A meta-analysis of the effects of SGAs on cognition has recently been published, with clozapine performing poorly in some domains 
Interestingly, other research has hinted at the possible benefits of tailoring clozapine to norclozapine (N-desmethylclozapine, NDMC) ratios:
Prediction of Working Memory Performance in Schizophrenia by Plasma Ratio of Clozapine to N-Desmethylclozapine.
Clozapine’s potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia. Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity. The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains. This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.
A patent has been filed: “Use of N-desmethylclozapine to treat human neuropsychiatric disease”
“Administration of clozapine to human subjects results in the formation of two major metabolites N-desmethylclozapine (NDMC) and clozapine-N-oxide. However, clozapine-N-oxide is a polar metabolite that is rapidly excreted and likely does not contribute to the biological activity of the parent compound. A correlation exists between the dose of clozapine administered to a subject, and the serum levels of total clozapine moieties, yet the levels of NDMC can vary widely between individual subjects. Generally, NDMC constitutes 40-75% of the total serum clozapine concentrations during steady state kinetics in humans… observations demonstrate that NDMC has been routinely administered to human subjects, and is well tolerated.
Surprisingly, and unlike the closely related compound clozapine, it has been found that the compound N-desmethylclozapine (NDMC) possesses heretofore unappreciated functional activity as a muscarinic receptor agonist. Ex vivo experiments have demonstrated that NDMC crosses the blood brain barrier and acts as an agonist at central muscarinic receptors in rats. These observations have practical applications that support the use of NDMC as an antipsychotic, antimania agent, antidementia agent, and as a therepeutic agent to treat glaucoma or neuropathic pain.”
Pharmacological profile of NDMC:
“NDMC is a metabolite of clozapine with a similar receptor profile as clozapine; it has partial agonist activity at the dopamine 2 (D2) receptor family, but is non-reactive at D3. N-desmethylclozapine (NDMC) is an allosteric partial agonist at the M1 receptor, where clozapine is a functional antagonist or partial agonist. NDMC has high agonist efficacy at M1 (partial), M4, and M5, but antagonist activity at M3; this would lead to fewer adverse side effects. NDMC-induced phosphorylation of mitogen-activated protein kinase, which was dose-dependent, was blocked by scopolamine; this action is consistent with M1 activation. NDMC also crosses the blood-brain barrier and induces c-fos expression in rat forebrain in a manner similar to clozapine and other SGAs.
NDMC activates the M1 receptor in vivo, not just in vitro. It is unknown whether NDMC shares its parent compound’s risk for agranulocytosis. One study that measured NDMC plasma levels in patients taking clozapine found that a high NDMC:clozapine ratio predicts better enhancement of cognition in patients; however, other studies have not replicated this result. In rats, NDMC did not induce catalepsy or increase prolactin, but also only partially inhibited amphetamine-induced locomotion (a stand-in for psychosis) and inhibited conditioned avoidance response only at the highest dose of 100 mg/kg (whereas antipsychotics inhibited as early as 20 minutes).
Another study showed that NDMC did inhibit amphetamine-induced hyperactivity. NDMC was also noted to decrease errors in an eight-arm maze test (in which clozapine induced errors); this effect was reversed by an M1 antagonist. NDMC had no effect on a novel object recognition task, whereas clozapine and other antipsychotics worsened performance. Early human studies of NDMC have demonstrated safety and tolerability in oral formulation and outcomes consistent with antipsychotic actions. However, studies of this drug focused on cognitive dysfunction in schizophrenia remain to be done. NDMC appears to be a good candidate to test the therapeutic potential of M1 muscarinic stimulation on cognition in schizophrenia because of its agonist potency at the M1 and M5 receptors.”
A comprehensive functional pharmacological screen of nearly all known antipsychotics, and many of their metabolites, at a majority of the known biogenic amine G-protein-coupled receptors (GPCRs) identified NDMC as pharmacologically unique. NDMC is a potent inverse agonist of 5HT2A receptors. However, unlike any other compound tested, NDMC is a potent and efficacious muscarinic receptor agonist. Specifically, NDMC is a potent partial agonist of M1 (K,=50nM) and M5 receptors (K,=25nM). NDMC also displays agonism of M2, M3, and M4 receptors, however this interaction is 10-fold less potent than the interaction with other subtypes and indeed, under physiological conditions NDMC is able to competitively antagonize M3 receptors. In comparison, clozapine is a potent competitive antagonist of M1, M3, and M5 receptors, a weak agonist of M2 receptors, and a potent partial agonist of M4 receptors. Furthermore, olanzapine, an antipsychotic structurally related to NDMC and clozapine is an antagonist of all 5 muscarinic subtypes. Haloperidol, risperidone, and ziprasidone do not interact with any of these receptors at concentrations up to 1 μM. Thus, the agonist activity of NDMC at muscarinic receptors, particularly M1 and M5 receptors, is unique among antipsychotic drugs.
In addition to its activity at D2, 5HT2A, and muscarinic receptors, NDMC has affinity for α1, α2, D1, H1, δ2, 5HT1A, 5HT1B, 5HT3, 5HT6, and 5HT7 receptors, and Ca2+ channels in ligand binding assays. Functionally it is a potent competitive antagonist of 5HT2c, H1, and α1A receptors and an inverse agonist of 5HT6A and 5HT7A receptors.
Like clozapine, NDMC attenuates both MK-801 -induced and amphetamine-induced hyperactivity in mice at doses lower or similar to those that reduce spontaneous activity. Unlike clozapine and haloperidol, NDMC does not attenuate apomorphine-induced climbing in mice. This may reflect the reduced affinity of NDMC for D2 receptors compared to these other antipsychotics. NDMC administration results in a dose-dependent activation of mitogen-activated protein kinase (MAPK) in the CA1 region of hippocampus and this activation can be blocked by the non-selective muscarinic antagonist scopolamine. Given that M1 receptors are the predominant subtype of muscarinic receptor responsible for MAPK activation in the CA1 region of the hippocampus, this finding supports the in vivo agonism of M1 receptors by NDMC. Clozapine administration does not result in MAPK activation. Additional evidence of pharmacological activity of NDMC comes from the observation that NDMC administration increases cFOS expression in the prefrontal cortex and nucleus accumbens, but not in the striatum. The lack of cFOS expression in the striatum suggests that NDMC is unlikely to produce extrapyramidal side effects.
Muscarinic agonism on the cortex by NDMC has been disputed:
“Clozapine, an atypical antipsychotic medication that demonstrates efficacy against the positive and negative symptoms of patients with chronic and/or treatment-resistant schizophrenia (Kane et al., 1988, Meltzer, 1997 and Volavka et al., 2002), was the first atypical medication to show nootropic attributes (Hagger et al., 1993). Clozapine was found to induce mild improvements across a number of cognitive functions, including learning and memory (Bilder et al., 2002 and Meltzer and McGurk, 1999), which was eventually attributed to the drugs capacity to manipulate the muscarinic system. N-Desmethylclozapine (NDMC), the major metabolite of clozapine, was found to act as a potent M1 receptor allosteric agonist and promote the release of ACh in animal analogues of brain regions key to cognition, including the prefrontal cortex and hippocampus ( Li et al., 2005, Sur et al., 2003 and Weiner et al., 2004). It was subsequently documented that the ratio of NDMC/clozapine in the plasma of patients with schizophrenia was a better predictor of cognitive function and quality of life compared to clozapine plasma levels ( Weiner et al., 2004). This led to the hypothesis that NDMC was driving the cognitive improvements documented in patients after treatment with clozapine and could potentially be administered in isolation to help improve cognitive function.
Unfortunately it was discovered that, in contrast to its agonistic attributes in rat cortex, in human cortex NDMC acts as a M1 receptor antagonist (Thomas et al., 2010) and was documented as failing to cause any significant improvements in patient symptom severity in a double-blind, placebo-controlled phase IIB clinical trial (Anon, 2014). Despite this unfavourable NDMC finding, the muscarinic system is still considered a target for the development of novel treatments aimed at improving the symptoms of schizophrenia.” 
On the contrary, increasing the clozapine to norclozapine ratio via CYP1A2 inhibition has been suggested:
Increasing the clozapine: norclozapine ratio with co-administration of fluvoxamine to enhance efficacy and minimize side effects of clozapine therapy.
Although clozapine is the only antipsychotic agent to have demonstrated superior efficacy in treatment-refractory schizophrenia, one- to two-thirds of patients do not respond adequately despite acceptable dosages and plasma levels. Moreover, a significant number of patients stop the therapy for various reasons, including its side effects, many of which are thought to be related to its active metabolite, norclozapine. However, combining clozapine with the SSRI antidepressant fluvoxamine decreases norclozapine formation by inhibiting the CYP450 1A2 isoenzyme. Lowering norclozapine levels in this way while maintaining therapeutic clozapine levels increases the clozapine: norclozapine ratio; the potential benefits include both a reduction of such side effects as sedation, weight gain, metabolic disturbances, and neutropenia, and an increase in efficacy. The optimal ratio of clozapine to norclozapine has not yet been defined, but a ratio of two or more implies that saturation of clozapine metabolism has been reached. We hypothesize that co-administration of clozapine and fluvoxamine at dosages that will produce therapeutic plasma levels of clozapine and a clozapine: norclozapine ratio of two or more will increase efficacy and tolerability of clozapine therapy in treatment-resistant schizophrenic patients.
“N-desmethylclozapine (norclozapine), clozapine’s main active metabolite, is formed by the oxidative metabolism of clozapine by CYP1A2, and to a lesser extent, by CYP2C19, CYP3A4, CYP2C9, and CYP2D6. Norclozapine is also metabolized by CYP1A2. It is thought to have less antipsychotic activity than its parent compound and may be responsible for many of the side effects attributed to clozapine therapy
…some studies have found that the clozapine: norclozapine ratio can predict clinical outcome better than either the clozapine or norclozapine level alone. Norclozapine levels usually range between 65% and 90% of total clozapine levels. A clozapine: norclozapine ratio greater than two suggests that clozapine metabolism has become saturated. Several studies and case reports have shown that if norclozapine plasma levels are increased while adequate clozapine plasma levels are maintained and the clozapine: norclozapine ratio is thus increased (mainly through the use of concomitant fluvoxamine), many patients display an increased clinical response and/or decreased side effects to clozapine therapy. It should be noted, though, that at least two studies have concluded that low clozapine: norclozapine ratios are positively correlated with clinical response…
…in animal models, agonism of M1 muscarinic receptors by norclozapine has been linked to improved cognition, which may be a factor in the unique efficacy of clozapine. The decrease in norclozapine plasma levels brought on by co-administration might thus result in the loss of the cognitive benefits of clozapine therapy. One study has concluded, though, that the lower norclozapine levels generated by combined therapy, as compared to the higher levels associated with clozapine monotherapy, do not alter global functioning in schizophrenic patients…”
Higher clozapine+ norclozapine concentrations have been associated with depression-anxiety symptom dimensions: “high clozapine concentrations were associated with depression-anxiety symptoms, but the causality remains unknown.” 
Interestingly, diet may play a role in the metabolism of clozapine: see ‘Effect of various diets on the expression of phase-I drug-metabolizing enzymes in livers of mice.’
See also: Muscarinic Agonists for the Treatment of Cognition in Schizophrenia