CYP2D6: Poor metabolizers (PM) with two detrimental CYP2D6 alleles and ultrarapid metabolizers (UR) with gene duplication, homozygous (EM hom) and heterozygous (EM het) extensive (normal) metabolizers, influence drug concentration with parenteral medication as well as with oral medication.


It looks like depot medications are becoming more acceptable in the clinical setting. Why?

In the early 80s I remember that perphenazine enanthate, haloperidol, fluphenazine and flupenthixol decanoate were widely used, but they were often regarded with negativity because of the assumption of punishment and control. Also, when the patient unfortunately had severe uncontrollable muscle contractions of dystonia type, it was difficult to eliminate them due to the long duration of action. Since the new SGA risperidone as long-acting injectables (LAI) was launched in the US in 2003 the LAIs became increasingly acceptable, but slowly in the US due to economic barriers for many patients and legal fears among psychiatrists. As a result of favorable side effect profile and lower frequency (less motor and cognitive deficits) the use of SGA LAIs in the US increased from around 2 to 18% of patients with schizophrenia and in Sweden the use of LAIs is now estimated to be 35- 40% (the figures are very uncertain since pharmacy sales include all conceivable indications, including senile agitation and supplements for bipolar conditions). Including indications other than schizophrenia LAI prescriptions in Sweden make up around 20% of all antipsychotic prescriptions and the LAI form of FGAs and SGAs are prescribed equally.

Are the depot injections really a better choice for the patient with free will and capacity to make choices? I am thinking especially of the young patients with recent onset of psychosis.

This is largely a question of the doctor's ability to deliver knowledge and about confidence- building in patient communication. The healthcare database in Stockholm has shown, in more than 6 000 patients with schizophrenia, that when switching from oral to injections of an antipsychotic the frequency of visits to the emergency rooms dropped significantly and hospitalizations decreased by almost 50%.

In order to save the brain from grey matter reduction, which is seen in adolescents with schizophrenia, several investigators worldwide report that they now advocate the idea of early LAI use in young patients at their first psychotic episode.

What do you think are the main challenges in improving the treatment of psychotic disorders?

Still, with all the tools available, the treatment regimen of schizophrenia needs to be multi-professional in even closer cooperation with relatives (family intervention), community care and primary health care. We need to build a strong network around the patient to enable successful treatment.

Finally, what is around the corner in the pharmacological treatment of schizophrenia?

I would say it's what comes out of the newly discovered pathoaetiology of schizophrenia. Researchers in neurobiology seem to consider schizophrenia as an autoimmune disease with both dopamine and glutamate abnormalities due to antibodies that cause NMDA and AMPA-receptor hypofunction and lack of its superior control system for dopamine activity in the limbic structures. Another focus in research of neuropathology and treatment of schizophrenia is how to deal with the genetic variant, high complement C4 overexpression that causes microglial activation, increased synapse elimination, and extensive grey matter reduction in the schizophrenic brain.

I hope that in the near future we will have screening markers as diagnostic tools to examine our patients with first-episode "inflammatory schizophrenia", in order to offer them adjunctive immunotherapy, monoclonal antibodies or other treatments that act on the immune system and can save the brain. □


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