Psycodex #3: Psychosis
Kraeplin, schizo-related disorders, and the history of neuroleptics.
This is the third post in a series of weekly primers on what Australian medical students learn in psychiatry. “/” indicates content taught within the medical curriculum; “\” indicates content beyond. Past posts: Introduction, #1 Depression, #2 Mania.
\ Nosological Origins of Schizophrenia
The German psychiatrist, Emil Kraepelin (1856 - 1926) is often considered one of the forefathers of modern psychiatry.
One reason, perhaps, is due to his pioneering idea of the Kraepelinian Dichotomy - dividing primary psychoses into two forms: Dementia praecox (later termed Schizophrenia in 1908 by Eugen Bleuler, another prominent Swiss psychiatrist), and manic-depressive psychoses (now known as Bipolar Disorder). Before this, all forms of psychoses were considered variations of the same underlying disease process.
The key insight of Kraeplin’s system was that psychiatric disorders were not distinguished by a particular pathognomonic symptom (such as Beck’s triad in cardiac tamponade), but instead the particular pattern. Pure psychoses were different to psychoses coinciding with mood changes; the implication of which are different courses, outcomes, and prognoses. In a similar vein, Kurt Schneider (1887 - 1967) expanded this distinction through finding symptoms more characteristic of schizophrenia - known as the Schneiderian First-Rank Symptoms, although these have since been outdated due to poor validity.
Kraeplin’s ideas were built on a biological framework - working alongside Alois Alzheimer, he helped define the first clinical boundaries of the neurodegenerative disease of the same name. Thus, he believed there to be the same biological process which underlies all the major psychiatric diseases today.
However, like all methods of carving non-objective reality, Kraepelin’s psychiatric nosology is vulnerable to his own biases. Freud’s overfixation on sex biased his psychodynamic theories; Kraepelin’s beliefs, as well as Bleuler’s, were founded on ideas that criminals were born, that mental illness was a result of society’s moral degeneration, leading to ultimately eugenic conclusions.
It is with these foundations, that we now turn to the modern conception of psychosis.
/ Modern Psychosis: Abridged
The DSM-V considers there to be a spectrum of psychotic disorders, ranging from Schizophrenia, Schizophreniform, Schizoaffective, and Schizotypal personality disorders.
There are two forms of symptoms - positive and negative symptoms. Positive symptoms include delusions, hallucinations, disorganised speech, and disorganised behaviour - which borrow from the Schneiderian First Rank symptoms - with at least one of the bolded symptoms required. Negative symptoms are often memorised with the 5As; Alogia, Avolition (apathy most common), Anhedonia, Asociality, blunted Affect.
One key distinction between these psychotic disorders comes from timing. Schizophrenia requires a significant 1mth period of at least 2 symptoms (the active period), with residual symptoms across at least 6mths (prodromal period). Schizophreniform Disorder, is distinguished through symptoms lasting less than 6mth. Brief Psychotic Disorder requires only one symptom, longer than a day but less than a month. Schizoaffective Disorder, on the other hand, has both a temporal requirement (psychotic symptoms for at least 2 weeks without a mood episode) and a categorical requirement (the presence of a manic or depressed episode).
These distinctions exist to guide treatment. Schizoaffective Disorder is distinct from a psychotic depression or a psychotic mania, which represent mood disorders - implicating the need for antipsychotics on top of mood stabilisers. Brief Psychotic Disorder calls for short term antipsychotics, Schizophreniform also suggests short term antipsychotics, whereas Schizophrenia calls for long term maintenance antipsychotics.
Finally, all of the above are excluded based on Foulds’ hierarchy - an organic cause takes precedent. Psychotic episodes can be caused by drugs (i.e. psychedelics, alcohol, stimulants), or neurological conditions (i.e. delirium, epilepsy, dementias, encephalitis, strokes, etc.), which override any primary psychiatric diagnoses.
The clinical management of schizophrenia (ie 2016 RANZCP guidelines) goes as follows:
Acute Management: Benzodiazepines (for agitation, anxiety, sleep disturbance)
First Line: Second Generation Antipsychotics (Amisulpride, Aripiprazole, Quetiapine, Risperidone, Ziprasidone)
If fail, switch to Olanzapine
Second Line (if two SGAs fail): Clozapine
Antipsychotics are notorious for the host of side effects that they cause, variance in efficacy, all of which factor into whether patients are willing to take them. And of course, like all psychiatric drugs, its modern use is filled with historical footnotes and caveats.
\ More than you need to know about Neuroleptics
Antipsychotics were previously known as neuroleptics - first coined by Delay/Deniker in 1955 with its Greek roots meaning ‘to take hold of one’s nerves’. Understanding the current treatment of psychosis requires a cursory dive into two linked areas; how the drugs were discovered (1), and the proposed neuroscientific theories (2).
The first neuroleptic was Chlorpromazine, synthesised in 1950. As we’ll see with many antipsychotics, Chlorpromazine’s origins are not based on psychosis. Instead, it belongs to a class of phenothiazine derivatives, such as promethazine - which were initially used pre-operatively in 1949 for its sedative anti-histaminic effects. It was this subdued ‘pharmacological lobotomy’ effect which led to the first trial in 1952 on a manic patient, and the subsequent pivotal RCT (Elkes and Elkes, 1954). This came at a time when Evidence-Based Medicine was only just coming into force, with the very first RCT having been conducted a few years earlier in 1948. It was this, which paved the groundwork for the neurobiological basis of schizophrenia.
Chlorpromazine, along with others like Haloperidol, Thioridazine, are now considered first generation, or ‘typical’, antipsychotics. These drugs were considered to have significant effects on psychoses, but came at devastating costs. Here, we will take a detour into dopaminergic pathways, and the subsequent side effects.
/ Typical antipsychotics have the highest affinity for dopamine D2 receptors (D2R), and thus antagonise dopamine’s effects. A simplified summary across the last few decades of research suggest the following pathways are considered to play a role:
Mesolimbic (Ventral Tegmental Area -> Striatum): The mesolimbic hypothesis is one of the earliest models of schizophrenia - based on evidence that amphetamines induced psychosis, and animal-based studies where antipsychotic injection into this pathway reduced the psychosis. Thus, it was hypothesised that this pathway causes the positive symptoms of schizophrenia, conjectured to be relevant to associating higher salience to irrelevant stimuli - but more recent studies suggest the story is more complex.
Nigrostriatal (Substantia Nigra pars compacta -> Striatum): Produces the extrapyramidal side effects from excessive blockade of D2R, including dystonias (including oculogyric crises), tardive dyskinesia, parkinsonism, tremors, akathisias. The mechanism is thought to be similar to how Parkinson’s develops, where less dopaminergic activity reduces the indirect pathway of the striatum, causing progressive inhibition of movement.
Tuberoinfundibular (Hypothalamus -> Pituitary): Produces the hyperprolactinaemia symptoms such as decreased libido and galactorrhea, as a result of antagonising D2Rs of the pituitary, thus enabling excess prolactin production.
Mesocortical (Ventral Tegmental Area -> Prefrontal Cortex): Believed to produce neuroleptic induced deficit syndrome, akin to the negative symptoms of schizophrenia.
But that’s not all - antipsychotics are often considered ‘dirty’ drugs, because of how many other receptors these drugs have an affinity for. This is also why antipsychotic effects are dose-dependent; their effects vary based on the dosage. Quetiapine, for instance, is a sedative at low dosages (ie 50mg/day) due to its predominant anti-histaminergic effect. It is only at higher dosages (ie 300mg) that quetiapine’s anti-dopaminergic and anti-sertoinergic (and thus, antipsychotic) effects are seen.
These other systems (and subsequent side effects) include:
Muscarinic (M1): Anticholinergic side effects like constipation, dry mouth, blurry vision.
Histaminergic (H1): Sedative effects, similar to other antihistamines.
Adrenergic (α1/α2): Adrenergic side effects like reflex tachycardia, postural hypotension.
Serotinergic (5-HT2A): Relevant for antipsychotic effects, but also weight gain and low libido.
This cocktail of side effects, and particularly the dopaminergic dystonias and extrapyramidal side effects, prompted the search for better drugs.
\ In 1958, in the flurry of synthesis of tricyclic compounds within a Swiss laboratory, Clozapine heard this call and answered it. It was not until 1966, where human trials continued with clozapine, which found it to be an effective antipsychotic with limited neurological side effects - so much so that clinicians at the time were skeptical, believing that only true antipsychotics yielded the Parksonian side effects. They were wrong, and thus Clozapine heralded the second generation, or ‘atypical’ antipsychotics. The key purported difference? These drugs had a much stronger affinity for serotonin receptors, and thus relied on their dopaminergic blockade less to produce the antipsychotic effect.
Aside: One of the most baffling realisations during this research was that Clozapine was a “tricyclic dibenzodiazepine” in terms of chemical structure. Yes, the tricyclics that we’re heard in antidepressants, and the benzodiazepines for sedation. This class of drugs truly is non-specific.
But Clozapine, as many will know today, is not the miracle drug it purports to be. Across the 1970s, studies found key side effects of this miracle drug - including blood dyscrasias like agranulocytosis (reduction in a type of white blood cell) in Finland causing several deaths (although this is also reported in Chlorpromazine). Further, the reduction of dopaminergic side effects is paralleled by the serotonergic metabolic side effects, with issues of weight gain, diabetes, and cardiac complications (ie myocarditis). Several other second generation antipsychotics are now in the market, with varying levels of side effects.
But there is one final player in this story; the proposed third generation of antipsychotics, with the introduction of Xanomeline/Trospium Chloride, AKA Cobenfy. After an antipsychotic winter leading to new drugs but no new mechanisms, Cobenfy was FDA approved in 2024, with the novel mechanism with no direct antidopaminergic activity - instead, only focusing on M1 and M4. This marks the first novel therapeutic for schizophrenia since 1950. Nils Wendel, MD provides a great breakdown of the clinical trial which spurred these results, but the headline is: Very little side effects. Although cautiously noting the results (only 5-weeks of outcome data), the promise is of no dystonic symptoms, and no metabolic symptoms. If the results play out this way, this drug truly heralds a miracle and a new generation of medications.
The history of schizophrenia is lined with problematic and fascinating stories, drugs, and deaths. Although the classification itself is heterogeneous, one can hope for a future where the biologic aspects of psychosis are no longer seen as an unsympathetic, debilitating condition, but instead as just another modifiable part of the human experience.
(1) See Ramachandraiah et al. (2009) for a nice overview, and Dattani (2024) for a fantastic visualisation and summary.
(2) Like many topics, this especially warrants an entire article. The wikipedia page provides a nice overview of the evidence for and against the dopamine hypothesis.
P.S. I’d love to hear what you found interesting, and what you’d like more of in the comments.