Despite the lack of guidance available for practitioners, extensive polypharmacy has become the primary method of treating patients with severe and chronic mood, anxiety, psychotic or behavioral disorders. This ground-breaking new book provides an overview of psychopharmacology knowledge and decision-making strategies, integrating findings from evidence-based trials with real-world clinical presentations. It adopts the approach and mind-set of a clinical investigator and reveals how prescribers can practice 'bespoke psychopharmacology', tailoring care to the individualized needs of patients.
Deficit States and Negative Symptoms
Schizophrenia cannot be understood without understanding despair.
▢ Differentiate negative symptoms from depressive states
▢ Describe the strengths and limitations of existing pharmacotherapies, including antidepressants, stimulants and other pro-dopaminergic drugs, antiglutamatergic agents, and hormonal therapies to treat negative symptoms
▢ Identify emerging and experimental pharmacotherapies to treat negative symptoms
Swiss psychiatrist Eugen Bleuler, who coined the term schizophrenia, identified affect, association, ambivalence and autism as the so-called “Four As” of negative symptom schizophrenia. Latter-day observers have sometimes added alogia, anergia, anhedonia, and apathy/amotivation to the original list.
Negative symptoms, as classically associated with schizophrenia, refer to the absence of normal function (hence, they are “deficit” states), as contrasted with positive symptoms (that is, the excess presentations of otherwise normal brain functions). In that sense, negative symptoms also differ fundamentally from depression insofar as the latter represents a kind of positive symptom, one characterized by the “feelingful” presence of emotions (anguish, despair) – quite different from the emotional vacancy of flat (rather than sad) affect. The schizophrenia literature often refers explicitly to “the deficit syndrome.” True negative symptoms can be among the hardest of symptoms to leverage pharmacologically. (Indeed, for the conventional operational definition of “response” for negative symptoms, the bar has generally been lowered so as to achieve only a 20% (or more) improvement from baseline symptom severity.) Clinicians sometimes cross their fingers with the hope that deficit states may just represent depression, and prescribe antidepressants vigorously and often sequentially (possibly even convincing themselves that nonresponse to antidepressants affirms the presence of TRD, rather than a different condition for which antidepressants may not be so helpful). Yet, the likely pathophysiology of negative symptoms is different from that seen with depression, making effective management a different kind of undertaking than that used in TRD.
A prevailing view is that negative symptoms arise from hypofunctioning of mesocortical DA circuitry, as touched upon earlier in Chapter 15 (e.g., see Figure 15.2). Once again, the notion of relative balance of dopaminergic functioning in different brain pathways bears on our understanding of positive versus negative symptoms. In the same vein, one might differentiate primary negative symptoms (arising from inherent hypodopaminergic tone in mesocortical pathways) from secondary negative symptoms as being more iatrogenic phenomena that result from the collateral damage to D2 mesocortical circuitry caused by D2 blockade from most if not all FGAs and some SGAs.
But what leads to the hypodopaminergic tone of mesocortical circuitry that is thought to account for negative symptoms? Recall from Chapter 15 (Figure 15.3) that in the case of positive symptoms, prevailing thinking is that hyperdopaminergic function in mesolimbic pathways is a downstream consequence of diminished corticolimbic glutamatergic excitation (believed to result from faulty cortical pyramidal neuron NMDA receptor functioning); GABA interneurons that would ordinarily inhibit mesolimbic DA tracts are understimulated and therefore fail to do so, giving mesolimbic DA free rein to run amok. In the case of mesocortical DA, it is thought that once again, faulty glutamatergic stimulation descending from the VMPFC to the ventral tegmental area (VTA) fails to “turn on” mesocortical DA, resulting in direct understimulation. No GABAergic middle-men this time.
Clinicians should have a clear concept of the phenomenology of negative symptoms and understand how to categorize and quantify their features and severity. Examples of relevant elements to note when interviewing a patient would include features such as an unchanging facial expression, decreased spontaneous movements, a paucity of expressive gestures, poor eye contact, lack of vocal inflections, poverty of content of speech, thought blocking, and an increased latency of response to questions. In most modern clinical trials, negative symptoms are quantified using either the negative symptoms factor subscale of the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) or else the Schedule for the Assessment of Negative Symptoms (SANS; Andreason, 1982). Component items of these scales are summarized in Box 16.1.
|PANSS negative symptom factors||Schedule for the Assessment of Negative Symptoms (SANS)|