30mg of aripiprazole – some experiences. Tackling cravings? The DAergic effects of stress?

It’s interesting to be on a higher (30mg/day) dose of aripiprazole. That said, my mind is all over the place and the agitation is somewhat relieved by a blog post… Time for a bit of ‘catharsis’…

While aripiprazole has high affinity for D2 receptors, it has low intrinsic efficacy (from 25-30% of DA to only about 6% under ‘ideal antipsychotic therapy), acting as a partial agonist. It is also a partial agonist at the 5-HT1A receptor, antagonises 5-HT2A and 5-HT7 receptors and acts as a partial agonist at the 5-HT2C receptor, with high affinity. Aripiprazole has been touted as a “dopamine system stabiliser” because in vivo studies demonstrate that it reduces dopamine release via presynaptic agonism to behave as a functional antagonist of some postsynaptic D2 receptors and as an agonist at others. D2/D3 receptor occupancy ranged from 40% (at 0.5 mg/day) to 95% (at 30 mg/day) and binding rates are high throughout the brain [1, 2].

Aripiprazole: from pharmacological profile to clinical use

 …a strong correlation exists between aripiprazole dose and plasma levels. They state that dopamine receptor occupancy appears to reach a plateau at doses above 10 mg and suggest that, from dose-response studies, the optimal dose of aripiprazole may be 10 mg/day. However, this refers to prolonged treatment with the drug, whereas the point we make here relates to the use of aripiprazole in an acute setting in association with symptom exacerbation, a condition that may be sustained by an overt activation of the dopaminergic system. Hence, as illustrated…, a higher dose of aripiprazole [30mg] will be necessary to compete with dopamine and blunt receptor activation.

Subjective experiences:

The lower doses (5-20mg) were slightly activating but lacked any substantial additional effect on positive symptoms when combined with clozapine (at subtherapeutic levels). One big positive was the effect it seemed to have on clozapine-induced weight gain, as I’ve detailed here. Thankfully, I’m coming off the clozapine and don’t mind a few side effects from the aripiprazole (so far)…

While the higher dose is associated with some pretty activating effects and potentially some slight akathisia, it initially showed promise in treating my auditory hallucinations [3]. Some stress related to study and other challenging situations has precipitated a slight decline in its efficacy towards positive symptoms (and a subjective increase in dissociation [4]). Initially there were some improvements in mood but my affect is quite labile and I’ve sunk into a few really dark places, too. Nothing unmanageable as yet (also on venlafaxine 375mg/day).

Impulsivity is slightly increased and there is slight disinhibition (likely amplified by the acute effects of the increase in pregabalin to 150mg tds).

I can’t rule out a decrease in clozapine as being a factor in these changes, nor can I rule out an increase in pregabalin as another confounding variable. The pregabalin does slightly improve the aripiprazole-induced agitation but if it continues at this intensity, it could soon be problematic.

My attention span is poor, potentially worse than on the lower doses of aripiprazole. Hopefully I can work on that somehow…

Patients with a low striatal D2/3 receptor binding potential (BPp) have a better treatment response than patients with a high BPp. Functioning may decline at high levels of dopamine receptor blockade [including partial agonism] [5].

Substance cravings and self-medication

Being a D2 partial agonist, I’m particularly interested to see how it goes for substance cravings. The activating effect has really increased my desire for nicotine and caffeine (both indirectly DAergic, the latter potentially having an effect on striatal D2/D3 receptor availability [6]) which seem to be calming. Theanine (400mg) is slightly helpful for alleviating the agitation [7, 8].

On that:

Revisiting the ‘self-medication’ hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behavior.

Persons with schizophrenia are at a high risk, almost 4.6 times more likely, of having drug abuse problems than persons without psychiatric illness. Among the influential proposals to explain such a high comorbidity rate, the ‘self-medication hypothesis’ proposed that persons with schizophrenia take to drugs in an effort to cope with the illness and medication side effects. In support of the self-medication hypothesis, data from our earlier clinical study confirmed the strong association between neuroleptic dysphoria and negative subjective responses and comorbid drug abuse. Though dopamine has been consistently suspected as one of the major culprits for the development of neuroleptic dysphoria, it is only recently our neuroimaging studies correlated the emergence of neuroleptic dysphoria to the low level of striatal dopamine functioning. Similarly, more evidence has recently emerged linking low striatal dopamine with the development of vulnerability for drug addictive states in schizophrenia. The convergence of evidence from both the dysphoria and comorbidity research, implicating the role of low striatal dopamine in both conditions, has led us to propose that the person with schizophrenia who develops dysphoria and comorbid addictive disorder is likely to be one and the same.

“…we have experimentally induced neuroleptic dysphoria, following dopamine depletion using α-methylparatyrosine (AMPT) in a group of medication-free persons with schizophrenia who have consistently experienced dysphoria upon administration of antipsychotic medications [Voruganti et  al. 2001]. Our dopamine depletion single photon emission computed tomography (SPECT) study proved to be the first to link emerging dysphoria to striatal dopamine binding ratio. Details of the study design, as well as complete results, are outlined in a previous publication [Vorguanti et al. 2001]. Additionally, observations over the subsequent 48 hours allowed us to note the cascade of subjective and behavioral events that followed dopamine depletion, which served as the experimental equivalent of dopamine blockade by antipsychotic. The severity of dysphoric responses inversely correlated with the incremental changes in D2 receptor binding ratios (r=-0.82, p< 0.01). Such observations provided for the first time an explanation of why not every patient receiving antipsychotic medications develops neuroleptic dysphoria. Only those patients who have lower dopamine receptor functioning to start with seem to be more vulnerable to the blocking effect of potent dopamine D2 antagonists which, in turn, further impairs striatal dopamine functioning. A number of other neuroimaging studies added more confirmation to our findings in support of the role of low striatal dopamine in the genesis of dysphoric responses [de Haan et al.2006; Mizrahi et  al. 2009]. Additionally, observing the cascade of events that followed dopamine depletion over the next 48 hours, the earliest behavioral change noted was the altered subjective state, which was experienced just a few hours after ingestion of the medication [Voruganti and Awad, 2006]. Such an experimental finding is consistent with clinical observations of patients experiencing dysphoric response as early as a few hours after ingesting the medication [Awad and Hogan, 1985]. Additionally, our data revealed that the phenomenon of neuroleptic dysphoria is not simply an affective change, but is more complex and includes motor, cognitive and motivational components.”

  • Reduction in dopamine D2 receptor binding has also been associated with enhanced impulsivity in rats, a mechanism implicated in the genesis of addictive behavior

“…recent data suggest that persons with schizophrenia and comorbid drug abuse suffer from combined dysfunction: increased dopamine sensitivity in the area of the striatum more responsible for psychotic symptoms and the reduced sensitivity to dopamine-release in the striatal region associated with reward and enforcement. The interpretation of such important findings is that such alterations in dopamine release could initiate a vicious circle of using drugs to self-medicate, which in turn can only worsen the psychotic symptoms. Such reported blunting of dopamine release in all striatal regions in persons with schizophrenia and comorbid drug abuse can also explain the reported frequent association of vulnerability to addictive behavior and the development of neuroleptic dysphoria, as we reported earlier”

“Such new information also has implications for the choice of the antipsychotic medication used for treatment of psychosis with comorbid drug abuse. The preference for choosing an antipsychotic in such a situation needs to be based on the pharmacological properties of medications, selecting an antipsychotic which has low potency for dopamine D2 antagonism or an antipsychotics that does not stay long on the dopamine receptor, so as not to further impair striatal dopamine functioning [Samaha, 2014; Awad, 2012]. Chronic dopamine blockade can lead to postsynaptic upregulation, which in turn enhances the reinforcement properties of drugs of abuse. Such new information can explain the reported beneficial effects of medications such as clozapine [Green et al. 2008] or other new atypical antipsychotics, such as olanzapine [Littrell et  al. 2001] and risperidone [Smelson et al. 2002]. Aripiprazole being an agonist/antagonist is expected theoretically to be a useful antipsychotic in such situations; however, results from the ongoing clinical trials are not yet available.”

“Based on recent data demonstrating the role of low striatal dopamine in the genesis of neuroleptic-induced dysphoria as well as comorbid vulnerability for addictive states, we propose that the person with schizophrenia experiencing negative subjective and dysphoric responses can be one and the same who develops vulnerability to comorbid addictive states. Such a new formulation not only adds basic clarification about the link between both conditions, but provides neurobiological support of the ‘self-medication hypothesis’. As subjective and dysphoric neuroleptic responses are the earliest experiences following ingestion of the antipsychotic medication, it is possible that such subjective negative responses can serve as an early clinical marker for potential development of vulnerability to addictive states. Similarly, it underscores the importance of choosing an antipsychotic appropriate to such clinical situations ( i.e. an antipsychotic which is not a strong dopamine D2 blocker) in order to not further compromise dopamine striatal functioning. Such a new understanding also clarifies why not many patients with schizophrenia and comorbid drug abuse treated with the potent dopamine D2 blockers, such as haloperidol, have been rarely able to exert adequate control over their addictive behavior. It also highlights the urgent need to re-examine the process of development of new antipsychotics by establishing comorbid substance abuse in schizophrenia as possibly a new indication for medication development.”

Stress and Dopamine

A recent review has been published:

The Dopaminergic Response to Acute Stress in Health and Psychopathology: A Systematic Review

“Stress-induced dorsal striatal DAergic activity may reflect the somatosensory experience induced by the stressor, but also involvement in active avoidance behavior or cognitive aspects of stress. The experience of stress, however, seems to be more directly related to mPFC DAergic activity, serving as a threat evaluation system, and ventral striatal DAergic activity, possibly related to expectations about the stressor. In dysregulated stress-systems, preliminary results indicate a blunted striatal DAergic response in pain-related disorders and cannabis use and an augmented striatal DAergic response in psychosis. However, the scarcity of studies, modest sample sizes and inconsistent findings prevent any firm conclusions.”

Some areas covered:

  • The healthy ventral striatal response: Whereas the dorsal striatal DA response seems to be associated with the sensory and affective properties related to the stressor itself, DAergic activity in the ventral striatum varies with subjective expectations about the stressor. Only when controlled for pain-specific components does an increase in ventral striatal DAergic activity become apparent, which correlates with pain, stress-related negative affect and fear
  • The healthy extrastriatal response: DAergic activity here was positively associated with subjective stress ratings and heart rate, directly relating this response to experiential and physiological measures of stress. As with the striatal response, DAergic activity in the mPFC might be valence-unspecific
  • In individuals who reported low maternal bonding, and are assumed to be at risk for a broad range of psychopathology, psychological stress increased DAergic activity in the ventral striatum.
  • Results partly affirm increased stress-related dorsal striatal DAergic activity in the psychosis spectrum. The mixed results within the striatum are unexpected considering the solid evidence for aberrant striatal DAergic functioning in psychosis in combination with the well-validated putative link between stress and psychosis
  • In cortical areas, no main effect of stress has been reported in the psychosis spectrum

A recent study [9] found a widespread DAergic deficit extending to many cortical and extrastriatal regions including the midbrain in schizophrenia, with blunted DA release potentially affecting frontal cortical function